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WO2018187574A1 - Compositions and methods for the treatment of fungal infections - Google Patents

Compositions and methods for the treatment of fungal infections Download PDF

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Publication number
WO2018187574A1
WO2018187574A1 PCT/US2018/026261 US2018026261W WO2018187574A1 WO 2018187574 A1 WO2018187574 A1 WO 2018187574A1 US 2018026261 W US2018026261 W US 2018026261W WO 2018187574 A1 WO2018187574 A1 WO 2018187574A1
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Prior art keywords
optionally substituted
compound
independently
formula
pharmaceutically acceptable
Prior art date
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PCT/US2018/026261
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French (fr)
Inventor
James M. Balkovec
Thomas P. Brady
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Cidara Therapeutics Inc
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Cidara Therapeutics Inc
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Publication of WO2018187574A1 publication Critical patent/WO2018187574A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C

Definitions

  • Candida albicans and the filamentous fungus, Aspergillus fumigatus (Bow, Br. J. Haematol., 101 :1 , 1998; Wamock, J. Antimicrob. Chemother., 41 :95, 1998).
  • There are an estimated 200,000 patients per year who acquire nosocomial fungal infections (Beck-Sague et al., J. Infect. Dis., 167:1247, 1993).
  • Also adding to the increase in the numbers of fungal infections is the emergence of Acquired Immunodeficiency Syndrome (AIDS) where virtually all patients become affected with some form of mycoses during the course of the disease (Alexander et al., Drugs, 54:657, 1997; Hood et al., J.
  • AIDS Acquired Immunodeficiency Syndrome
  • drugs for the treatment of fungal infections include amphotericin B, a macrolide polyene that interacts with fungal membrane sterols, flucytosine, a fluoropyrimidine that interferes with fungal protein and DNA biosynthesis, and a variety of azoles (e.g., ketoconazole, itraconazole, and fluconazole) that inhibit fungal membrane-sterol biosynthesis (Alexander et al., Drugs, 54:657, 1997).
  • azoles e.g., ketoconazole, itraconazole, and fluconazole
  • Each agent in this class of compound acts by inhibition of ⁇ -1 ,3-D-glucan synthase, which is a key enzyme in the synthesis of glucan in the cell wall of many fungi. All three of these drugs are made semisynthetically, starting with natural products obtained through fermentation.
  • the echinocandins are a broad group of antifungal agents that typically are composed of a cyclic hexapeptide and lipophilic tail, the latter of which is attached to the hexapeptide core through an amide linkage.
  • many echinocandins are natural products, the clinically relevant members of this class have all been semisynthetic derivatives.
  • the naturally occurring echinocandins possess some degree of anti-fungal activity, they have not been suitable as therapeutics, primarily because of poor aqueous solubility, insufficient potency, and/or hemolytic action.
  • the approved echinocandins are the products of intense efforts to generate derivatives that maintain or improve upon the glucan synthase inhibition, but do not cause the hemolytic effects.
  • the poor aqueous solubility and poor intestinal absorption of these compounds have relegated them to delivery by intravenous infusion. There is a need in the art for improved compounds and methods of treatment for fungal infections.
  • the disclosure relates to compounds, compositions, and methods for the treatment of fungal infections.
  • such compounds include bifunctional molecules including a ⁇ -1 ,3-glucan synthase inhibitor and at least one monosaccharide or oligosaccharide moiety, ⁇ -1 ,3-glucan synthase inhibitors bind to and inhibit the function of ⁇ -1 ,3-glucan synthase, a glucosyltransferase enzyme involved in the generation of ⁇ -glucan in the cell wall of fungi, resulting in disrupting the integrity of the fungal cell well and leading to fungal cell death.
  • Such compounds are useful in methods for the inhibition of fungal growth and in methods for the treatment of fungal infections, such as those caused by a fungus of the genus Candida.
  • the invention features a compound including a ⁇ -1 ,3-glucan synthase inhibitor conjugated to at least one monosaccharide or oligosaccharide moiety by way of a linker, wherein the
  • R 1 is a lipophilic moiety
  • R 2 is hydrogen or methyl
  • each of R 3 and R 4 is, independently, hydrogen or hydroxyl
  • R 5 is hydrogen, methyl, or optionally substituted C1 -C5 alkamino
  • R 6 is hydrogen, hydroxyl, methyl, or amino
  • R 7 is hydrogen or hydroxyl
  • R 8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(0(CH 2 ) a )bR', -(NH(CH 2 ) a )bR', -(S(CH 2 ) a )bR', -(0(CH 2 ) a ) b N(R') 2 , -(NH(CH 2 ) a ) b N(R') 2 , -(S(CH 2 ) a ) b N(R') 2 , -(0(CH 2 ) a ) b N + (R') 3 ,
  • R 9 is hydrogen, hydroxyl, or amino; n is 0 or 1 ; d is 1 , 2, 3, 4, 5, or 6; each of a and b is, independently, an integer from 1 to 5; each R' is, independently, hydrogen, optionally substituted C1 -C1 0 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyi, optionally substituted C3-
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , n, d, L, and E are as defined above, or a pharmaceutically acceptable salt thereof.
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen or methyl
  • R 8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(O(CH2)a)bR’,
  • each of a and b is, independently, an integer from 1 to 5; d is 1, 2, 3, 4, 5, or 6; each R’ is, independently, hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyi, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1 -C10 heteroaryl; L is a linker; and each E is, independently
  • the invention features a compound including a ⁇ -1 ,3-glucan synthase inhibitor conjugated to at least one monosaccharide or oligosaccharide moiety by way of a linker, wherein the compound is described by formula (II):
  • R 1 is a lipophilic moiety
  • R 2 is hydrogen or methyl
  • each of R 3 and R 4 is, independently, hydrogen or hydroxyl
  • R 6 is hydrogen, hydroxyl, methyl, or amino
  • R 7 is hydrogen or hydroxyl
  • R 8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(0(CH2) a )bR', -(NH(CH2) a )bR',
  • R 9 is hydrogen, hydroxyl, or amino
  • n is 0 or 1
  • each of a and b is, independently, an integer from 1 to 5
  • d is 1 , 2, 3, 4, 5, or 6
  • each R' is, independently, hydrogen, optionally substituted C1 -C10 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyi, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1 -C10 heteroaryl
  • each R" is, independently, hydrogen or C1 -C10 alkyl
  • L is a linker
  • each E is, independently, a monosaccharide or oligosaccharide mo
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , n, d, L, and E are as defined above, or a pharmaceutically acceptable salt thereof.
  • R 1 is a lipophilic moiety
  • R 6 is hydrogen or methyl
  • R 8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(0(CH 2 ) a )bR', -(NH(CH 2 ) a )bR', -(S(CH 2 ) a )bR', -(0(CH 2 ) a )bN(R')2,
  • each R' is, independently, hydrogen, optionally substituted C1 -C10 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1 -C10 heteroaryl ; each of R" is, independently, hydrogen or C1 -C10 alkyl; L is a linker; and each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the invention features a compound including a ⁇ -1 ,3-glucan synthase inhibitor conjugated to at least one monosaccharide or oligosaccharide moiety by way of a linker, wherein the compound is described by formula (III):
  • R 1 is a lipophilic moiety
  • R 2 is hydrogen or methyl
  • each of R 3 and R 4 is, independently, hydrogen or hydroxyl
  • R 5 is hydrogen, methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen, hydroxyl, methyl, or amino
  • R 7 is hydrogen or hydroxyl
  • R 9 is hydrogen, hydroxyl, or amino
  • X is O or NH
  • n is 0 or 1
  • d is 1 , 2, 3, 4, 5, or 6
  • L is a linker
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , X, n, d, L, and E are as defined above, or a pharmaceutically acceptable salt thereof.
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen or methyl
  • X is O or NH
  • d is 1 , 2, 3, 4, 5, or 6
  • L is a linker
  • each E is, independently, a
  • R 8 is -(0(CH2) a )bR', -(NH(CH 2 ) a )bR', -(S(CH 2 ) a )bR', -(0(CH 2 ) a )bN(R')2, -(NH(CH 2 ) a )bN(R')2, -(S(CH 2 ) a )bN(R')2,
  • each of a and b is, independently, an integer from 1 to 5; and each R' is, independently, hydrogen or optionally substituted C1 -C5 alkyi, or a pharmaceutically acceptable salt thereof.
  • R 8 is -OCH2CH 2 N(R')2, -NHCH2CH 2 N(R')2, -(NHCH 2 CH2)2N(R')2, -NHCH2CH2OR', -(NHCH 2 CH2)20R', -OCH2CH2NHCH2CH 2 N(R')2, -NHCH2CH 2 OCH2CH2N(R')2,
  • each R' is, independently, hydrogen or methyl; or a pharmaceutically acceptable salt thereof.
  • R 8 is -(0(CH2) a )bR', -(NH(CH 2 ) a )bR', -(S(CH 2 ) a )bR', -(0(CH 2 )a)bN(R')2, -(NH(CH 2 )a)bN(R")2, -(S(CH 2 )a)bN(R')2,
  • R 8 is -OCH2CH2N(R')2,
  • each R' is, independently, hydrogen or methyl
  • each R" is, independently, hydrogen or methyl
  • R 8 is
  • R 8 is
  • each of a and b is, independently, an integer from 1 to 5; and each R' is, independently, hydrogen or optionally substituted C1 -C5 alkyl, or a pharmaceutically acceptable salt thereof.
  • R 8 is -OCH2CH 2 N + (R')3, -(OCH 2 CH2)2N + (R')3, -NHCH2CH 2 N + (R')3, or -(NHCH 2 CH2)2N + (R')3; each R' is, independently, hydrogen or methyl, or a pharmaceutically acceptable salt thereof. In some embodiments, R 8 is
  • R' is
  • each R A is, independently, hydrogen or optionally substituted C1 -C1 0 alkyl.
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (I-4) or (I-5):
  • R 1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) is described by formula
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (I-7):
  • R 1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) is described by formula
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (I-9) or (1-10):
  • R 1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof.
  • the compound of formula (II) is described by formula
  • R 1 is a lipophilic moiety
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (II-4):
  • R 1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof.
  • the compound of formula (II) is described by formula
  • R 1 is a lipophilic moiety
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (II-6):
  • R 1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof.
  • the compound of formula (II) is described by formula
  • R 1 is a lipophilic moiety
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (II-8):
  • R 1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof.
  • the compound of formula (III) is described by formula
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (III-4):
  • R 1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof.
  • R 1 is
  • each of X and Y is, independently, optionally substituted alkyl, optionally substituted heteroalkyi, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene, or is absent;
  • Z is optionally substituted alkyl, optionally substituted heteroalkyi, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl,
  • -CH2 CH2-,or a pharmaceutically acceptable salt thereof.
  • R 1 is and X, Y, and Z,
  • R B is an optionally substituted C1 -C10 alkyl, or a
  • R 1 is and X, Y, and Z,
  • R B is optionally substituted C1 -C10 alkyl, or a
  • R 1 is and X, Y, and Z,
  • R B is optionally substituted C1 -C8 alkyl, or a pharmaceutically acceptable salt thereof.
  • R 1 is and X, Y, and Z,
  • R B is optionally substituted C1 -C6 alkyl, or a pharmaceutically acceptable salt thereof.
  • R 1 is
  • the compound is described by formula (I-11) or (I-12):
  • R 5 is methyl, -CH2CH2NH2, or -CH 2 (CO)NH 2 ;
  • R 6 is hydrogen or methyl;
  • R B is optionally substituted C1 -C6 alkyl;
  • d is 1 , 2, 3, or 4;
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (1-13) or (1-14):
  • R B is optionally substituted C1 -C6 alkyl, or a pharmaceutically acceptable salt thereof.
  • R 5 is methyl, -CH2CH2NH2, or -CH 2 (CO)NH 2 ;
  • R 6 is hydrogen or methyl;
  • d is 1 , 2, 3, or 4;
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (1-16):
  • the compound is described by formula (1-17) or (1-18):
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2;
  • R 6 is hydrogen or methyl;
  • R B is optionally substituted C1 -C6 alkyl;
  • d is 1 , 2, 3, or 4;
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (1-19) or (I-20):
  • R B is optionally substituted C1 -C6 alkyl, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (II-9) or (11-10):
  • R 6 is hydrogen or methyl; R B is optionally substituted C1 -C6 alkyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (11-1 1 ) or (11-12):
  • R B is optionally substituted C1 -C6 alkyl, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (11-13) or (11-14):
  • R 6 is hydrogen or methyl; R B is optionally substituted C1 -C6 alkyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (11-15) or (11-16):
  • R B is optionally substituted C1 -C6 alkyl, or a pharmaceutically acceptable salt thereof.
  • R 6 is hydrogen or methyl; and R B is optionally substituted C1 -C6 alkyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the compound is described by formula (11-19) or (II-20):
  • the compound is described by formula -5) or (111-6):
  • R B is optionally substituted C1 -C6 alkyl
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • L is a bond
  • L is described by formula (L-l):
  • I 1 is a bond attached to the ⁇ -1 ,3-glucan synthase inhibitor
  • I 2 is a bond attached to E
  • U 1 , U 2 , U 3 , and U 4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -
  • V 1 , V 2 , V 3 , V 4 , and V 5 is, independently, O, S, NR.', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl
  • heterocycloalkyl optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C5-C15 heteroaryl ; and each of f, g, h, i, j, k, I, m, and n is, independently, 0 or 1 .
  • each of U 1 , U 2 , U 3 , and U 4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C1 5 arylene, or optionally substituted C1 -C15 heteroarylene; each of V 1 , V 2 , V 3 , V 4 , and V 5 is,
  • R' is H or optionally substituted C1 -C20 alkyl; and each of f, g, h, i, j, k, I, m, and n is, independently, 0 or 1 .
  • L is described by formula (L- II ):
  • I 1 is a bond attached to the ⁇ -1 ,3-glucan synthase inhibitor
  • I 2 is a bond attached to E
  • L is described by formula (L-I2):
  • I 1 is a bond attached to the ⁇ -1 ,3-glucan synthase inhibitor
  • I 2 is a bond attached to E
  • L is described by formula (L-I3):
  • I 1 is a bond attached to the ⁇ -1 ,3-glucan synthase inhibitor
  • I 2 is a bond attached to E
  • L is described by formula (L-I4):
  • I 1 is a bond attached to the ⁇ -1 ,3-glucan synthase inhibitor; I 2 is a bond attached to E;
  • each of U 1 , U 2 , U 3 , and U 4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C15 arylene, or optionally substituted C1 -C15 heteroarylene; each of V 2 , V 3 , and V 4 is, independently, O, S, NR', P, carbonyl ; R' is H or optionally substituted C1 -C20 alkyl; and each of h, i, j, k, I, and m is, independently, 0 or 1 .
  • L is N
  • each of p, q, r, and s is, independently, an integer from 1 to 10.
  • L is described by formula (L-II):
  • L A is described by formula G A1 -(Z A1 )g1-(Y A1 )h1-(Z A2 )i1-(Y A2 )j1-(Z A3 )k1-(Y A3 )l1-(Z A4 )m1-(Y A4 )n1- (Z A5 )o1-G A2 ;
  • L B is described by formula G B1 -(Z B1 )g2-(Y B1 )h2-(Z B2 )i2-(Y B2 )j2-(Z B3 )k2-(Y B3 )l2-(Z B4 )m2-(Y B4 )n2- (Z B5 )o2-G B2 ;
  • L C is described by formula G C1 -(Z C1 )g3-(Y C1 )h3-(Z C2 )i3-(Y C2 )j3-(Z C3 )k3-(Y C3 )l3-
  • R i is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C5-C15 heteroaryl; and each of g1, h1, i1, j1, k1, l1, m1, n1, o1, g2, h
  • each of Y A1 , Y A2 , Y A3 , Y A4 , Y B1 , Y B2 , Y B3 , Y B4 , Y C1 , Y C2 , Y C3 , and Y C4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C15 arylene, or optionally substituted C1-C15 heteroarylene; each of Z A1 , Z A2 , Z A3 , Z A4 , Z A5
  • L is
  • each of p, q, r, s, and t is, independently, an integer from 1 to 10.
  • L is N
  • L is N
  • each of p, q, r, s, t, and u is, independently, an integer from 1 to 10.
  • L is described by formula (L-III):
  • L A is described by formula G A1 -(Z A1 )g1-(Y A1 )h1-(Z A2 )i1-(Y A2 )j1-(Z A3 )k1-(Y A3 )l1-(Z A4 )m1-(Y A4 )n1- (Z A5 )o1-G A2 ;
  • L B is described by formula G B1 -(Z B1 )g2-(Y B1 )h2-(Z B2 )i2-(Y B2 )j2-(Z B3 )k2-(Y B3 )l2-(Z B4 )m2-(Y B4 )n2- (Z B5 )o2-G B2 ;
  • L C is described by formula G C1 -(Z C1 )g3-(Y C1 )h3-(Z C2 )i3-(Y C2 )j3-(Z C3 )k3-(Y C3 )l3-
  • each of Y A1 , Y A2 , Y A3 , Y A4 , Y B1 , Y B2 , Y B3 , Y B4 , Y C1 , Y C2 , Y C3 , Y C4 , Y D1 , Y D2 , Y D3 , Y D4 , Y E1 , Y E2 , Y E3 , Y E4 , Y F1 , Y F2 , Y F3 , Y F4 , Y G1 , Y G2 , Y G3 , and Y G4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2- C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-
  • L is N
  • each of p, q, r, s, t, u, v, w, x, y, and z is, independently, an integer from 1 to 10.
  • L is N
  • L is
  • each of p, q, r, s, and t is, independently, an integer from 1 to 10.
  • L is described by formula (L-IV):
  • L A is described by formula G A1 -(Z A1 )g1-(Y A1 )h1-(Z A2 )i1-(Y A2 )j1-(Z A3 )k1-(Y A3 )l1-(Z A4 )m1-(Y A4 )n1- (Z A5 )o1-G A2 ;
  • L B is described by formula G B1 -(Z B1 )g2-(Y B1 )h2-(Z B2 )i2-(Y B2 )j2-(Z B3 )k2-(Y B3 )l2-(Z B4 )m2-(Y B4 )n2- (Z B5 )o2-G B2 ;
  • L C is described by formula G C1 -(Z C1 )g3-(Y C1 )h3-(Z C2 )i3-(Y C2 )j3-(Z C3 )k3-(Y C3 )l3-
  • G C2 is a bond attached to a second monosaccharide or oligosaccharide moiety, E 2 ;
  • G D1 is a bond attached to C in formula (L-IV);
  • G D2 is a bond attached to a third monosaccharide or oligosaccharide moiety, E 3 ;
  • each of Y A1 , Y A2 , Y A3 , Y A4 , Y B1 , Y B2 , Y B3 , Y B4 , Y C1 , Y C2 , Y C3 , Y C4 , Y D1 , Y D2 , Y D3 , and Y D4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkyny
  • L is N
  • each of p, q, r, s, and t is, independently, an integer from 1 to 10.
  • E is
  • E is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • the monosaccharide moiety includes an optionally substituted C6-C9 monosaccharide residue. In some embodiments of the compounds described herein, the oligosaccharide moiety includes 2-18 optionally substituted C6-C9 monosaccharide residues.
  • each of the optionally substituted C6-C9 monosaccharide residues is, independently, glucose (Glc), galactose (Gal), mannose (Man), allose (All), altrose (Alt), gulose (Gul), idose (Ido), talose (Tal), fucose (Fuc), rhamnose (Rha or L-Rha), thia-rhamnose (thia-Rha or thia-L- Rha), quinovose (Qui), 2-deoxyglucose (2-dGlc), glucosamine (GlcN), galactosamine (GaIN), mannosamine (ManN), fucosamine (FucN), quinovosamine (QuiN), N-Acetyl-glucosamine (GlcNAc), N-Acetyl-galactosamine (GalNAc), N-Acetyl-mannosamine (ManNAc), N-acety
  • each of the optionally substituted C6-C9 monosaccharide residues is, independently, an optionally substituted C6 monosaccharide residue
  • the optionally substituted C6 monosaccharide residue is
  • E is any one of the moieties in Tables 2A and 2B.
  • E directly or indirectly activates an immune cell.
  • a concentration of the compound, or a pharmaceutically acceptable salt thereof, that activates an immune cell is less than or equal to 10,000 nM.
  • the concentration of the compound, or a pharmaceutically acceptable salt thereof, that activates an immune cell is less than or equal to equal to 1 ,000 nM.
  • the concentration of the compound, or a pharmaceutically acceptable salt thereof, that activates an immune cell is less than or equal to equal to 100 nM.
  • E is a ligand to an innate immune receptor.
  • the innate immune receptor is AICL, BDCA2, CLEC2, Complement receptor 3, Complement receptor 4, DCIR, dectin-1 , dectin-2, DC-SIGN, a C-Type lectin receptor, MMR, langerin, TLR2, Mincle, MBL, or KCR.
  • E binds to an antibody.
  • the antibody is a natural antibody (e.g., an antibody of the immunoglobulin M (IgM) isotype).
  • the antibody is anti-aGal antibody or anti-aRha antibody.
  • E binds to an antibody and is any one of the moieties in Tables 2A and 2B.
  • the invention features a compound selected from
  • the pharmaceutically acceptable salt of any one of Compounds 1 -3, 4a, 4b, 5a-5c, and 6 is a formate salt.
  • the compound is Compound 1 ,
  • the pharmaceutically acceptable salt of Compound 1 is a formate salt. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is an acetate salt.
  • the compound is Compound 4a
  • the pharmaceutically acceptable salt of Compound 4a is a formate salt. In some embodiments, the pharmaceutically acceptable salt of Compound 4a is an acetate salt.
  • the invention features a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the invention features a method of treating a fungal infection in a subject by administering to the subject a pharmaceutical composition including a compound described herein in an amount sufficient to treat the infection.
  • the invention features a method of stabilizing or inhibiting a fungal infection in a subject by administering to the subject a pharmaceutical composition including a compound described herein in an amount sufficient to stabilize or inhibit the infection.
  • the subject is immunocompromised.
  • the pharmaceutical composition is administered intravenously. In some embodiments, the pharmaceutical composition is administered subcutaneously. In some embodiments, the pharmaceutical composition is administered topically. In some embodiments, the pharmaceutical composition is administered orally.
  • the pharmaceutical composition is administered to treat a blood stream infection or tissue infection in the subject.
  • the infection is selected from candidemia, invasive candidiasis, tinea capitis, tinea corporis, tinea pedis, onychomycosis, perionychomycosis, pityriasis versicolor, oral thrush, vaginal candidiasis, respiratory tract candidiasis, biliary candidiasis, eosophageal candidiasis, urinary tract candidiasis, systemic candidiasis, mucocutaneous candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, fungal sinusitis, or chronic sinusitis.
  • the infection is candidemia or invasive candidiasis.
  • the fungal infection is an infection of Candida albicans, C. parapsilosis, C. glabrata, C. guilliermondii, C. krusei, C. tropicalis, C. lusitaniae, Aspergillus fumigatus, A. flavus, A. terreus, A. niger, A. candidus, A. clavatus, or A. ochraceus.
  • the fungal infection is an infection of
  • Exserohilum longirostratum or Exserohilum mcginnisii.
  • the fungal infection is a
  • the pharmaceutical composition includes any one of Compounds 1 -6, or a pharmaceutically acceptable salt thereof.
  • the invention also features a method of stabilizing or inhibiting the growth of fungi, or killing fungi, the method including contacting the fungi or a site susceptible to fungal growth with a compound described herein, or a pharmaceutically acceptable salt thereof.
  • covalently attached refers to two parts of a compound that are linked to each other by a covalent bond formed between two atoms in the two parts of the compound.
  • L serves as a linker that covalently attaches a ⁇ -1 ,3-glucan synthase inhibitor to at least one monosaccharide or oligosaccharide moiety.
  • An amine group in the ⁇ -1 ,3-glucan synthase inhibitor may for an amide bond with a carboxylic acid in the linker and a carbon atom in the monosaccharide or oligosaccharide moiety may form a C-0 bond with an oxygen atom in the linker.
  • linker and “L,” as used herein, refer to a covalent linkage or connection between two or more components in a compound (e.g., the ⁇ -1 ,3-glucan synthase inhibitor and one or more monosaccharide or oligosaccharide moieties in a compound described herein).
  • a compound e.g., the ⁇ -1 ,3-glucan synthase inhibitor and one or more monosaccharide or oligosaccharide moieties in a compound described herein.
  • a compound described herein may contain a linker that has a divalent structure (e.g., a divalent linker), in which one terminus of the linker is conjugated to the ⁇ -1 ,3-glucan synthase inhibitor and the other terminus of the linker is conjugated to a monosaccharide or oligosaccharide moiety.
  • a compound described herein may contain a linker that has a trivalent structure (e.g., a trivalent linker).
  • a trivalent linker has three arms, in which each arm is conjugated to a component of the compound (e.g., a first arm conjugated to the ⁇ -1 ,3-glucan synthase inhibitor, a second arm conjugated to a first monosaccharide or oligosaccharide moiety, and a third arm conjugated to a second monosaccharide or oligosaccharide moiety).
  • a component of the compound e.g., a first arm conjugated to the ⁇ -1 ,3-glucan synthase inhibitor, a second arm conjugated to a first monosaccharide or oligosaccharide moiety, and a third arm conjugated to a second monosaccharide or oligosaccharide moiety.
  • Molecules that may be used as linkers include at least two functional groups, which may be the same or different, e.g., two carboxylic acid groups, two amine groups, two sulfonic acid groups, a carboxylic acid group and an amine group, or a carboxy group and a sulfonic acid group.
  • the first functional group may form a covalent linkage with a first component in the compound and the second functional group may form a covalent linkage with the second component in the compound.
  • the first arm of the linker may contain a dicarboxylic acid that can form a form a covalent linkage (e.g., an amide bond) with the ⁇ -1 ,3-glucan synthase inhibitor
  • the second arm of the linker may for a covalent linkage (e.g., a C-0 bond) with a first monosaccharide or oligosaccharide moiety in the compound
  • the third arm of the linker may for a covalent linkage (e.g., a C-0 bond) with a second monosaccharide or oligosaccharide moiety in the compound.
  • the divalent linker may contain two carboxylic acids, in which the first carboxylic acid may form a covalent linkage with one component (e.g., the ⁇ -1 ,3-glucan synthase inhibitor) in the compound and the second carboxylic acid may form a covalent linkage with another component (e.g., the monosaccharide or oligosaccharide moiety) in the compound.
  • one component e.g., the ⁇ -1 ,3-glucan synthase inhibitor
  • another component e.g., the monosaccharide or oligosaccharide moiety
  • a molecule containing one or more sulfonic acid groups may be used as a linker, in which the sulfonic acid group may form a sulfonamide linkage with a component in the compound.
  • a molecule containing one or more isocyanate groups may be used as a linker, in which the isocyanate group may form a urea linkage with a component in the compound.
  • a molecule containing one or more haloalkyl groups may be used as a linker, in which the haloalkyl group may form a covalent linkage, e.g., C-N and C-0 linkages, with a component in the compound.
  • a linker provides space, rigidity, and/or flexibility between the two or more components.
  • a linker may be a bond, e.g., a covalent bond.
  • the term "bond" refers to a chemical bond, e.g., an amide bond, a disulfide bond, a C-0 bond, a C-S bond, a C-0 bond, a N-N bond, or any kind of bond created from a chemical reaction, e.g., chemical conjugation.
  • a linker includes no more than 250 atoms (e.g., no more than 225, 200, 175, 1 50, 125, 100, 50, 25, 20, 15, or 10 atoms).
  • a linker includes no more than 250 non-hydrogen atoms (e.g., no more than 225, 200, 1 75, 150, 125, 100, 50, 25, 20, 15, or 10 non-hydrogen atoms).
  • the backbone of a linker includes no more than 250 atoms (e.g., no more than 225, 200, 175, 1 50, 125, 1 00, 50, 25, 20, 15, or 10 atoms).
  • the "backbone" of a linker refers to the atoms in the linker that together form the shortest path from one part of a compound to another part of the compound (e.g., the shortest path linking a ⁇ -1 ,3-glucan synthase inhibitor and a monosaccharide or oligosaccharide moiety).
  • the atoms in the backbone of the linker are directly involved in linking one part of a compound to another part of the compound (e.g., linking a ⁇ -1 ,3-glucan synthase inhibitor and a monosaccharide or oligosaccharide moiety).
  • hydrogen atoms attached to carbons in the backbone of the linker are not considered as directly involved in linking one part of the compound to another part of the compound.
  • a linker may include a synthetic group derived from, e.g., a synthetic polymer (e.g., a polyethylene glycol (PEG) polymer).
  • a linker may include one or more amino acid residues, such as D- or L-amino acid residues.
  • a linker may be a residue of an amino acid sequence (e.g., a 1 -25 amino acid, 1 -10 amino acid, 1 -9 amino acid, 1 -8 amino acid, 1 -7 amino acid, 1 -6 amino acid, 1 -5 amino acid, 1 -4 amino acid, 1 -3 amino acid, 1 -2 amino acid, or 1 amino acid sequence).
  • a linker may include one or more, e.g., 1 -100, 1 -50, 1 -25, 1 -10, 1 -5, or 1 -3, optionally substituted alkylene, optionally substituted heteroalkylene (e.g., a PEG unit), optionally substituted alkenylene, optionally substituted
  • heteroalkenylene optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted cycloalkenylene, optionally substituted heterocycloalkenylene, optionally substituted cycloalkynylene, optionally substituted heterocycloalkynylene, optionally substituted arylene, optionally substituted heteroarylene (e.g., pyridine), O, S, NR' (R' is H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkenyl, optionally substituted cycloalkynyl, optionally
  • a linker may include one or more optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene (e.g., a PEG unit), optionally substituted C2-C20 alkenylene (e.g., C2 alkenylene), optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene (e.g., cyclopropylene, cyclobutylene), optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene (e
  • lipophilic moiety refers to a portion, substituent, or functional group of a compound that is, in general, hydrophobic and non-polar.
  • a moiety is lipophilic if it has a hydrophobicity determined using a cLogP value of greater than 0, such as about 0.25 or greater, about 0.5 or greater, about 1 or greater, about 2 or greater, 0.25-5, 0.5-4 or 2-3.
  • cLogP refers to the calculated partition coefficient of a molecule or portion of a molecule.
  • the partition coefficient is the ratio of concentrations of a compound in a mixture of two immiscible phases at equilibrium (e.g., octanol and water) and measures the hydrophobicity or hydrophilicity of a compound.
  • cLogP can be determined using quantitative structure-property relationship algorithms known in the art (e.g., using fragment based prediction methods that predict the logP of a compound by determining the sum of its non-overlapping molecular fragments).
  • a moiety is considered lipophilic if it has a cLogP value described above in at least one of the above methods.
  • a lipophilic moiety having the stated cLogP value will be considered lipophilic, even though it may have a positive charge or a polar substituent.
  • a lipophilic moiety contains entirely hydrocarbons.
  • a lipophilic moiety may contain one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms, wherein each heteroatom is, independently, selected from N, O, and S (e.g., an indolyl), or one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, halo groups, which, due to the structure of the moiety and/or small differences in electronegativity between the heteroatoms or halo groups and the hydrocarbons, do not induce significant chemical polarity into the lipophilic moiety.
  • a lipophilic moiety having, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms and/or, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, halo atoms may still be considered non-polar.
  • a lipophilic moiety may be optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, or optionally substituted heteroaryl, or halo forms thereof, wherein the optional substituents are also lipophilic (such as alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
  • heteroalkynyl, aryl, or heteroaryl or are not lipophilic but do not change the overall lipophilic character of the moiety, i.e., the moiety has a cLogP value of greater than 0.
  • octanol contains a polar group, OH, but is still a lipophilic moiety.
  • a lipophilic moiety may be benzyl, isobutyl, sec-butyl, isopropyl, n-propyl, methyl, biphenylmethyl, n-octyl, or substituted indolyl (e.g., alkyl substituted indolyl).
  • a lipophilic moiety may be the side chain of a hydrophobic amino acid residue, e.g., leucine, isoleucine, alanine, phenylalanine, valine, and proline, or groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and pyrrolidinyl.
  • R 1 in a compound described herein may be a lipophilic moiety.
  • alkyl straight-chain and branched-chain monovalent substituents, as well as combinations of these, containing only C and H when unsubstituted.
  • alkyl group includes at least one carbon-carbon double bond or carbon-carbon triple bond, the alkyl group can be referred to as an "alkenyl” or “alkynyl” group respectively.
  • alkenyl or alkynyl group respectively.
  • the monovalency of an alkyl, alkenyl, or alkynyl group does not include the optional substituents on the alkyl, alkenyl, or alkynyl group.
  • alkyl, alkenyl, or alkynyl group is attached to a compound
  • monovalency of the alkyl, alkenyl, or alkynyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl, alkenyl, or alkynyl group.
  • the alkyl or heteroalkyl group may contain, e.g.,
  • the alkenyl, heteroalkenyl, alkynyl, or heteroalkynyl group may contain, e.g., 2-20, 2-18, 2-16, 2-14, 2-12, 2-10,
  • 2- 8, 2-6, or 2-4 carbon atoms e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2- C6, or C2-C4
  • Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, tert-butyl, 2-propenyl, and 3-butynyl.
  • cycloalkyl represents a monovalent saturated or unsaturated non- aromatic cyclic alkyl group.
  • a cycloalkyl may have, e.g., three to twenty carbons (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C1 1 , C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkyl).
  • cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • the cycloalkyl group includes at least one carbon-carbon double bond, the cycloalkyl group can be referred to as a "cycloalkenyl" group.
  • a cycloalkenyl may have, e.g., four to twenty carbons (e.g., a C4-C7, C4-C8, C4-C9, C4-C10, C4-C1 1 , C4-C12, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenyl).
  • Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • the cycloalkyl group includes at least one carbon-carbon triple bond, the cycloalkyl group can be referred to as a "cycloalkynyl" group.
  • a cycloalkynyl may have, e.g., eight to twenty carbons (e.g., a C8-C9, C8-C10, C8-C1 1 , C8-C12, C8-C14, C8-C16, C8-C18, or C8-C20 cycloalkynyl).
  • the term "cycloalkyl” also includes a cyclic compound having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.1 .]heptyl and adamantane.
  • cycloalkyl also includes bicyclic, tricyclic, and tetracyclic fused ring structures, e.g., decalin and spiro cyclic compounds.
  • aryl refers to any monocyclic or fused ring bicyclic or tricyclic system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system, e.g., phenyl, naphthyl, or phenanthrene.
  • a ring system contains 5-15 ring member atoms or 5-10 ring member atoms.
  • An aryl group may have, e.g., five to fifteen carbons (e.g., a C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5-C1 1 , C5-C12, C5-C13, C5-C14, or C5-C15 aryl).
  • heteroaryl also refers to such monocyclic or fused bicyclic ring systems containing one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms selected from O, S and N.
  • a heteroaryl group may have, e.g., one to fifteen carbons (e.g., a C1 -C3, C1 -C4, C1 -C5, C1 -C6, C1 -C7, C1 -C8, C1 -C9.
  • heteroaryl systems include, e.g., pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzoisoxazolyl, and imidazolyl.
  • a group such as phthalimido is also considered heteroaryl.
  • the aryl or heteroaryl group is a 5- or 6-membered aromatic rings system optionally containing 1 -2 nitrogen atoms.
  • the aryl or heteroaryl group is an optionally substituted phenyl, pyridyl, indolyl, pyrimidyl, pyridazinyl, benzothiazolyl, benzimidazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, or imidazopyridinyl.
  • the aryl group is phenyl.
  • an aryl group may be optionally substituted with a substituent such an aryl substituent, e.g., biphenyl.
  • alkaryl refers to an aryl group that is connected to an alkylene, alkenylene, or alkynylene group. In general, if a compound is attached to an alkaryl group, the alkylene, alkenylene, or alkynylene portion of the alkaryl is attached to the compound.
  • an alkaryl is C6-C35 alkaryl (e.g., C6-C16, C6-C14, C6-C12, C6-C10, C6-C9, C6-C8, C7, or C6 alkaryl), in which the number of carbons indicates the total number of carbons in both the aryl portion and the alkylene, alkenylene, or alkynylene portion of the alkaryl.
  • alkaryls include, but are not limited to, (C1 -C8)alkylene(C6-C12)aryl, (C2-C8)alkenylene(C6-C12)aryl, or (C2-C8)alkynylene(C6-C12)aryl.
  • an alkaryl is benzyl.
  • one or more heteroatoms selected from N, O, and S may be present in the alkylene, alkenylene, or alkynylene portion of the alkaryl group and/or may be present in the aryl portion of the alkaryl group.
  • the substituent may be present on the alkylene, alkenylene, or alkynylene portion of the alkaryl group and/or may be present on the aryl portion of the alkaryl group.
  • amino represents -N(R X )2 or -N + (R X )3, where each R x is, independently, H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R x combine to form a heterocycloalkyl.
  • the amino group is -NH2.
  • alkamino refers to an amino group, described herein, that is attached to an alkylene (e.g., C1 -C5 alkylene), alkenylene (e.g., C2-C5 alkenylene), or alkynylene group (e.g., C2-C5 alkenylene).
  • alkylene e.g., C1 -C5 alkylene
  • alkenylene e.g., C2-C5 alkenylene
  • alkynylene group e.g., C2-C5 alkenylene
  • the amino portion of an alkamino refers to -N(R X )2 or -N + (R X )3, where each R x is, independently, H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R x combine to form a heterocycloalkyl.
  • the amino portion of an alkamino is -NH2.
  • An example of an alkamino group is C1 -C5 alkamino, e.g., C2 alkamino (e.g., CH2CH2NH2 or CH2CH2N(CH3)2).
  • heteroalkamino group one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms selected from N, O, and S may be present in the alkylene, alkenylene, or alkynylene portion of the heteroalkamino group.
  • an alkamino group may be optionally substituted.
  • the substituent may be present on the alkylene, alkenylene, or alkynylene portion of the alkamino group and/or may be present on the amino portion of the alkamino group.
  • alkamide refers to an amide group that is attached to an alkylene (e.g., C1 -C5 alkylene), alkenylene (e.g., C2-C5 alkenylene), or alkynylene (e.g., C2-C5 alkenylene) group.
  • alkylene e.g., C1 -C5 alkylene
  • alkenylene e.g., C2-C5 alkenylene
  • alkynylene e.g., C2-C5 alkenylene
  • the amide portion of an alkamide refers to -C(0)-N(R X )2, where each R x is, independently, H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two R x combine to form a heterocycloalkyl.
  • the amide portion of an alkamide is -C(0)NH 2 .
  • An alkamide group may be -(CH 2 ) 2 -C(0)NH 2 or -CH 2 -C(0)NH 2 .
  • heteroalkamide group one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms selected from N, O, and S may be present in the alkylene, alkenylene, or alkynylene portion of the heteroalkamide group.
  • an alkamide group may be optionally substituted.
  • the substituent may be present on the alkylene, alkenylene, or alkynylene portion of the alkamide group and/or may be present on the amide portion of the alkamide group.
  • alkylene refers to divalent groups having a specified size.
  • an alkylene may contain, e.g., 1 -20, 1 -18, 1 -16, 1 -14, 1 -12, 1 -10, 1 -8, 1 -6, 1 -4, or 1 -2 carbon atoms (e.g., C1 -C20, C1 -C18, C1 -C1 6, C1 -C14, C1 -C12, C1 -C10, C1 -C8, C1 -C6, C1 -C4, or C1 -C2).
  • an alkenylene or alkynylene may contain, e.g., 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4).
  • Alkylene, alkenylene, and/or alkynylene includes straight-chain and branched-chain forms, as well as combinations of these. The divalency of an alkylene, alkenylene, or alkynylene group does not include the optional substituents on the alkylene, alkenylene, or alkynylene group.
  • a ⁇ -1 ,3-glucan synthase inhibitor and a monosaccharide or oligosaccharide moiety may be attached to each other by way of a linker that includes alkylene, alkenylene, and/or alkynylene, or combinations thereof.
  • a linker that includes alkylene, alkenylene, and/or alkynylene, or combinations thereof.
  • Each of the alkylene, alkenylene, and/or alkynylene groups in the linker is considered divalent with respect to the two attachments on either end of alkylene, alkenylene, and/or alkynylene group.
  • a linker includes -(optionally substituted alkylene)-(optionally substituted alkenylene)-(optionally substituted alkylene)-
  • the alkenylene is considered divalent with respect to its attachments to the two alkylenes at the ends of the linker.
  • the optional substituents on the alkenylene are not included in the divalency of the alkenylene.
  • the divalent nature of an alkylene, alkenylene, or alkynylene group refers to both of the ends of the group and does not include optional substituents that may be present in an alkylene, alkenylene, or alkynylene group.
  • Alkylene, alkenylene, and/or alkynylene groups can be substituted by the groups typically suitable as substituents for alkyl, alkenyl and alkynyl groups as set forth herein.
  • -HCR-C ⁇ C- may be considered as an optionally substituted alkynylene and is considered a divalent group even though it has an optional substituent, R.
  • Heteroalkylene, heteroalkenylene, and/or heteroalkynylene groups refer to alkylene, alkenylene, and/or alkynylene groups including one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms, e.g., N, O, and S.
  • a polyethylene glycol (PEG) polymer or a PEG unit -(CH2)2-0- in a PEG polymer is considered a heteroalkylene containing one or more oxygen atoms.
  • cycloalkylene refers to a divalent cyclic group linking together two parts of a compound. For example, one carbon within the cycloalkylene group may be linked to one part of the compound, while another carbon within the cycloalkylene group may be linked to another part of the compound.
  • a cycloalkylene group may include saturated or unsaturated non-aromatic cyclic groups.
  • a cycloalkylene may have, e.g., three to twenty carbons in the cyclic portion of the cycloalkylene (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C1 1 , C3-C12, C3-C14, C3-C16, C3-C1 8, or C3-C20 cycloalkylene).
  • the cycloalkylene group includes at least one carbon-carbon double bond
  • the cycloalkylene group can be referred to as a "cycloalkenylene" group.
  • a cycloalkenylene may have, e.g., four to twenty carbons in the cyclic portion of the cycloalkenylene (e.g., a C4-C7, C4-C8, C4-C9. C4-C10, C4-C1 1 , C4-C12, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenylene).
  • the cycloalkylene group includes at least one carbon-carbon triple bond
  • the cycloalkylene group can be referred to as a "cycloalkynylene" group.
  • a cycloalkynylene may have, e.g., four to twenty carbons in the cyclic portion of the cycloalkynylene (e.g., a C4-C7, C4-C8, C4-C9, C4-C10, C4-C1 1 , C4-C12, C4-C14, C4-C16, C4-C1 8, or C8-C20 cycloalkynylene).
  • a cycloalkylene group can be substituted by the groups typically suitable as substituents for alkyl, alkenyl and alkynyl groups as set forth herein.
  • Heterocycloalkylene refers to a cycloalkylene group including one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms, e.g., N, O, and S.
  • Examples of cycloalkylenes include, but are not limited to, cyclopropylene and cyclobutylene.
  • a tetrahydrofuran may be considered as a
  • arylene refers to a multivalent (e.g., divalent or trivalent) aryl group linking together multiple (e.g., two or three) parts of a compound. For example, one carbon within the arylene group may be linked to one part of the compound, while another carbon within the arylene group may be linked to another part of the compound.
  • An arylene may have, e.g., five to fifteen carbons in the aryl portion of the arylene (e.g., a C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5- C1 1 , C5-C12, C5-C13, C5-C14, or C5-C15 arylene).
  • An arylene group can be substituted by the groups typically suitable as substituents for alkyl, alkenyl and alkynyl groups as set forth herein.
  • Heteroarylene refers to an aromatic group including one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms, e.g., N, O, and S.
  • a heteroarylene group may have, e.g., two to fifteen carbons (e.g., a C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9, C2-C10, C2-C1 1 , C2-C12, C2-C13, C2-C14, or C1 -C15 heteroarylene).
  • substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, alkaryl, acyl, heteroaryl, heteroalkyi, heteroalkenyl, heteroalkynyl, heteroalkaryl, halogen, oxo, cyano, nitro, amino, alkamino, hydroxy, alkoxy, alkanoyl, carbonyl, carbamoyl, guanidinyl, ureido, amidinyl, any of the groups or moieties described above, and hetero versions of any of the groups or moieties described above.
  • Substituents include, but are not limited to, F, CI, methyl, phenyl, benzyl, OR, NR 2 , SR, SOR, SO2R, OCOR, NRCOR, NRCONR2, NRCOOR, OCONR2, RCO, COOR, alkyl-OOCR, SO3R, CONR2, SO2NR2, NRSO2NR2, CN, CF 3 , OCF 3 , S1R3, and NO2, wherein each R is, independently, H, alkyl, alkenyl, aryl, heteroalkyi, heteroalkenyl, or heteroaryl, and wherein two of the optional substituents on the same or adjacent atoms can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members, or two of the optional substituents on the same atom can be joined to form an optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members
  • an optionally substituted group or moiety refers to a group or moiety (e.g., any one of the groups or moieties described above) in which one of the atoms (e.g., a hydrogen atom) is optionally replaced with another substituent.
  • an optionally substituted alkyl may be an optionally substituted methyl, in which a hydrogen atom of the methyl group is replaced by, e.g., OH.
  • a substituent on a heteroalkyi or its divalent counterpart, heteroalkylene may replace a hydrogen on a carbon or a hydrogen on a heteroatom such as N.
  • the hydrogen atom in the group -R-NH-R- may be substituted with an alkamide substituent, e.g., -R- N[(CH2C(0)N(CH3)2]-R.
  • an optional substituent is a noninterfering substituent.
  • noninterfering substituent refers to a substituent that leaves the ability of the compounds described herein (e.g., compounds of any one of formulas (l)-(lll)) to bind to ⁇ -1 ,3-glucan synthase and/or to kill or inhibit the growth of fungi qualitatively intact. Thus, in some embodiments, the substituent may alter the degree of such activity.
  • a noninterfering substituent leaves the ability of a compound described herein (e.g., a compound of any one of formulas (l)-(lll)) to kill or inhibit the growth of fungi qualitatively intact as determined by measuring the minimum inhibitory concentration (MIC) against at least one fungi as known in the art.
  • MIC minimum inhibitory concentration
  • hetero when used to describe a chemical group or moiety, refers to having at least one heteroatom that is not a carbon or a hydrogen, e.g., N, O, and S. Any one of the groups or moieties described above may be referred to as hetero if it contains at least one heteroatom.
  • a heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl group refers to a cycloalkyl, cycloalkenyl, or cycloalkynyl group that has one or more heteroatoms, wherein each heteroatom is, independently, selected from, e.g., N, O, and S.
  • heterocycloalkenyl group is a maleimido.
  • a heteroaryl group refers to an aromatic group that has one or more heteroatoms, wherein each heteroatom is, independently, selected from, e.g., N, O, and S.
  • One or more heteroatoms may also be included in a substituent that replaced a hydrogen atom in a group or moiety as described herein.
  • a substituent e.g., methyl
  • the substituent may also contain one or more heteroatoms (e.g., methanol).
  • acyl refers to a group having the structure: wherein R z is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyi, cycloalkenyl, cycloalkynyl, aryl, alkaryl, alkamino, heteroalkyi, heteroalkenyl, heteroalkynyl, heterocycloalkyi, heterocycloalkenyl, heterocycloalkynyl, heteroaryl, heteroalkaryl, or heteroalkamino.
  • halo refers to any halogen atom, e.g., F, CI, Br, or I. Any one of the groups or moieties described herein may be referred to as a "halo moiety" if it contains at least one halogen atom, such as haloalkyl.
  • hydroxyl represents an -OH group.
  • carbonyl refers to a group having the structure
  • thiocarbonyl refers to a group having the structure
  • phosphate represents the group having the structure:
  • phosphoryl represents the group having the structure:
  • amino represents the group having the structure:
  • R is an optional substituent
  • V-protecting group represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N- protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 5th Edition (John Wiley & Sons, New York, 2014), which is incorporated herein by reference.
  • /V-protecting groups include, e.g., acyl, aryloyl, and carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t- butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, carboxybenzyl (CBz), 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acid residues such as alanine, leucine, phenylalanine; sulfonyl-containing groups such as benzenesulfonyl and p-toluenesulfonyl; carb
  • amino acid means naturally occurring amino acids and non- naturally occurring amino acids.
  • Naturally occurring amino acids means amino acids including Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val.
  • non-naturally occurring amino acid means an alpha amino acid that is not naturally produced or found in a mammal.
  • non-naturally occurring amino acids include D-amino acids; an amino acid having an acetylaminomethyl group attached to a sulfur atom of a cysteine; a pegylated amino acid; the omega amino acids of the formula NH2(CH2) n COOH where n is 2-6, neutral nonpolar amino acids, such as sarcosine, t-butyl alanine, t-butyl glycine, N- methyl isoleucine, and norleucine; oxymethionine; phenylglycine; citrulline; methionine sulfoxide; cysteic acid; ornithine; diaminobutyric acid; 3-aminoalanine; 3-hydroxy-D-proline; 2,4-diaminobutyric acid; 2-aminopentanoic
  • amino acids are a-aminobutyric acid, ⁇ -amino-a-methylbutyrate, aminocyclopropane-carboxylate, aminoisobutyric acid, aminonorbornyl-carboxylate, L-cyclohexylalanine, cyclopentylalanine, L-N-methylleucine, L-N-methylmethionine, L-N-methylnorvaline, L-N-methylphenylalanine, L-N-methylproline,
  • L-N-methylserine L-N-methyltryptophan, D-ornithine, L-N-methylethylglycine, L-norleucine, a-methyl- aminoisobutyrate, a-methylcyclohexylalanine, D-a-methylalanine, D-a-methylarginine,
  • D-a-methylasparagine D-a-methylaspartate, D-a-methylcysteine, D-a-methylglutamine,
  • D-a-methylhistidine D-a-methylisoleucine, D-a-methylleucine, D-a-methyllysine,
  • D-a-methylmethionine D-a-methylornithine, D-a-methylphenylalanine, D-a-methylproline,
  • D-a-methylserine D-N-methylserine, D-a-methylthreonine, D-a-methyltryptophan, D-a-methyltyrosine, D-a-methylvaline, D-N-methylalanine, D-N-methylarginine, D-N-methylasparagine,
  • D-N-methylaspartate D-N-methylcysteine, D-N-methylglutamine, D-N-methylglutamate,
  • D-N-methylhistidine D-N-methylisoleucine, D-N-methylleucine, D-N-methyllysine, N-methylcyclohexylalanine, D-N-methylornithine, N-methylglycine, N-methylaminoisobutyrate, N-(1 -methylpropyl)glycine, N-(2-methylpropyl)glycine, D-N-methyltryptophan, D-N-methyltyrosine, D-N-methylvaline, ⁇ -aminobutyric acid, L-t-butylglycine, L-ethylglycine, L-homophenylalanine, L-a-methylarginine, L-a-methylaspartate, L-a-methylcysteine, L-a-methylglutamine,
  • L-a-methylhistidine L-a-methylisoleucine, L-a-methylleucine, L-a-methylmethionine,
  • L-a-methylnorvaline L-a-methylphenylalanine, L-a-methylserine, L-a-methyltryptophan,
  • L-a-methylvaline N-(N-(2,2-diphenylethyl) carbamylmethylglycine, 1 -carboxy-1 -(2,2-diphenyl- ethylamino) cyclopropane, 4-hydroxyproline, ornithine, 2-aminobenzoyl (anthraniloyl),
  • L-N-methylglutamine L-N-methylglutamic acid, L-N-methylhistidine, L-N-methylisoleucine,
  • L-N-methyllysine L-N-methylnorleucine, L-N-methylornithine, L-N-methylthreonine,
  • N-(2-methylthioethyl)glycine L-a-methyllysine, L-a-methylnorleucine, L-a-methylornithine,
  • L-a-methylproline L-a-methylthreonine, L-a-methyltyrosine, L-N-methyl-homophenylalanine,
  • amino acid residues may be charged or polar.
  • Charged amino acids include alanine, lysine, aspartic acid, or glutamic acid, or non-naturally occurring analogs thereof.
  • Polar amino acids include glutamine, asparagine, histidine, serine, threonine, tyrosine, methionine, or tryptophan, or non-naturally occurring analogs thereof.
  • a terminal amino group in the amino acid may be an amido group or a carbamate group.
  • fungal infection refers to the invasion of a subject's cells, tissues, and/or organs by fungi (e.g., Candida spp. or Aspergillus spp.), thus, causing an infection.
  • the fungi may grow, multiply, and/or produce toxins in the subject's cells, tissues, and/or organs.
  • a fungal infection can be any situation in which the presence of a fungal population(s) is latent within or damaging to a host body.
  • a subject is "suffering" from a fungal infection when a latent fungal population is detectable in or on the subject's body, an excessive amount of a fungal population is present in or on the subject's body, or when the presence of a fungal population(s) is damaging the cells, tissues, and/or organs of the subject.
  • the term "dermatophytosis” or “dermatophyte infection” refers to an infection caused by dermatophytes, which are fungi that require keratin for growth. Dermatophytes are fungi in the genus Microsporum, Epidermophyton, and Trichophyton. These fungi can cause superficial infections of the skin, hair, and/or nails. Dermatophytes are spread by direct contact from other people (anthropophilic organisms), animals (zoophilic organisms), and soil (geophilic organisms), as well as indirectly from fomites.
  • protecting against a fungal infection refers to preventing a subject from developing a fungal infection or decreasing the risk that a subject may develop a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.).
  • Prophylactic drugs used in methods of protecting against a fungal infection in a subject are often administered to the subject prior to any detection of the fungal infection.
  • a subject e.g., a subject at risk of developing a fungal infection
  • a compound described herein e.g., a compound having any one of formulas (l)-(lll)
  • treating refers to a therapeutic treatment of a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.) in a subject.
  • a therapeutic treatment may slow the progression of the fungal infection, improve the subject's outcome, and/or eliminate the infection.
  • a therapeutic treatment of a fungal infection e.g., a fungal infection caused by Candida spp.
  • a subject in a subject may alleviate or ameliorate of one or more symptoms or conditions associated with the fungal infection, diminish the extent of the fungal infection, stabilize (i.e., not worsening) the state of the fungal infection, prevent the spread of the fungal infection, and/or delay or slow the progress of the fungal infection, as compare the state and/or the condition of the fungal infection in the absence of therapeutic treatment.
  • the term "immunocompromised” refers to a subject (e.g., a human) having a weakened immune system.
  • the subject's immune system can be weakened or compromised by a disease (e.g., an HIV infection, an autoimmune disease, cancer), a medical procedure (e.g., an organ transplant (e.g., a solid organ transplant) or a bone marrow transplant), a drug (e.g., an HIV infection, an autoimmune disease, cancer), a medical procedure (e.g., an organ transplant (e.g., a solid organ transplant) or a bone marrow transplant), a drug (e.g., an HIV infection, an autoimmune disease, cancer), a medical procedure (e.g., an organ transplant (e.g., a solid organ transplant) or a bone marrow transplant), a drug (e.g., an HIV infection, an autoimmune disease, cancer), a medical procedure (e.g., an organ transplant (e.g., a solid
  • the immune system of the host may also have a congenital defect that renders the host more susceptible to infection.
  • an immunosuppression therapy refers to a therapy that uses one or more immunosuppressants to reduce the activation and/or efficacy of the immune system of a subject (e.g., a human).
  • an immunosuppression therapy is used to prevent the body from rejecting a transplant (e.g., an organ transplant (e.g., a solid organ transplant) or a bone marrow transplant), to treat graft-versus-host disease after a bone marrow transplant, and/or to treat autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, multiple sclerosis, myasthenia gravis, Sarcoidosis, Behcet's disease).
  • autoimmune diseases e.g., systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, multiple sclerosis, myasthenia gravis, Sarcoidosis, Behcet's disease
  • Immunosuppressants include, but are not limited to, calcineurin inhibitors, mTOR inhibitors, and tyrosine kinase inhibitors (e.g., cyclosporine A, cyclosporine G, voclosporin, tacrolimus, pimecrolimus, sirolimus, temsirolimus, deforolimus, everolimus, zotarolimus, biolimus, imatinib, dasatinib, nilotinib, erlotinib, sunitinib, gefitinib, bosutinib, neratinib, axitinib, crizotinib, lapatinib, toceranib and vatalanib).
  • calcineurin inhibitors e.g., cyclosporine A, cyclosporine G, voclosporin, tacrolimus, pimecrolimus, sirolimus, temsirolimus,
  • activating an immune cell refers to the ability of a compound to directly or indirectly bind to an immune cell to produce an effective immune response.
  • the ability of a compound to directly or indirectly bind to an immune cell to produce an effective immune response may be quantified by measuring the concentration of the compound at which such immune response is produced.
  • the concentration of a compound that binds to an immune cell receptor such as dectin-1 or binds to an antibody (e.g., anti-aGal or anti-aRha antibody, which then binds to an immune cell) to trigger an effective immune response may be less than or equal to 10,000 nM as measured in accordance with, e.g., an enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay
  • an aGal epitope, that binds to an antibody, such as an anti-aGal antibody may be detected using an ELISA.
  • oligosaccharide moiety may be immobilized on a support or surface using conventional techniques in the art. After the compound is immobilized to the surface, an antibody that is specific for the particular monosaccharide or oligosaccharide moiety in the compound is applied over the surface so it is captured by the compound through binding to the monosaccharide or oligosaccharide moiety in the compound.
  • the antibody is often linked to an enzyme (e.g., horseradish peroxidase) for subsequent signal amplification.
  • the enzyme's substrate e.g., 3,3'-diaminobenzidine
  • the antibody itself can be detected using a secondary antibody, which is linked to an enzyme.
  • the concentration of a compound that binds to an immune cell receptor such as dectin-1 or binds to an antibody (e.g., anti-aGal or anti-aRha antibody, which then binds to an immune cell) to trigger an effective immune response may be less than or equal to 1000 nM or less than or equal to 100 nM as measured in accordance with an ELISA.
  • innate immune receptor refers to a natural receptor, such as a natural receptor on an immune cell, that binds to a carbohydrate (e.g., a monosaccharide or oligosaccharide moiety) or an optionally substituted carbohydrate and causes a response in the immune system.
  • an innate immune receptor binds to the monosaccharide or oligosaccharide moiety of the compounds described herein (e.g., compounds of any one of formulas (l)-(lll)).
  • an innate immune receptor binds to a moiety in Table 2A or 2B.
  • natural antibody refers to a naturally existing antibody in the circulation of a mammal (e.g., a human) that has not been previously exposed to deliberate immunization.
  • a natural antibody is an antibody of the immunoglobulin M (IgM) isotype.
  • IgM immunoglobulin M
  • a natural antibody binds to the monosaccharide or
  • a natural antibody binds to a moiety in Table 2A or 2B.
  • a natural antibody is anti-aGal antibobody or anti-aRha antibody.
  • subject can be a human, non-human primate, or other mammal, such as but not limited to dog, cat, horse, cow, pig, turkey, goat, fish, monkey, chicken, rat, mouse, and sheep.
  • terapéuticaally effective amount refers to an amount, e.g., pharmaceutical dose, effective in inducing a desired effect in a subject or in treating a subject having a condition or disorder described herein (e.g., a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.)). It is also to be understood herein that a “therapeutically effective amount” may be interpreted as an amount giving a desired therapeutic and/or preventative effect, taken in one or more doses or in any dosage or route.
  • an effective amount of a compound is, for example, an amount sufficient to prevent, slow down, or reverse the progression of the fungal infection as compared to the response obtained without administration of the compound.
  • composition refers to a medicinal or
  • compositions that contains at least one active ingredient (e.g., a compound of any one of formulas (l)-(lll)) as well as one or more excipients and diluents to enable the active ingredient suitable for the method of administration.
  • active ingredient e.g., a compound of any one of formulas (l)-(lll)
  • excipients and diluents to enable the active ingredient suitable for the method of administration.
  • the pharmaceutical composition of the present disclosure includes pharmaceutically acceptable components that are compatible with a compound described herein (e.g., a compound of any one of formulas (l)-(lll)).
  • a pharmaceutically acceptable carrier refers to an excipient or diluent in a pharmaceutical composition.
  • a pharmaceutically acceptable carrier may be a vehicle capable of suspending or dissolving the active compound (e.g., a compound of any one of formulas (l)-(lll)).
  • the pharmaceutically acceptable carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient.
  • the pharmaceutically acceptable carrier must provide adequate pharmaceutical stability to a compound described herein.
  • the nature of the carrier differs with the mode of administration. For example, for oral administration, a solid carrier is preferred; for intravenous administration, an aqueous solution carrier (e.g., WFI, and/or a buffered solution) is generally used.
  • pharmaceutically acceptable salt represents salts of the compounds described herein (e.g., compounds of any one of formulas (l)-(lll)) that are, within the scope of sound medical judgment, suitable for use in methods described herein without undue toxicity, irritation, and/or allergic response.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Pharmaceutical Salts:
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.
  • FIGS. 1 A and 1 B are fluorescent images showing the binding of the secondary anti-rabbit lgG1 (red fluorescence) to rabbit anti-Rha antibodies, which in turn are bound to A. fumigatus hyphae treated with Compound 1 (FIG. 1 A) or CD101 acetate (FIG. 1 B).
  • FIGs. 2A and 2B are graphs, and corresponding tables, showing Compound 1 concentrations as measured in frozen plasma collected from mice treated with 3 mg/kg or 10 mg/kg Compound 1 IV (Fig. 2A) or mice treated with 3 mg/kg or 10 mg/kg Compound 1 IP (Fig. 2B).
  • FIGs. 3A and 3B are graphs, and corresponding tables, showing Compound 1 concentrations as measured in lung homogenates prepared from mice treated with 3 mg/kg or 10 mg/kg Compound 1 IV (Fig. 3A) or mice treated with 3 mg/kg or 10 mg/kg Compound 1 IP (Fig. 3B).
  • FIGs. 4A and 4B are tables summarzing Compound 1 concentrations as measured in lung homogenates or plasma isolated from mice treated with 3 mg/kg or 10 mg/kg Compound 1 IV (Fig. 4A) or mice treated with 3 mg/kg or 10 mg/kg Compound 1 IP (Fig. 4B).
  • the disclosure features compounds, compositions, and methods for the treatment of fungal infections (e.g., fungal infections caused by Candida spp. or Aspergillus spp.J.
  • fungal infections e.g., fungal infections caused by Candida spp. or Aspergillus spp.J.
  • the inventors have found that compounds disclosed herein have increased antifungal activity due to their ability to bind to the fungal cell wall through inhibition of ⁇ -1 ,3-glucan synthase, thereby driving a concentration gradient near the locus of infection.
  • the compounds disclosed herein include a ⁇ -1 ,3-glucan synthase inhibitor covalently conjugated to a monosaccharide or oligosaccharide moiety by way of a linker.
  • the compounds disclosed herein include a ⁇ -1 ,3-glucan synthase inhibitor covalently conjugated to at least one monosaccharide or oligosaccharide moiety by way of a linker, ⁇ -1 ,3-glucan synthase is a glucosyltransferase enzyme involved in the generation of ⁇ -glucan in the cell wall of fungi. Inhibition of this enzyme results in disrupting the integrity of the fungal cell well and serves as a pharmacological target for antifungal drugs.
  • the monosaccharide or oligosaccharide moiety in the compounds described herein serve as a gradient against which immune cells chemotax to the site of fungal infection and/or growth.
  • ⁇ -1 ,3-glucan synthase inhibitor may be synthesized using available chemical synthesis techniques in the art.
  • available functional groups in the ⁇ -1 ,3-glucan synthase inhibitor, the linker, and the monosaccharide or oligosaccharide moiety e.g., amines, carboxylic acids, and/or hydroxyl groups, may be used in making the compounds described herein.
  • the nitrogen atom in an amine group of the ⁇ -1 ,3-glucan synthase inhibitor may form an amide bond with the carbon in a carboxylic acid group of the linker.
  • a molecule may be derivatized using conventional chemical synthesis techniques that are well known in the art.
  • the compounds described herein contain one or more chiral centers.
  • the compounds include each of the isolated stereoisomeric forms as well as mixtures of stereoisomers in varying degrees of chiral purity, including racemic mixtures. It also encompasses the various diastereomers, enantiomers, and tautomers that can be formed.
  • R 1 is a lipophilic moiety
  • R 2 is hydrogen or methyl
  • each of R 3 and R 4 is, independently, hydrogen or hydroxyl
  • R 5 is hydrogen, methyl, or optionally substituted C1-C5 alkamino
  • R 6 is hydrogen, hydroxyl, methyl, or amino
  • R 7 is hydrogen or hydroxyl
  • R 8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(O(CH2)a)bR’, -(NH(CH2)a)bR’, -(S(CH2)a)bR’, -(O(CH2)a)bN(R’)2, -(NH(CH2)a)bN(R’)2, -(S(CH2)a)bN(R’)2, -(O(CH2)a)bN + (R’)3, -(NH(CH2)a)bN + (R’)3, -(S(CH2)a)bN + (R’)3, -(S(CH2)
  • R 9 is hydrogen, hydroxyl, or amino; n is 0 or 1; d is 1, 2, 3, 4, 5, or 6; each of a and b is, independently, an integer from 1 to 5; each R’ is, independently, hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-10 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl
  • the disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (1-1 ):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , n, d, L, and E are as described above.
  • the disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (I-2):
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH 2 (CO)NH 2
  • R 6 is hydrogen or methyl
  • R 8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(0(CH2) a )bR',
  • each of a and b is, independently, an integer from 1 to 5; d is 1 , 2, 3, 4, 5, or 6; each R’ is, independently, hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-10 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1-C10 heteroaryl; L is a linker; and each
  • R 8 is -(O(CH2)a)bR’, -(NH(CH2)a)bR’, -(S(CH2)a)bR’, -(O(CH2)a)bN(R’)2, -(NH(CH2)a)bN(R’)2, -(S(CH2)a)bN(R’)2, -(O(CH2)a)bOR’, -(NH(CH2)a)bOR’,
  • R 8 is -OCH2CH2N(R’)2, -NHCH2CH2N(R’)2, -(NHCH2CH2)2N(R’)2, -NHCH2CH2OR’, -(NHCH2CH2)2OR’, -OCH2CH2NHCH2CH2N(R’)2,
  • R 1 is a lipophilic moiety
  • R 2 is hydrogen or methyl
  • each of R 3 and R 4 is, independently, hydrogen or hydroxyl
  • R 6 is hydrogen, hydroxyl, methyl, or amino
  • R 7 is hydrogen or hydroxyl
  • R 8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(O(CH 2 ) a ) b R’, -(NH(CH 2 ) a ) b R’,
  • R 9 is hydrogen, hydroxyl, or amino; n is 0 or 1 ; each of a and b is, independently, an integer from 1 to 5; d is 1 , 2, 3, 4, 5, or 6; each R' is, independently, hydrogen, optionally substituted C1 -C10 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyl, optionally substituted C3
  • the disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (11-1 ):
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , n, d, L, and E are as defined above.
  • the disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (II-2):
  • R 1 is a lipophilic moiety
  • R 6 is hydrogen or methyl
  • R 8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(O(CH2)a)bR’, -(NH(CH2)a)bR’, -(S(CH2)a)bR’, -(O(CH2)a)bN(R’)2, -(NH(CH2)a)bN(R’’)2, -(S(CH2)a)bN(R’)2, -(O(CH2)a)bN + (R’)3, -(NH(CH2)a)bN + (R’)3, -(S(CH2)a)bN + (R’)3, -(O(CH2)a)bOR’, -(NH(CH2)a)bOR’, -(S(CH2)a)bOR’, -(OCH2CH2)a(NHCH2CH2)
  • each of a and b is, independently, an integer from 1 to 5; d is 1, 2, 3, 4, 5, or 6; each R’ is, independently, hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-10 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C
  • R 8 is -(O(CH2)a)bR’, -(NH(CH2)a)bR’, -(S(CH2)a)bR’, -(O(CH2)a)bN(R’)2, -(NH(CH2)a)bN(R’’)2, -(S(CH2)a)bN(R’)2, -(O(CH2)a)bOR’, -(NH(CH2)a)bOR’,
  • each R’ is, independently, hydrogen or optionally substituted C1-C5 alkyl; and each R’’ is, independently, hydrogen, or C1-C10 alkyl, or a
  • R 8 is -OCH2CH2N(R’)2,
  • each R’ is, independently, hydrogen or methyl; each R’’ is,
  • R 8 is
  • R 8 is -(O(CH2)a)bN + (R’)3, -(NH(CH2)a)bN + (R’)3, -(S(CH2)a)bN + (R’)3,
  • R 8 is -OCH2CH2N + (R’)3, -(OCH2CH2)2N + (R’)3, -NHCH2CH2N + (R’)3, or -(NHCH2CH2)2N + (R’)3; each R’ is, independently, hydrogen or methyl, or a pharmaceutically acceptable salt thereof.
  • R 8 is
  • R’ is
  • each R A is, independently, hydrogen or optionally substituted C1-C10 alkyl.
  • the disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (III):
  • R 1 is a lipophilic moiety
  • R 2 is hydrogen or methyl
  • each of R 3 and R 4 is, independently, hydrogen or hydroxyl
  • R 5 is hydrogen, methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen, hydroxyl, methyl, or amino
  • R 7 is hydrogen or hydroxyl
  • R 9 is hydrogen, hydroxyl, or amino
  • X is O or NH
  • n is 0 or 1
  • d is 1 , 2, 3, 4, 5, or 6
  • L is a linker
  • each E is, independently, a monosaccharide or oligosaccharide moiety.
  • the disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (III-1 ):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , X, n, d, L, and E are as defined above.
  • the disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (111-2):
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH 2 (CO)NH 2
  • R 6 is hydrogen or methyl
  • X is O or NH
  • d is 1 , 2, 3, 4, 5, or 6
  • L is a linker
  • each E is, independently, a monosaccharide or oligosaccharide moiety.
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • R 1 is a lipophilic moiety
  • R 6 is hydrogen or methyl
  • d is 1 , 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • R 1 is a lipophilic moiety
  • R 5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2
  • R 6 is hydrogen or methyl
  • d is 1, 2, 3, or 4
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • R 1 is each of X and Y is, independently, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene, or is absent;
  • Z is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted heteroalkenyl
  • X, Y, and Z together, form wherein R B is an optionally substituted C1-C10 alkyl, or a pharmaceutically acceptable salt thereof.
  • X, Y, and Z together, form wherein R B is optionally substituted C1- C10 alkyl, or a pharmaceutically acceptable salt thereof.
  • R B is optionally substituted C1- C10 alkyl, or a pharmaceutically acceptable salt thereof.
  • R B is optionally substituted C1-C8 alkyl, or a pharmaceutically acceptable salt thereof.
  • R 5 is methyl, -CH2CH2NH2, or -CH 2 (CO)NH 2 ;
  • R 6 is hydrogen or methyl;
  • R B is optionally substituted C1 -C6 alkyl;
  • d is 1 , 2, 3, or 4;
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • R 6 is hydrogen or methyl; R B is optionally substituted C1 -C6 alkyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the disclosure also provides a compound of any one of the following formulas:
  • each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
  • the portion in a compound described herein indicates that one or more (e.g., 1 , 2, 3, 4; 5, or 6; 1 -2, 1 -3, 1 -4, 1 -5, or 1 -6) monosaccharide or oligosaccharide moieties may be attached to L at any atom(s) within L.
  • E represents a monosaccharide or oligosaccharide moiety.
  • the portion is not to be construed as a single bond between one or more monosaccharide or oligosaccharide moieties and an atom in L. In some embodiments, when d is 1 , one monosaccharide or oligosaccharide moiety may be attached to an atom in L.
  • a linker in a compound described herein may be a branched structure.
  • a linker in a compound described herein may be a multivalent structure, e.g., divalent, trivalent, tetravalent, pentavalent, hexavalent, or heptavalent structure, containing two, three, four, five, six, or seven arms, respectively.
  • one arm may be attached to a ⁇ -1 ,3-glucan synthase inhibitor and the remaining arm(s) (e.g., the remaining one, two, three, four, five, or six arms) may each be attached to a monosaccaride or oligosaccharide moiety.
  • L in the portion may have multiple arms attached to multiple monosaccharide or oligosaccharide moieties.
  • ⁇ -1 ,3-glucan synthase inhibitors that can be functionalized to covalently conjugate to at least one monosaccharide or oligosaccharide moiety by way of a linker are shown below.
  • the disclosure also features a compound selected from
  • the pharmaceutically acceptable salt of any one of Compounds 1 -3, 4a, 4b, 5a-5c, and 6 is a formate salt. In some embodiments, the pharmaceutically acceptable salt of any one of Compounds 1 -3, 4a, 4b, 5a-5c, and 6 is an acetate salt.
  • the compound is Compound 1 ,
  • the pharmaceutically acceptable salt of Compound 1 is a formate salt. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is an acetate salt. In some embodiments, the compound is Compound 4a
  • the pharmaceutically acceptable salt of Compound 4a is a formate salt. In some embodiments, the pharmaceutically acceptable salt of Compound 4a is an acetate salt.
  • a linker refers to a linkage or connection between two or more components in a compound (e.g., between the ⁇ -1 ,3-glucan synthase inhibitor and the monosaccharide or oligosaccharide moiety in a compound described herein (e.g., a compound of any one of formulas (l)-(lll)).
  • a linker in a compound described herein e.g., L
  • L may be a branched structure.
  • a linker in a compound described herein may be a multivalent structure, e.g., divalent, trivalent, tetravalent, pentavalent, hexavalent, or heptavalent structure, containing two, three, four, five, six, or seven arms, respectively, in which each arm is covalently conjugated to either a ⁇ -1 ,3-glucan synthase inhibitor or a monosaccharide or oligosaccharide moiety.
  • a divalent linker L in the compound of any one of formulas (l)-(lll) is described by formula (L-l):
  • I 1 is a bond attached to the ⁇ -1 ,3-glucan synthase inhibitor
  • I 2 is a bond attached to a monosaccharide or oligosaccharide moiety (E);
  • each of U 1 , U 2 , U 3 , and U 4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20
  • R' is H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C5-C15 heteroaryl ; and each of f, g, h, i, j, k, I, m, and n is, independently,
  • a divalent linker is described by formula (L-11 ):
  • I 1 is a bond attached to the ⁇ -1 ,3-glucan synthase inhibitor
  • I 2 is a bond attached to a monosaccharide or oligosaccharide moiety (E);
  • a divalent linker is described by formula (L-I2), (L-I3), or (L-I4):
  • I 1 is a bond attached to the ⁇ -1 ,3-glucan synthase inhibitor
  • I 2 is a bond attached to a monosaccharide or oligosaccharide moiety (E);
  • a divalent linker is
  • a trivalent linker L in the compound of any one of formulas (I)-(III) is described by formula (L-II):
  • L A is described by formula G A1 -(Z A1 ) g1 -(Y A1 ) h1 -(Z A2 ) i1 -(Y A2 ) j1 -(Z A3 ) k1 -(Y A3 ) l1 -(Z A4 ) m1 -(Y A4 ) n1 - (Z A5 )o1-G A2 ;
  • L B is described by formula G B1 -(Z B1 )g2-(Y B1 )h2-(Z B2 )i2-(Y B2 )j2-(Z B3 )k2-(Y B3 )l2-(Z B4 )m2-(Y B4 )n2- (Z B5 )o2-G B2 ;
  • L C is described by formula G C1 -(Z C1 )g3-(Y C1 )h3-(Z C2 )i3-(Y C2 )j3-(Z
  • R i is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3- C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C5-C15 heteroaryl ; and each of g1 , hi , i1 , j1 , k1 , 11 , ml ,
  • each of Y A1 , Y A2 , Y A3 , Y M , Y B1 , Y B2 , Y B3 , Y B4 , Y C1 , Y C2 , Y C3 , and Y C4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C1 5 arylene, or optionally substituted C1 -C15 heteroarylene; each of Z A1 , Z A2 , Y A3 , Y M , Y B1
  • a trivalent linker is
  • each of p, q, r, s, and t is, independently, an integer from 1 to 10.
  • a trivalent linker is
  • each of p, q, r, s, t, and u is, independently, an integer from 1 to 10.
  • a linker in a compound described herein may also have a tetravalent, pentavalent, hexavalent, or heptavalent structure, containing four, five, six, or seven arms, respectively.
  • the linker has four or more (e.g., five, six, or seven) arms, one arm may be attached to a ⁇ -1 ,3-glucan synthase inhibitor and the remaining arms (e.g., remaining three, four, or five arms) may each be attached to a monosaccharide or oligosaccharide moiety.
  • a linker L in the compound of any one of formulas (I)-(III) is described by formula (L-III):
  • L A is described by formula G A1 -(Z A1 ) g1 -(Y A1 ) h1 -(Z A2 ) i1 -(Y A2 ) j1 -(Z A3 ) k1 -(Y A3 ) l1 -(Z A4 ) m1 -(Y A4 ) n1 - (Z A5 )o1-G A2 ;
  • L B is described by formula G B1 -(Z B1 )g2-(Y B1 )h2-(Z B2 )i2-(Y B2 )j2-(Z B3 )k2-(Y B3 )l2-(Z B4 )m2-(Y B4 )n2- (Z B5 )o2-G B2 ;
  • L C is described by formula G C1 -(Z C1 )g3-(Y C1 )h3-(Z C2 )i3-(Y C2 )j3-(Z
  • each of Y A1 , Y A2 , Y A3 , Y A4 , Y B1 , Y B2 , Y B3 , Y B4 , Y C1 , Y C2 , Y C3 , Y C4 , Y D1 , Y D2 , Y D3 , Y D4 , Y E1 , Y E2 , Y E3 , Y E4 , Y F1 , Y F2 , Y F3 , Y F4 , Y G1 , Y G2 , Y G3 , and Y G4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20
  • heteroalkylene optionally substituted C2-C20 alkenylene, optionally substituted C2-C20
  • a multivalent linker in a compound described herein is
  • each of p, q, r, s, t, u, v, w, x, y, and z is, independently, an integer from 1 to 10.
  • a multivalent linker in a compound described herein is
  • each of p, q, r, s, and t is, independently, an integer from 1 to 10.
  • a linker L in the compound of any one of formulas (I)-(III) is described by formula (L-IV):
  • L A is described by formula G A1 -(Z A1 )g1-(Y A1 )h1-(Z A2 )i1-(Y A2 )j1-(Z A3 )k1-(Y A3 )l1-(Z A4 )m1-(Y A4 )n1- (Z A5 )o1-G A2 ;
  • L B is described by formula G B1 -(Z B1 )g2-(Y B1 )h2-(Z B2 )i2-(Y B2 )j2-(Z B3 )k2-(Y B3 )l2-(Z B4 )m2-(Y B4 )n2- (Z B5 )o2-G B2 ;
  • L C is described by formula G C1 -(Z C1 )g3-(Y C1 )h3-(Z C2 )i3-(Y C2 )j3-(Z C3 )k3-(Y C3 )l3-
  • a multivalent linker in a compound described herein is
  • each of p, q, r, s, and t is, independently, an integer from 1 to 10.
  • a linker provides space, rigidity, and/or flexibility between the ⁇ -1 ,3- glucan synthase inhibitor and the monosaccharide or oligosaccharide moiety.
  • a linker may be a bond, e.g., a covalent bond, e.g., an amide bond, a disulfide bond, a C-N bond, a N- N bond, or any kind of bond created from a chemical reaction, e.g., chemical conjugation.
  • a linker includes no more than 250 atoms (e.g., 1-2, 1-4, 1-6, 1-8, 1-10, 1-12, 1-14, 1- 16, 1-18, 1-20, 1-25, 1-30, 1-35, 1-40, 1-45, 1-50, 1-55, 1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95, 1-100, 1-110, 1-120, 1-130, 1-140, 1-150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-210, 1-220, 1-230, 1- 240, or 1-250 atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 atom(s)).
  • a linker includes no more than 250 non- hydrogen atoms (e.g., 1-2, 1-4, 1-6, 1-8, 1-10, 1-12, 1-14, 1-16, 1-18, 1-20, 1-25, 1-30, 1-35, 1-40, 1- 45, 1 -50, 1 -55, 1 -60, 1 -65, 1 -70, 1 -75, 1 -80, 1 -85, 1 -90, 1 -95, 1 -100, 1-110, 1-120, 1 -130, 1 -140, 1 - 150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-210, 1-220, 1-230, 1-240, or 1-250 non-hydrogen atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26,
  • the backbone of a linker includes no more than 250 atoms (e.g., 1-2, 1-4, 1-6, 1-8, 1-10, 1-12, 1-14, 1-16, 1-18, 1-20, 1-25, 1-30, 1-35, 1-40, 1-45, 1-50, 1-55, 1- 60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95, 1-100, 1-110, 1-120, 1-130, 1-140, 1-150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-210, 1-220, 1-230, 1-240, or 1-250 atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 atom(s)).
  • the "backbone" of a linker refers to the atoms in the linker that together form the shortest path from one part of the compound to another part of the compound.
  • the atoms in the backbone of the linker are directly involved in linking one part of the compound to another part of the compound.
  • hydrogen atoms attached to carbons in the backbone of the linker are not considered as directly involved in linking one part of the compound to another part of the compound.
  • a divalent linker may contain two carboxylic acids, in which the first carboxylic acid may form a covalent linkage with one component (e.g., a ⁇ -1 ,3-glucan synthase inhibitor) in the compound and the second carboxylic acid may form a covalent linkage with another component (e.g., a monosaccharide or oligosaccharide moiety) in the compound.
  • one component e.g., a ⁇ -1 ,3-glucan synthase inhibitor
  • another component e.g., a monosaccharide or oligosaccharide moiety
  • one end of the linker may form a covalent linkage with the ⁇ -1 ,3-glucan synthase inhibitor in the compound and the other end of the linker may form a covalent linkage (e.g., a C-0 bond, a C-S bond, or a C-N bond) with the monosaccharide or oligosaccharide moiety.
  • a covalent linkage e.g., a C-0 bond, a C-S bond, or a C-N bond
  • dicarboxylic acid molecules may be used as linkers (e.g., a dicarboxylic acid linker).
  • linkers e.g., a dicarboxylic acid linker
  • the first carboxylic acid in a dicarboxylic acid molecule may form a covalent linkage with the ⁇ -1 ,3-glucan synthase inhibitor and the second carboxylic acid may form a covalent linkage with the monosaccharide or oligosaccharide moiety.
  • dicarboxylic acids molecules that may be used to serve as linkers in compounds disclosed herein (e.g., compounds of formulas (l)-(lll)) include, but are not limited to,
  • dicarboxylic acid molecules such as the ones described herein, may be further functionalized to contain one or more additional functional groups, which may be used to conjugate to one or more monosaccharide or oligosaccharide moieties.
  • a molecule containing one or more sulfonic acid groups may be used to form a linker, in which the sulfonic acid group may form a sulfonamide linkage with a nitrogen in a ⁇ -1 ,3-glucan synthase inhibitor .
  • a molecule containing one or more isocyanate groups may be used to form a linker, in which the isocyanate group may form a urea linkage with a nitrogen in a ⁇ -1 ,3-glucan synthase inhibitor.
  • a molecule containing one or more haloalkyl groups may be used to form a linker, in which the haloalkyl group may form a covalent linkage, e.g., C-N and C-0 linkages, with a ⁇ -1 ,3-glucan synthase inhibitor.
  • a linker may include a synthetic group derived from, e.g., a synthetic polymer (e.g., a polyethylene glycol (PEG) polymer).
  • a linker may include one or more amino acid residues.
  • a linker may be an amino acid sequence (e.g., a 1 -25 amino acid, 1 -10 amino acid, 1 -9 amino acid, 1 -8 amino acid, 1 -7 amino acid, 1 -6 amino acid, 1 -5 amino acid, 1 -4 amino acid, 1 -3 amino acid, or 1 -2 amino acid sequence).
  • a linker may include one or more optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene (e.g., a PEG unit), optionally substituted C2-C20 alkenylene (e.g., C2 alkenylene), optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene (e.g., cyclopropylene, cyclobutylene), optionally substituted C3-C20
  • heterocycloalkylene optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene (e.g., C6 arylene), optionally substituted C1 -C15 heteroarylene (e.g., imidazole, pyridine), O, S, NR' (R' is H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocyclo
  • L in a compound of any one of formulas (l)-(lll) may have a formula of (L-l), (L-ll), (L-lll), or (L-IV).
  • Covalent conjugation of two or more components in a compound using a linker may be accomplished using well-known organic chemical synthesis techniques and methods.
  • Complementary functional groups on two components may react with each other to form a covalent bond.
  • Examples of complementary reactive functional groups include, but are not limited to, e.g., amine and activated carboxylic acid, thiol and maleimide, activated sulfonic acid and amine, isocyanate and amine, azide and alkyne, and alkene and tetrazine.
  • Other examples of functional groups capable of reacting with amino groups include, e.g., alkylating and acylating agents.
  • amino-reactive acylating groups include, e.g., (i) an isocyanate and an isothiocyanate; (ii) a sulfonyl chloride; (iii) an acid halide; (iv) an active ester, e.g., a nitrophenylester or N-hydroxysuccinimidyl ester; (v) an acid anhydride, e.g., a mixed, symmetrical, or N- carboxyanhydride; (vi) an acylazide; and (vii) an imidoester. Aldehydes and ketones may be reacted with amines to form Schiff's bases, which may be stabilized through reductive amination.
  • a monosaccharide moiety is a molecular moiety that has one optionally substituted C6-C9 (exclusive of the substituents) monosaccharide residue.
  • An oligosaccharide moiety is a molecular moiety that includes at least two, e.g., 2-150 (e.g., 2-149, 2-140, 2-130, 2-120, 2-1 10, 2-100, 2-90,
  • an oligosaccharide moiety includes 2-18 optionally substituted C6-C9 (exclusive of the substituents) monosaccharide residues. In some embodiments, an oligosaccharide moiety includes 2-12 optionally substituted C6-C9 (exclusive of the substituents) monosaccharide residues.
  • an oligosaccharide moiety has a molecule weight that does not exceed 30 kDa, 25 kDa, 24 kDa, 23 kDa, 22 kDa, 21 kDa, 20 kDa, 19 kDa, 18 kDa, 17 kDa, 16 kDa, 1 5 kDa, 14 kDa, 13 kDa, 12 kDa, 1 1 kDa, 10 kDa, 9 kDa, 8 kDa, 7 kDa, 6 kDa, 5 kDa or 3 kDa.
  • a monosaccharide moiety has an optionally substituted C6-C9 monosaccharide residue selected from glucose (Glc), galactose (Gal), mannose (Man), allose (All), altrose (Alt), gulose (Gul), idose (Ido), talose (Tal), fucose (Fuc), rhamnose (Rha; also called
  • a monosaccharide moiety has an optionally substituted C6-C9 monosaccharide residue selected from Rha, Gal, Glc, GlcA (Glucuronic acid), GlcNAc, GalNAc, GlcN(Gc) (N-Glycolyl-Glucosamine), Neu5Ac, Neu5Gc (N-Glycolyl-neuraminic acid), Fuc, Man, -htePOsMan (mannose phosphate), 6-H2PO3GIC (glucose phosphate), Mur (muramoyl), Mur-L-Ala-D-i- Gln-Lys, (Mur)-3-0-GlcNAc, sulfate-galactose (Su-Gal), disulfate-galactose (Su2-Gal), sulfate-glucose (Su-Glc), sulfate-GlcNAc (Su-Glc
  • Rhamnose occurs in nature in its L-form, thus, rhamnose is also referred to as
  • L-rhamnose or L-Rha may be in a form (also called a-Rha or a-L-Rha) or ⁇ form (also called ⁇ -Rha or ⁇ -L-Rha).
  • Thia-rhamnose has -SH attached at the anomeric carbon instead of -OH.
  • Thia-rhamnose is also referred to as thia-Rha or thia-L-Rha.
  • Thia-rhamnose may be in a form (also called thia-a-Rha or thia-a-L-Rha) or in ⁇ form (also called thia ⁇ -Rha or thia ⁇ -L-Rha).
  • the structures of Rha, a-Rha, and ⁇ -Rha are shown below.
  • the monosaccharide moiety is an optionally substituted a-Rha or an optionally substituted thia-a-Rha.
  • a compounds described herein may contain a-Rha.
  • each of the optionally substituted C6-C9 monosaccharide residues may, independently, joined to an adjacent monosaccharide residue through an O-glycosidic, S-glycosidic, N-glycosidic linkage, or C-glycosidic.
  • the binding at an O-glycosidic, S- glycosidic, N-glycosidic, or C-glycosidic linkage may be an a- or ⁇ -configuration, for example, through 1 ,2-, 1 ,3-, 1 ,4-, 1 ,6-, 2,3-, 2,6-, or 2,8-linkage, or a linkage such as 3-0, for example, a1 -2, a1 -3, a1 -4, ⁇ 1 -6, ⁇ 2-3, ⁇ 2-6, ⁇ 2-8, ⁇ 1 -2, ⁇ 1 -3, ⁇ 1 -4, or ⁇ 1 -6.
  • each of the optionally substituted C6-C9 monosaccharide residues is, independently, glucose (Glc), galactose (Gal), mannose (Man), allose (All), altrose (alt), gulose (Gul), idose (ido), talose (Tal), fucose (Fuc), rhamnose (Rha), quinovose (Qui), 2-deoxyglucose (2-dGlc), glucosamine (GlcN), galactosamine (GaIN), mannosamine (ManN), fucosamine (FucN), quinovosamine (QuiN), N-Acetyl-glucosamine (GlcNAc); N-Acetyl-galactosamine (GalNAc), N-Acetyl-mannosamine (ManNAc), N-acetyl-fucosamine (FucNAc), N-acetyl-quinovosamine (QuiNAc
  • each of the optionally substituted C6-C9 monosaccharide residues is, independently, Rha, Gal, Glc, GlcA (Glucuronic acid), GlcNAc, GalNAc, GlcN(Gc) (N-Glycolyl-Glucosamine), Neu5Ac, Neu5Gc (N-Glycolyl-neuraminic acid), Fuc, Man, -FtePCbMan (mannose phosphate), 6-H2PO3GIC (glucose phosphate), Mur
  • an oligosaccharide moiety may be straight or branched.
  • the optionally substituted monosaccharide residue(s) i.e., at least one monosaccharide residue
  • the optionally substituted monosaccharide residue(s) is substituted with one or more, such as 1 -3, substituents independently selected from sulfate, phosphate, methyl, acetyl, naturally amino acids, and non-naturally occurring amino acids.
  • the optionally substituted monosaccharide residue(s) i.e., at least one monosaccharide residue
  • the optionally substituted monosaccharide residue(s) is substituted with one or more, such as 1 -3, substituents, wherein each substituent is, independently, selected from sulfate, phosphate, methyl, acetyl.
  • the optionally substituted monosaccharide residue(s) i.e., at least one monosaccharide residue
  • the monosaccharide residue or oligosaccharide moiety is substituted with one or more, such as 1 -3, substituents, wherein each substituent is, independently, selected from naturally occurring amino acids and non-naturally occurring amino acids.
  • the linkage may be, for example, a a1 -0 linkage.
  • the linkage may be through a hydroxyl group, for example, a 2-0, 3-0 , 4-0, or 6-0 linkage, such as 3-0-Su-Gal, (6-0-Su)Gal, (6-0-Su)Glc, 6-0-Su-GlcNAc, (6-0- Su)GalNAc, 3,6-0-Su2-Gal, 3,4-0-Su2-Gal, or 4-0-Su-Gal.
  • a 2-0, 3-0 , 4-0, or 6-0 linkage such as 3-0-Su-Gal, (6-0-Su)Gal, (6-0-Su)Glc, 6-0-Su-GlcNAc, (6-0- Su)GalNAc, 3,6-0-Su2-Gal, 3,4-0-Su2-Gal, or 4-0-Su-Gal.
  • Naturally occurring amino acids include Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, He, Leu,
  • a non-naturally occurring amino acid is an amino acid that is not naturally produced or found in a mammal.
  • non-naturally occurring amino acids include D-amino acids; an amino acid having an acetylaminomethyl group attached to a sulfur atom of a cysteine; a pegylated amino acid; the omega amino acids of the formula NH2(CH2)nCOOH where n is 2-6, neutral nonpolar amino acids, such as sarcosine, t-butyl alanine, t-butyl glycine, N- methyl isoleucine, and norleucine; oxymethionine; phenylglycine; citrulline; methionine sulfoxide; cysteic acid; ornithine; diaminobutyric acid; and hydroxyproline.
  • amino acids are a- aminobutyric acid, ⁇ -amino-a-methylbutyrate, aminocyclopropane-carboxylate, aminoisobutyric acid, aminonorbornyl-carboxylate, L-cyclohexylalanine, cyclopentylalanine, L-N-methylleucine,
  • L-N-methylmethionine L-N-methylnorvaline, L-N-methylphenylalanine, L-N-methylproline,
  • L-N-methylserine L-N-methyltryptophan, D-ornithine, L-N-methylethylglycine, L-norleucine, a-methyl- aminoisobutyrate, a-methylcyclohexylalanine, D-a-methylalanine, D-a-methylarginine,
  • D-a-methylasparagine D-a-methylaspartate, D-a-methylcysteine, D-a-methylglutamine,
  • D-a-methylhistidine D-a-methylisoleucine, D-a-methylleucine, D-a-methyllysine,
  • D-a-methylmethionine D-a-methylornithine, D-a-methylphenylalanine, D-a-methylproline,
  • D-a-methylserine D-N-methylserine, D-a-methylthreonine, D-a-methyltryptophan, D-a-methyltyrosine, D-a-methylvaline, D-N-methylalanine, D-N-methylarginine, D-N-methylasparagine,
  • D-N-methylaspartate D-N-methylcysteine, D-N-methylglutamine, D-N-methylglutamate,
  • D-N-methylhistidine D-N-methylisoleucine, D-N-methylleucine, D-N-methyllysine,
  • L-a-methylarginine L-a-methylaspartate, L-a-methylcysteine, L-a-methylglutamine,
  • L-a-methylhistidine L-a-methylisoleucine, L-a-methylleucine, L-a-methylmethionine,
  • L-a-methylnorvaline L-a-methylphenylalanine, L-a-methylserine, L-a-methyltryptophan,
  • L-a-methylvaline N-(N-(2,2-diphenylethyl) carbamylmethylglycine, 1 -carboxy-1 -(2,2-diphenyl- ethylamino) cyclopropane, 4-hydroxyproline, ornithine, 2-aminobenzoyl (anthraniloyl),
  • L-N-methylglutamine L-N-methylglutamic acid, L-N-methylhistidine, L-N-methylisoleucine,
  • L-N-methyllysine L-N-methylnorleucine, L-N-methylornithine, L-N-methylthreonine,
  • N-(3-indolylyethyl)glycine N-methyl-Y-aminobutyrate, D-N-methylmethionine,
  • N-(p-hydroxyphenyl)glycine N-(thiomethyl)glycine, penicillamine, L-a-methylalanine,
  • L-a-methylasparagine L-a-methyl-t-butylglycine, L-methylethylglycine, L-a-methylglutamate,
  • L-a-methylhomophenylalanine N-(2-methylthioethyl)glycine, L-a-methyllysine, L-a-methylnorleucine, L-a-methylornithine, L-a-methylproline, L-a-methylthreonine, L-a-methyltyrosine, L-N-methyl- homophenylalanine, N-(N-(3,3-diphenylpropyl) carbamylmethylglycine, L-pyroglutamic acid,
  • D-pyroglutamic acid O-methyl-L-serine, O-methyl-L-homoserine, 5-hydroxylysine,
  • amino acid residues may be charged or polar.
  • Charged amino acids include alanine, lysine, aspartic acid, or glutamic acid, or non-naturally occurring analogs thereof.
  • Polar amino acids include glutamine, asparagine, histidine, serine, threonine, tyrosine, methionine, or tryptophan, or non-naturally occurring analogs thereof.
  • non-natural amino acids that may be included in a compound described herein (e.g., a compound of any one of formulas (l)-(lll)), for example, in the linker portion of the compound, include, but are not limited to, D-Ser, D-Pro, D-Leu, D-Nle (D-norleucine), D-Thr, D-Val, L-Abu (L-2-aminobutyric acid), 3-(2H-tetrazol-5-yl)alanine, 3-aminoalanine, piperazine-2- carboxylic acid, 2,4-diaminobutyric acid, 3-hydroxyproline, 2-amino-4-phenylbutyric acid,
  • the optionally substituted monosaccharide residue(s) i.e., at least one monosaccharide residue
  • the optionally substituted monosaccharide residue(s) i.e., at least one monosaccharide residue in the monosaccharide or oligosaccharide moiety is an optionally substituted C6 monosaccharide residue.
  • the optionally substituted C6 monosaccharide residue is optionally substituted Gal or optionally substituted Glc.
  • the optionally substituted Gal is optionally substituted a1 -3Gal.
  • the optionally substituted Glc is an optionally substituted ⁇ -glucan having 1 -6 Glc moieties.
  • the optionally substituted monosaccharide residue(s) i.e., at least one monosaccharide residue
  • the optionally substituted monosaccharide residue(s) in the monosaccharide or oligosaccharide moiety is an optionally substituted C9 monosaccharide residue, e.g., sialic acid (Sia), Neuraminic acid (Neu), N-Acetyl- neuraminic acid (Neu5Ac), or N-Glycolyl-neuraminic acid (Neu5Gc).
  • the optionally substituted monosaccharide residue(s) may include a hexose residue, e.g., glucose (Glc), galactose (Gal), mannose (Man), allose (All), altrose (alt), gulose (Gul), idose (ido), or talose (Tal).
  • a hexose residue e.g., glucose (Glc), galactose (Gal), mannose (Man), allose (All), altrose (alt), gulose (Gul), idose (ido), or talose (Tal).
  • the optionally substituted monosaccharide residue(s) may include a deoxyhexose residue, e.g., a hexose residue without the hydroxyl group at the 6-position or the 2-position, e.g., fucose (Fuc), rhamnose (Rha), quinovose (Qui), or 2-deoxyglucose (2-dGlc).
  • a deoxyhexose residue e.g., a hexose residue without the hydroxyl group at the 6-position or the 2-position, e.g., fucose (Fuc), rhamnose (Rha), quinovose (Qui), or 2-deoxyglucose (2-dGlc).
  • the optionally substituted monosaccharide residue(s) may also include an aminohexose residue, e.g., a hexose residue with an amino group or an N-acetylated amino group at the 2 -position, e.g., glucosamine (GlcN), galactosamine (GaIN), mannosamine (ManN), fucosamine (FucN), quinovosamine (QuiN), N-Acetyl-glucosamine (GlcNAc), N-Acetyl-galactosamine (GalNAc), N-Acetyl-mannosamine (ManNAc), N-acetyl-fucosamine (FucNAc), or N-acetyl-quinovosamine (QuiNAc).
  • an aminohexose residue e.g., a hexose residue with an amino group or an N-acetylated amino group at the 2 -position
  • the optionally substituted monosaccharide residue(s) may include a uronic acid residue, e.g., a hexose residue with a negatively charged carboxylate at the 6-position, e.g., glucuronic acid (GlcA), galacturonic acid (GalA), mannuronic acid (ManA), or iduronic acid (IdoA).
  • a uronic acid residue e.g., a hexose residue with a negatively charged carboxylate at the 6-position
  • glucuronic acid GlcA
  • GalA galacturonic acid
  • ManA mannuronic acid
  • IdoA iduronic acid
  • the optionally substituted monosaccharide residue(s) may include a sialic acid residue, e.g., a residue of a nine-carbon acidic sugar, e.g., a residue of. Sialic acid (Sia), Neuraminic acid (Neu), N-Acetyl-neuraminic acid (Neu5Ac), or N-Glycolyl-neuraminic acid (Neu5Gc).
  • the optionally substituted monosaccharide residue(s) may include a sugar alcohol, e.g., glucitol (Glc-ol), galactitol (Gal-ol), or mannitol (Man-ol).
  • a sugar alcohol e.g., glucitol (Glc-ol), galactitol (Gal-ol), or mannitol (Man-ol).
  • the optionally substituted monosaccharide residue(s) may include other compounds, e.g., thevetose (The), acofriose (Aco), digitoxose (Dig), cymarose (Cym), abequose (Abe), colitose (Col), tyvelose (Tyv), ascarylose (Asc), paratose (Par), and N-acetyl-muramic acid (MurNAc).
  • the optionally substituted monosaccharide residue(s) i.e., at least one monosaccharide residue
  • the monosaccharide or oligosaccharide moiety is Gal, such as aGal (for example, a1 -3Gal).
  • An aGal epitope i.e., an oligosaccharide moiety that exhibits specific binding to an anti-aGal antibody, may also include a moiety including an a-D-galactopyranoside moiety, Gal, Galal-3Gal, Galal-4Gal, Galal-6Gal, Galal-3Gala1 -3GlcNAc, Galal-3Gala1 -4Gal, Galal-3Gala1 - 4GlcNAc, Galal-3Gala1 -4Glc, Galal-3Gala1 -4[3-deoxy]GlcNAc, Galal-3Gala1 -4[6-deoxy]GlcNAc, Galal-3Gala1 -4Gala1 -3Gal, Galal-3Gala1 -4GlcNAca1 -3Gala1 -4Glc, and any multimers and combinations thereof.
  • Galal-3Gal 1 -4GlcNAc-R (aGal
  • aGal epitopes that may be included in a compound described here (e.g., a compound of any one of formulas (l)-(lll)) are shown below:
  • optional substituents may include 1 -3 substituents, wherein each substituent is, independently, selected from sulfate, phosphate, methyl, acetyl, naturally occurring amino acid residues, and non-naturally occurring amino acid residues on each monosaccharide residue. These may be linked through an O, S, or N, such as a sulfamate linkage through an S.
  • the amino acid residues may be charged or polar and includes isomers thereof.
  • Charged amino acids include alanine, lysine, aspartic acid, or glutamic acid.
  • Polar amino acids include glutamine, asparagine, histidine, serine, threonine, tyrosine, methionine, or tryptophan.
  • the amino acid substituent if present, may be alanine, lysine, serine, glutamine, or i-glutamine, or asparagine.
  • the optionally substituted monosaccharide residue(s) (i.e., at least one monosaccharide residue) in the monosaccharide or oligosaccharide moiety may contain at least one (such as 1 -12) of the following optionally substituted monosaccharide residues: Rha, Gal, Glc, GlcA (Glucuronic acid), GlcNAc, GalNAc, GlcN(Gc) (N-Glycolyl-Glucosamine), Neu5Ac, Neu5Gc
  • the 1 -12 optionally substituted C6-C9 monosaccharide residues in the monosaccharide or oligosaccharide moiety may be ⁇ -glucan residues.
  • the ⁇ -Glucan residue includes 2-12 optionally substituted glucopyranosyl monosaccharide residues, wherein each residue is, independently, joined to an adjacent glucopyranosyl monosaccharide residue via an O-glycosidic, S-glycosidic, N-glycosidic, or C-glycosidic linkage to form ⁇ -linked chains, which retain the ability to bind dectin-1 .
  • Optional substituents may include, e.g., 1 -3 substituents, such as with acetyl, sulfate, phosphate, or a natural or non-natural amino acid.
  • substituents include, e.g., 1 -3 substituents, such as with acetyl, sulfate, phosphate, or a natural or non-natural amino acid.
  • ⁇ -glucan residues include thia ⁇ -glucan residues such as the structures shown below:
  • an oligosaccharide moiety may be a ⁇ -glucan having more than 10 monosaccharides and/or a molecular weight of at least 3 kDa (e.g., 3-30 kDa; e.g., 3-29, 3-25, 3-20, 3-15, 3-10, 3-8, 3-6, 3-5, or 3-4 kDa).
  • an oligosaccharide moiety may be a ⁇ (1 ⁇ 3, 1 ⁇ 6)-glucan, e.g., laminarin, or a ⁇ (1 ⁇ 6)-glucan, e.g., pustulan.
  • a monosaccharide or oligosaccharide moiety directly or indirectly activates an immune cell.
  • the monosaccharide or oligosaccharide moiety directly binds an immune cell.
  • ⁇ -glucans bind dectin-1 receptors. When bound to dectin-1 , which internalizes the ⁇ -glucan, ⁇ -glucan mediates the production of reactive oxygen species (ROS), activation of NF- ⁇ , and subsequent secretion of proinflammatory cytokines.
  • ROS reactive oxygen species
  • the ⁇ - glucan receptor, dectin-1 is predominantly expressed on the surface of cells of
  • the monosaccharide or oligosaccharide moiety indirectly binds an immune cell.
  • the monosaccharide or oligosaccharide moiety may bind to an antibody.
  • the antibody in turn may bind to Fc receptors found on the surface of certain on immune cells including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, and mast cells.
  • aGal or aRha will bind to anti-aGal or anti-aRha antibody, respectively, thereby indirectly activating immune cells.
  • a monosaccharide or oligosaccharide moiety is a ligand to an innate immune receptor.
  • the innate immune receptor is AICL, BDCA2, CLEC2,
  • the monosaccharide or oligosaccharide moiety binds to an antibody.
  • the antibody is a natural antibody.
  • the natural antibody is an antibody of the immunoglobulin M (IgM) isotype. Glycans bound by antibodies contained in intravenous immunoglobulin (IVIG) are studied by Gunten et al., J. Allergy Clin Immunol.
  • a monosaccharide or oligosaccharide moiety in a compound described herein may be any one of the glycans listed in Tables I and E1 of Gunten et al. Examples of glycans studied by Gunten et al. are shown in Table 2A. Anti-carbohydrate antibodies found in normal sera have been studied by Huflejt et al., Molecular Immunology 46:3037-3049, 2009, using a library of glycans shown in Table 2B.
  • Gc glycolyl
  • GIcA glucuronic acid
  • Mur muramoyi
  • OS oligosaccharide
  • P phosphate
  • Ser. Sia Neu5Ac
  • Parameter that describe properties of immunoprofiles of carbohydrate-binding antibodies are median and median absolute deviation.
  • a low median indicates that most donors show low intensities of antibodies bound to the given glycan, while a large median suggests that there is a significant number of donors with large antibody binding intensities to the given glycan.
  • Any of the glycan moieties in Tables 2A and 2B may be used as the monosaccharide or oligosaccharide moiety herein, such as a glycan moiety with a relatively larger median.
  • a compounds described herein may contain one or more monosaccharide or oligosaccharide moieties having the structures shown below:
  • Methods of the invention include, e.g., methods of protecting against or treating a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.) in a subject and methods of stabilizing or inhibiting the growth of fungi, or killing fungi.
  • a method of treating a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.) in a subject includes administering to the subject a compound described herein (e.g., a compound of any one of formulas (l)-(lll)) or a pharmaceutical composition thereof.
  • a method of stabilizing or inhibiting the growth of fungi, or killing fungi includes contacting the fungi or a site susceptible to fungal growth with a compound described herein (e.g., a compound of any one of formulas (l)-(lll)) or a pharmaceutical composition thereof).
  • a compound described herein e.g., a compound of any one of formulas (l)-(lll)
  • a pharmaceutical composition thereof e.g., a compound of any one of formulas (l)-(lll)
  • a compound described herein e.g., a compound of any one of formulas (l)-(lll)
  • a pharmaceutical composition thereof may be administered to the subject intravenously, subcutaneously, topically, or orally.
  • a compound described herein e.g., a compound of any one of formulas (l)-(lll)
  • a pharmaceutical composition thereof is administered to treat a blood stream infection or tissue infection in the subject.
  • the subject may be immunocompromised, and thus, is at a higher risk for developing a fungal infection.
  • the subject is being prepared for an invasive medical procedure or undergoing long term antibiotic therapy.
  • the subject has been diagnosed with humoral immune deficiency, T cell deficiency, neutropenia, asplenia, or complement deficiency.
  • the subject is being treated or is about to be treated with immunosuppresive drugs.
  • the subject has been diagnosed with a disease which causes immunosuppression (e.g., cancer or acquired immunodeficiency syndrome).
  • the subject has cancer (e.g., leukemia, lymphoma, or multiple myeloma).
  • the subject has undergone or is about to undergo immunosuppression therapy. In some embodiments, the subject has undergone or is about to undergo hematopoietic stem cell transplantation. In some embodiments, the subject has undergone or is about to undergo an organ transplant.
  • the fungal infection is selected from candidemia, invasive candidiasis, tinea capitis, tinea corporis, tinea pedis, onychomycosis, perionychomycosis, pityriasis versicolor, oral thrush, vaginal candidiasis, respiratory tract candidiasis, biliary candidiasis, eosophageal candidiasis, urinary tract candidiasis, systemic candidiasis, mucocutaneous candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, fungal sinusitis, or chronic sinusitis.
  • the fungal infection is candidemia or invasive candidiasis.
  • the fungal infection is an infection of Candida albicans, C. glabrata, C. dubliniensis, C. krusei, C. parapsilosis, C. tropicalis, C.
  • orthopsilosis C. guilliermondii, C. rugosa, C. auris, C. lusitaniae, Aspergillus fumigatus, A. flavus, A. terreus, A. niger, A. candidus, A. clavatus, or A. ochraceus.
  • the fungal infection is an infection of Fusarium spp., Scedosporium spp., Mucor spp., Rhizopus spp., Rizomucor spp., Cunninghamella spp., Apophysomyces spp., Absidia spp., Saksenaea spp., Acremonium spp., Paecilomyces spp., Trichoderma spp., Stachybotrys spp., Trichophyton spp., Microsporum spp., Epidermophyton spp., Sporothrix spp., Histoplasma spp., Coccidioides spp., Blastomyces spp., Paracoccidioides spp., the
  • the Fusarium spp. is F. solani, F. oxysporum, F. verticillioides, or F. moniliforme.
  • the Scedosporium spp. is S. apiospermum or S. prolificans.
  • ffte Mt/cor spp. is M circinelloides, M. azygosporus, or M. circinelloides.
  • the Rhizopus spp. is ft oryzae.
  • the Rizomucor spp. is ft pusillus.
  • the Cunninghamella spp. is £ bertholletiae.
  • the Apophysomyces spp. is /A. elegans. In some embodiments, the Absidia spp. is /A. corymbifera. In some embodiments, the Saksenaea spp. is S. vasiformis. In some embodiments, the Acremonium spp. is /A. strictum. In some embodiments, the Paecilomyces spp. is P. Iilacinus or P. variotii. In some embodiments, the Trichoderma spp. is ⁇ . longibrachiatum, T. harzianum, T. koningii, T.
  • the Stachybotrys spp. is S.
  • the Trichophyton spp. is ⁇ . rubrum, T. mentagrophytes, T.
  • the Microsporum spp. is M gypseum.
  • the Epidermophyton spp. is E. floccosum.
  • the Sporothrix spp. is S. schenckii.
  • the Histoplasma spp. is -/. capsulatum.
  • the Coccidioides spp. is £ immitis or £ posadasii. In some embodiments, the
  • Blastomyces spp. is B. dermatitidis.
  • the Paracoccidioides spp. is P.
  • the Cladosporium spp. is C trichoides.
  • the Exophiala spp. is E. jeanselmei.
  • the Exserohilum spp. is E. rostratum, E. longirostratum, or E. mcginnisii.
  • a compound described herein may be formulated in a pharmaceutical composition for use in the methods described herein.
  • a compound described herein may be formulated in a pharmaceutical composition.
  • the pharmaceutical composition includes a compound described herein (e.g., a compound described by any one of formulas (l)-(lll)) and pharmaceutically acceptable carriers and excipients.
  • Acceptable carriers and excipients in the pharmaceutical compositions are nontoxic to recipients at the dosages and concentrations employed.
  • Acceptable carriers and excipients may include buffers such as phosphate, citrate, HEPES, and TAE, antioxidants such as ascorbic acid and methionine, preservatives such as hexamethonium chloride, octadecyldimethylbenzyl ammonium chloride, resorcinol, and benzalkonium chloride, proteins such as human serum albumin, gelatin, dextran, and immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acid residues such as glycine, glutamine, histidine, and lysine, and carbohydrates such as glucose, mannose, sucrose, and sorbitol.
  • buffers such as phosphate, citrate, HEPES, and TAE
  • antioxidants such as ascorbic acid and methionine
  • preservatives such as hex
  • excipients examples include, but are not limited to, antiadherents, binders, coatings, compression aids, disintegrants, dyes, emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, sorbents, suspensing or dispersing agents, or sweeteners.
  • excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylit
  • the compounds herein may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
  • These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds herein be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.
  • Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulphuric, hydrobromic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like for forming basic salts. Methods for preparation of the appropriate salts are well-established in the art.
  • Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate
  • alkali or alkaline earth metal salts include, but are not limited to, sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium,
  • a compound herein or a pharmaceutical composition thereof used in the methods described herein will be formulated into suitable pharmaceutical compositions to permit facile delivery.
  • a compound e.g., a compound of any one of formulas (l)-(lll)
  • a pharmaceutical composition thereof may be formulated to be
  • intramuscularly intravenously (e.g., as a sterile solution and in a solvent system suitable for intravenous use), intradermal ⁇ , intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally,
  • intravaginally intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally (e.g., a tablet, capsule, caplet, gelcap, or syrup), topically (e.g., as a cream, gel, lotion, or ointment), locally, by inhalation, by injection, or by infusion (e.g., continuous infusion, localized perfusion bathing target cells directly, catheter, lavage, in cremes, or lipid compositions).
  • infusion e.g., continuous infusion, localized perfusion bathing target cells directly, catheter, lavage, in cremes, or lipid compositions.
  • a compound herein or a pharmaceutical composition thereof may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, preparations suitable for iontophoretic delivery, or aerosols.
  • the compositions may be formulated according to conventional pharmaceutical practice.
  • a compound described herein may be formulated in a variety of ways that are known in the art.
  • a compound described herein can be formulated as pharmaceutical or veterinary compositions.
  • a compound described herein is formulated in ways consonant with these parameters.
  • a summary of such techniques is found in Remington: The Science and Practice of Pharmacy, 22nd Edition, Lippincott Williams & Wilkins (2012); and Encyclopedia of Pharmaceutical Technology, 4th Edition, J. Swarbrick and J. C. Boylan, Marcel Dekker, New York (2013), each of which is
  • Formulations may be prepared in a manner suitable for systemic administration or topical or local administration.
  • Systemic formulations include those designed for injection (e.g., intramuscular, intravenous or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration.
  • the formulation will generally include a diluent as well as, in some cases, adjuvants, buffers, and preservatives.
  • the compounds can be administered also in liposomal compositions or as microemulsions.
  • Systemic administration may also include relatively noninvasive methods such as the use of suppositories, transdermal patches, transmucosal delivery and intranasal administration.
  • Oral administration is also suitable for compounds herein. Suitable forms include syrups, capsules, and tablets, as is understood in the art.
  • compositions can be administered parenterally in the form of an injectable formulation.
  • Pharmaceutical compositions for injection can be formulated using a sterile solution or any pharmaceutically acceptable liquid as a vehicle.
  • Formulations may be prepared as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions.
  • Pharmaceutically acceptable vehicles include, but are not limited to, sterile water, physiological saline, and cell culture media (e.g., Dulbecco's Modified Eagle Medium (DMEM), a-Modified Eagles Medium (a-MEM), F-12 medium).
  • DMEM Dulbecco's Modified Eagle Medium
  • a-MEM a-Modified Eagles Medium
  • injectable compositions may also contain amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, such as sodium acetate and sorbitan monolaurate.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, such as sodium acetate and sorbitan monolaurate.
  • compositions can be prepared in the form of an oral formulation.
  • Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including
  • microcrystalline cellulose starches including potato starch, croscarmellose sodium, alginates, or alginic acid
  • binding agents e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol
  • lubricating agents, glidants, and antiadhesives e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc).
  • Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
  • compositions for oral formulations include, but are not limited to, colorants, flavoring agents, plasticizers, humectants, and buffering agents.
  • Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
  • Dissolution or diffusion controlled release of a compound described herein e.g., a compound of any one of formulas (l)-(lll)
  • a pharmaceutical composition thereof can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of the compound, or by incorporating the compound into an appropriate matrix.
  • a controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol
  • palmitostearate ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2- hydroxymethacrylate, methacrylate hydrogels, 1 ,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols.
  • the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax, and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.
  • the pharmaceutical composition may be formed in a unit dose form as needed.
  • the amount of active component, e.g., a compound described herein (e.g., a compound of any one of formulas (I)- (III)), included in the pharmaceutical compositions are such that a suitable dose within the designated range is provided (e.g., a dose within the range of 0.01 -100 mg/kg of body weight).
  • compounds herein may be administered by any appropriate route for treating or protecting against a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp), or for preventing, stabilizing, or inhibiting the growth of fungi, or killing fungi (e.g., Candida spp. or Aspergillus spp).
  • a fungal infection e.g., a fungal infection caused by Candida spp. or Aspergillus spp
  • Compounds described herein may be administered to humans, domestic pets, livestock, or other animals with a pharmaceutically acceptable diluent, carrier, or excipient.
  • administering includes administration of any of the compounds described herein (e.g., compounds of any one of formulas (l)-(lll)) or compositions intramuscularly, intravenously (e.g., as a sterile solution and in a solvent system suitable for intravenous use), intradermal ⁇ , intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally,
  • intravaginally intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally (e.g., a tablet, capsule, caplet, gelcap, or syrup), topically (e.g., as a cream, gel, lotion, or ointment), locally, by inhalation, by injection, or by infusion (e.g., continuous infusion, localized perfusion bathing target cells directly, catheter, lavage, in cremes, or lipid compositions).
  • infusion e.g., continuous infusion, localized perfusion bathing target cells directly, catheter, lavage, in cremes, or lipid compositions.
  • (l)-(lll)) or a pharmaceutical compositions thereof depends on factors including the route of administration, the disease to be treated (e.g., the extent and/or condition of the fungal infection), and physical characteristics, e.g., age, weight, general health, of the subject.
  • the amount of the compound or the pharmaceutical composition thereof contained within a single dose may be an amount that effectively prevents, delays, or treats the fungal infection without inducing significant toxicity.
  • a pharmaceutical composition may include a dosage of a compound described herein ranging from 0.01 to 500 mg/kg (e.g., 0.01 , 0.1 , 0.2, 0.3, 0.4, 0.5, 1 , 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg/kg) and, in a more specific
  • a compound described herein e.g., a compound of any one of formulas (l)-(lll)
  • a pharmaceutical composition thereof may be administered to a subject in need thereof, for example, one or more times (e.g., 1 -10 times or more; 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 times) daily, weekly, monthly, biannually, annually, or as medically necessary. Dosages may be provided in either a single or multiple dosage regimens. The timing between administrations may decrease as the medical condition improves or increase as the health of the patient declines. The dosage and frequency of administration may be adapted by the physician in accordance with conventional factors such as the extent of the infection and different parameters of the subject.
  • Analytical HPLC was performed using the following column and conditions: Atlantis T3, 3 micron, 3.0 x 75 mm ; 50°C, water/CH 3 CN + 0.1 % formic acid, 5 to 95% CH 3 CN over 1 1 min + 2 min hold.
  • Preparative HPLC was performed using the following column: Agilent ZORBAX SB-CN, 7 ⁇ , 21 .2 x 250 mm, CH3CN/H2O/0.1 % Acetic Acid various linear gradients as necessary at 20 mL/min.
  • Rapid LC A Waters BEH C18, 3.0 x 30 mm, 1 .7 ⁇ , was used at a temperature of 50 ° C and at a flow rate of 1 .5 mL/min, 2 ⁇ injection, mobile phase: (A) water with 0.1 % formic acid and 1 % acetonitrile, mobile phase (B) methanol with 0.1 % formic acid; retention time given in minutes.
  • Polar Stop-Gap An Agilent Zorbax Bonus RP, 2.1 x 50mm, 3.5 ⁇ , was used at a temperature of 50°C and at a flow rate of 0.8 mL/min, 2 ⁇ injection, mobile phase: (A) water with 0.1 % formic acid and 1 % acetonitrile, mobile phase (B) methanol with 0.1 % formic acid; retention time given in minutes.
  • NMR Spectra were acquired on either of two instruments: (1 ) Agilent (formerly Varian) Unitylnova 400 MHz NMR spectrometer equipped with a 5mm Automation Triple Broadband (ATB) probe. The ATB probe was simultaneously tuned to 1 H, 19F and 13C. (2) Agilent (formerly Varian) Unitylnova 500 MHz NMR spectrometer. Several NMR probes are available for use with the 500 MHz NMR spectrometer, including both 3 mm and 5 mm 1 H13C1 5N probes and a 3 mm X1 H19F NMR probe (usually X is tuned to 13C).
  • the pulse angle was 45 degrees, 8 scans were summed and the spectral width was 16 ppm (-2 ppm to 14 ppm).
  • a total of 32768 complex points were collected during the 5.1 second acquisition time, and the recycle delay was set to 1 second.
  • Spectra were collected at 25 S C.
  • 1 H NMR Spectra are typically processed with 0.3 Hz line broadening and zero-filling to 131072 points prior to Fourier transformation.
  • Step c Synthesis of benzyl (2-(2-(((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)carbamate
  • Succinic anhydride (156 mg, 1 .57 mmol) was added to a stirring mixture of INT-1 (375 mg, 1 .49 mmol) and DIEA (193 mg, 1 .49 mmol) in MeOH (7 mL) and the reaction was stirred at RT for 3 hours at room temperature.
  • the solvent was reduced by 80% on the rotary evaporator and the mixture was applied to reversed phase HPLC (5 to 50% acetonitrile in Dl water containing 0.1 % formic acid: 20 minute gradient).
  • Step f Synthesis of 4-[(2- ⁇ 2-[(6-deoxy-alpha-L- mannopyranosyl)oxy]ethoxy ⁇ ethyl)amino]-4-oxobutanoic acid (INT-2)
  • Example 3 Synthesis of 2-aminoethyl 2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl-(1->3)- 2,4,6-tri-0-acetyl-3-thio-beta-D-glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-1 ,3-dithio-beta-D- glucopyranoside (INT-3)
  • Step a Synthesis of (3aR,5R,6R,6aR)-5-((R)-2,2-dimethyl-1 ,3-dioxolan-4-yl)-2,2- dimethyltetrahydro-2H-furo[2,3-d][1 ,3]dioxol-6-yl trifluoromethanesulfonate
  • Triflic anhydride (7.8 mL, 46.39 mmol) was added over 30 minutes to a cold (0°C) solution of the diacetone allofuranose (10.50 g, 40.34 mmol) in pyridine (100 mL). After stirring in the ice-bath for 1 hour, the reaction was diluted with ethyl acetate (250 mL) and the organic layer was washed with a mixture of saturated sodium bicarbonate and brine (50 mL + 50 mL), dried (Na2S04) and concentrated under reduced pressure to provide the crude triflate.
  • Step b Synthesis of Thio-linked Disaccharide: ((2R,3R,4S,5R,6S)-2-[(acetyloxy)methyl]- 6- ⁇ [(3aR,5R,6S,6aS)-5-(2,2-dimethyl-1 dioxolan-4-yl)-2,2-dimethyltetrahydro-2H-furo[2,3- d][1 ,3]dioxol-6-yl]sulfanyl ⁇ oxane-3,4,5-triyl triacetate)
  • the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (400 mL), washed with water (200 mL), dried (Na2S04), and concentrated. Added 40 mL of EtOH to the residue to dissolve the foam followed by swirling the flask. The foam slowly turn to white solid. After standing still for 5 minutes, breaking down the solid cake and filtering and washing with 20% aq. EtOH (100 mL). After drying, 1 0.28 g of the title compound was obtained (44%). Check TLC of the mother liquor and some of the product remained in the mother liquor which was purified with normal phase flash column.
  • Step c Synthesis of 1 ,2,4,6-tetra-0-acetyl-3-S-(2,3,4,6-tetra-0-acetyl-beta-D- glucopyranosyl)-3-thio-D-glucopyranose
  • Step e Synthesis of (1->3)-Thiodisaccharide Thiol: 2,4,6-tri-0-acetyl-3-S-(2,3,4,6-tetra- 0-acetyl-beta-D-glucopyranosyl)-1 ,3-dithio-beta-D-glucopyranose
  • Step f Synthesis of Thio-linked Trisaccharide: 2,4,6-tri-0-acetyl-3-S-(2,3,4,6-tetra-0- acetyl-beta-D-glucopyranosyl)-1 ,3-dithio-beta-D-glucopyranose
  • Chloroform-d ⁇ 170.53 (e), 170.48(e), 170.16(e), 169.42(e), 1 69.26(e), 169.09(e), 168.47(e),
  • Step g Synthesis of Peracetylated (1->3)-Thiotrisaccharide: 2,3,4,6-tetra-O-acetyl-beta- D-glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-3-thio-beta-D-glucopyranosyl-(1->3)-1 ,2,4,6-tetra-0- acetyl-3-thio-D-glucopyranose
  • Step h Synthesis of (1->3)-Thiotrisaccharide Bromide: 2,3,4,6-tetra-O-acetyl-beta-D- glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-3-thio-beta-D-glucopyranosyl-(1->3)-1 ,2,4,6-tetra-0- acetyl-3-thio-D-glucopyranose
  • Step i Synthesis of (1->3)-Thiotrisaccharide Thiol: 2,3,4,6-tetra-O-acetyl-beta-D- glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-3-thio-beta-D-glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl- 1 ,3-dithio-beta-D-glucopyranose
  • Step j Synthesis of Peracetylated (1->3)-Thiotrisaccharide ethyleneamine: 2- aminoethyl 2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-3-thio-beta-D- glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-1 ,3-dithio-beta-D-glucopyranoside (INT-3)
  • TMP Trimethylphosphine
  • ADDP 1 ,1 '-(azodicarbonyl)dipiperidine
  • N-Cbz-ethanolamine (0.201 g, 1 .03 mmol) and 2,3,4,6-tetra-O- acetyl-beta-D-glucopyranosyl-(1 ->3)-2,4,6-tri-0-acetyl-3-thio-beta-D-glucopyranosyl-(1 ->3)-2,4,6-tri-0- acetyl-1 ,3-dithio-beta-D-glucopyranose (0.54 mmol in 5 mL of THF) were added sequentially to the solution, with further stirring at room temperature for 2 hours. Any precipitate was then filtered off and the solution evaporated to dryness.
  • Part 2 (Hydrogenolysis).
  • the compound from Example 3, Step j, Part 1 (0.500 g, 0.435 mmol) and 30% Pd/C (0.463 g, 1 .30 mmol) were in the flask with 20 ml_ of EtOH and 5 ml_ of CHC . Under H2, the reaction mixture was stirred overnight.
  • Check TLC and mass. Celite filtration and wash with EtOH gave the title compound 0.44 g (100%). Mass showed a strong detectable positive charge signal at tr 3 min with 8 min (5 ⁇ 95%)/highMW method (found M+H + : 1016.2).
  • INT-3 (1 eq) is dissolved in methanol and excess NaOMe (10 eq) is added. The reaction is stirred until LCMS shows substantial formation of the desired product (INT-4) with an exact mass of 595.14.
  • Example 5 Synthesis of (1->3)-Thiotrisaccharide ethyleneamine: 4-[(2- ⁇ [beta-D- glucopyranosyl-(1->3)-3-thio-beta-D-glucopyranosyl-(1->3)-3-thio-beta-D- glucopyranosyl]thio ⁇ ethyl)amino]-4-oxobutanoic acid (INT-5)
  • Step a Succinic anhydride (0.0879 g, 0.869 mmol) was added to INT-3 (0.4417 g, 0.435 mmol) in DCM/Py (20 mL). The reaction mixture was stirred at room temperature overnight. LC/MS 8min Positive/negative showed the desired peak mass at 4.3 min on negative ionization. The solvent was removed and the residue was loaded onto an Isco Gold 24g column and eluted with 4- 6%MeOH/DCM to give 0.27 g of the desired product.
  • Step b NaOMe in MeOH (25%, 1 .42 mL, 25 equiv.) was added into a 50-mL RB Flask which contained the product of Step a (0.270 g, 0.242 mmol) in 5 mL of MeOH. The mixture was stirred at room temperature for 60 hours. It was then acidified with 1 N aq. HCI and purified with reversed phase C18 column (0-3% CAN/water) to give 0.168 g (99.8%) of the title compound (INT-5). LC/MS 8 min pos/neg method showed negative mass at the very beginning (M-H, 694.2).
  • Step a Synthesis of 1 ,2,3,4-tetra-0-acetyl-6-deoxy-6-iodo-beta-D-glucopyranose
  • Step b Synthesis of (1->6)-Thiodisaccharide: 1 ,2,3,4-tetra-0-acetyl-6-S-(2,3,4,6-tetra-0- acetyl-beta-D-glucopyranosyl)-6-thio-beta-D-glucopyranose
  • Step c Synthesis of (1->6)-Thiodisaccharide Bromide: 2,3,4-tri-0-acetyl-6-S-(2,3,4,6- tetra-O-acetyl-beta-D-g lucopyranosyl)-6-th io-alpha-D-g lucopyranosyl brom ide
  • Step d Synthesis of (1->6)-Thiodisaccharide Thiol: 2,3,4-tri-0-acetyl-6-S-(2,3,4,6-tetra- 0-acetyl-beta-D-glucopyranosyl)-1 ,6-dithio-beta-D-glucopyranose
  • Step g Synthesis of (1->6)-Thiotrisaccharide Thiol: 2,3,4,6-tetra-O-acetyl-beta-D- glucopyranosyl-(1->6)-2,3,4-tri-0-acetyl-6-thio-beta-D-glucopyranosyl-(1->6)-2,3,4-tri-0-acetyl- 1 ,6-dithio-beta-D-glucopyranose
  • Step h Synthesis of Peracetylated (1->6)-Trisaccharide ethyleneamine: 2-aminoethyl 2,3,4,6-tetra-O-acetyl-beta-D-g lucopyranosyl-(1 ->6)-2,3,4-tri-0-acetyl-6-th io-beta-D- glucopyranosyl-(1->6)-2,3,4-tri-0-acetyl-1 ,6-dithio-beta-D-glucopyranoside
  • INT-7 is obtained having an exact mass of 595.14.
  • Example 8 Synthesis of (1->6)-Thiotrisaccharide ethyleneamine: 4-[(2- ⁇ [beta-D- glucopyranosyl-(1->6)-6-thio-beta-D-glucopyranosyl-(1->6)-6-thio-beta-D- glucopyranosyl]thio ⁇ ethyl)amino]-4-oxobutanoic acid (INT-8)
  • Step a An analogous procedure was used as that for the preparation of the compound from Example 5, Step a.
  • the desired compound (0.480 g) was obtained in 99% yield.
  • Step b An analogous procedure was used as that for the preparation of the compound from Example 5, Step b. INT-8 (0.275 g, 99% yield) was obtained. Negative ion was found (M-H-: 694.0). 1 3 C NMR (75 MHz, D 2 0): ⁇ 180.94 (e), 175.76 (e), 87.07 (0), 86.04 (0), 85.34 (0), 79.74 (0), 79.23 (0), 79.20 (0), 77.14 (0), 76.87 (0, 2C), 72.70 (0), 72.46 (0), 72.41 (0, 2C), 72.33 (0), 69.37 (0), 60.77 (e), 39.43 (e), 33.07 (e), 32.94 (e), 32.30 (e), 32.01 (e), 29.51 (e).
  • Example 9 Synthesis of INT-9
  • Triethylamine (1 .31 mL, 9.32 mmol) was added to a cold (0°C) solution of 2-(2- aminoethoxy)ethan-1 -ol (CAS# 929-06-6, 1 .00 g, 9.32 mmol) in anhydrous THF (100 mL).
  • Cbz chloride (1 .50 mL, 10.3 mmol).
  • the reaction was diluted with ethyl acetate (250 mL) and the organic layer was washed with a mixture of saturated sodium bicarbonate and brine (50 mL + 50 mL), dried (Na2S04) and concentrated under reduced pressure to provide the crude product.
  • Step b Synthesis of Per-acetyl Rhamnose Bromide: 2,3,4-tri-0-acetyl-6-deoxy-beta-L- mannopyranosyl bromide
  • Step d Synthesis of Rhamnose-PEG1-NHCbz: benzyl (2- ⁇ 2-[(2,3,4-tri-0-acetyl-6-deoxy- alpha-L-mannopyranosyl)thio]ethoxy ⁇ ethyl)carbamate
  • TMP Trimethylphosphine
  • ADDP 1 ,1 '- (azodicarbonyl)dipiperidine
  • Step f Synthesis of Rhamnosyl-PEG1-Succinic acid linker: 4-[(2- ⁇ 2-[(6-deoxy-alpha-L- mannopyranosyl)thio]ethoxy ⁇ ethyl)amino]-4-oxobutanoic acid (INT-9)
  • anidulafungin is nitrated and the nitro group reduced to provide INT-1 1 with an exact mass of 1 154.52.
  • pneumocandin Bo is nitrated and the nitro group reduced to provide INT-12 with an exact mass of 1079.57.
  • HATU 122 mg, 0.32 mmol, in 1 ml_ DMF
  • INT-2 1 18 mg, 0.34 mmol
  • INT-10 190 mg, 0.15 mmol
  • DMF 2 ml_
  • the reaction was stirred for an additional 20 minutes then applied directly to reversed phase HPLC (10 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 25 minute gradient).
  • the pure fractions were pooled and lyophilized to afford the product as a white solid.
  • the compound (a bis-rhamnose adduct) was dissolved in methanol (15 mL) and sodium carbonate ( ⁇ 5 mg) was added and the mixture stirred for 30 minutes at which point LC/MS analysis showed complete hydrolysis of the bis-rhamnose adduct and formation of the desired mon-rhamnose adduct.
  • the mixture was filtered and neutralized with glacial acetic acid ( ⁇ 1 mL), then concentrated and applied directly to reversed phase HPLC (10 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 25 minute gradient). The pure fractions were pooled and lyophilized to afford the product
  • Compound 3 is prepared from INT- 12 and INT-2.
  • Compound 3 has an exact mass of 1412.72.
  • Step b Acylation of Fmoc-caspofungin with INT-2
  • Step b Compound 4b with an exact mass of 1425.79 is prepared starting with caspofungin and INT-2.
  • 3'-Amino-htyr-CD101 (INT-10) (1 .0 mmol, 1 .0 eq) and trimethylamine (1 .1 mmol, 1 .1 eq) is dissolved in DMF (1 0 mL) and succinic anhydride (1 .1 mmol, 1 .1 eq) is added followed by DMAP (0.05 eq). The mixture is stirred until the INT-10 is mostly consumed as determined by analytical HPLC. The fractions containing compound with an exact mass of 1340.63 are collected by preparative reversed phase HPLC and lyophilization of those fractions gives the desired product.
  • test organisms consisted of strains from the Micromyx collection. Reference isolates were originally received from the American Type Culture Collection (ATCC; Manassas, VA).
  • Organisms received at Micromyx were initially streaked for isolation on Sabouraud dextrose or potato dextrose agar. Colonies were picked by swab from the medium and resuspended in the appropriate broth containing cryoprotectant. The suspensions were aliquoted into cryogenic vials and maintained at -80 S C. Prior to testing, Candida isolates were streaked from the frozen vials on Sabouraud dextrose agar. The yeast isolates were incubated at overnight at 35 S C before use. The fungal isolates were incubated at least 7 days on Sabouraud dextrose agar slants at 35 S C before harvesting. Test Media
  • Isolates were tested in RPMI medium (Catalog No. SH3001 1 .04; Lot No. AWA92121 B;
  • HyClone Labs, Logan, UT which was prepared according to CLSI guidelines.
  • the pH of the medium was adjusted to 7.0 with 1 N NaOH.
  • the medium was sterile filtered using a 0.2 ⁇ PES filter and stored at 4°C until used.
  • the MIC assay method employed automated liquid handlers to conduct serial dilutions and liquid transfers.
  • Automated liquid handlers included the Multidrop 384 (Labsystems, Helsinki, Finland), Biomek 2000 and Biomek FX (Beckman 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
  • the daughter plates were loaded with 185 ⁇ per well of RPMI described above using the Multidrop 384.
  • the daughter plates were prepared using the Biomek FX which transferred 5 ⁇ of drug solution from each well of a mother plate to the corresponding well of the daughter plate in a single step.
  • a standardized inoculum of each organism was prepared.
  • Candida colonies were picked from the streak plate and a suspension was prepared in RPMI medium equal to a 0.5 McFarland standard, then diluted 1 :100 in RPMI and transferred to compartments of sterile reservoirs divided by length (Beckman Coulter).
  • Aspergillus isolates previously prepared and quantitated suspensions were used to make dilutions in RPMI to reach 20X the final concentration. These dilutions were also transferred to compartments of sterile reservoirs divided by length (Beckman Coulter). The final concentration of the Aspergillus isolates was approximately 0.2-2.5 x 10 4 CFU/mL.
  • the Biomek 2000 was used to inoculate the plates. Daughter plates were placed on the Biomek 2000 work surface reversed so that inoculation took place from low to high drug
  • the Biomek 2000 delivered 10 ⁇ of standardized inoculum into each well.
  • the wells of the daughter plates ultimately contained 1 85 ⁇ of RPMI, 5 ⁇ of drug solution, and 10 ⁇ of inoculum.
  • the final concentration of DMSO in the test well was 2.5% for the evaluated comparators and 1 .25% for the investigational agents. Plates were stacked 3 high, covered with a lid on the top plate, placed into plastic bags, and incubated at 35 S C for approximately 24-48 hr prior to reading. Plates were read when inoculum was confluent in growth wells. Plates were viewed from the bottom using a plate viewer. An un-inoculated solubility control plate was observed for evidence of drug precipitation.
  • MICs were read where visible growth of the organism was inhibited. MECs were read where the growth shifted to a small, rounded, compact hyphal form as compared to the hyphal growth seen in the growth control well. MIC and MEC values are shown in Table 4 below.
  • Example 21 Compound 1 mediates binding of rabbit anti-Rha antibody to Aspergillus fumigatus
  • FIGS. 1 A and 1 B show binding of the secondary anti-rabbit lgG1 (red fluorescence) to rabbit anti-Rha antibodies which in turn are bound to A. fumigatus hyphae.
  • CD101 acetate which lacks the rhamnose of Compound 1 ; the structure of CD101 acetate is shown in Example 10.
  • CD101 acetate which lacks the rhamnose of Compound 1 ; the structure of CD101 acetate is shown in Example 10
  • Compound 1 is capable of coordinating the binding of anti-Rha antibodies to A. fumigatus hyphae. This is considered the first step in an immune response against the fungal pathogen.
  • Example 22 Inoculation of rabbits with OVA-Rha-linked vaccine, isolation of serum and purification of anti-Rha antibodies
  • Step a Synthesis of N-(2- ⁇ 2-[(6-deoxy-alpha-L-mannopyranosyl)oxy]ethoxy ⁇ ethyl)-4- [(2,5-dioxopyrrolidin-1-yl)oxy]-4-oxobutanamide
  • CFA Complete Freund's Adjuvant
  • IFA Sigma F5506 Incomplete Freund's Adjuvant
  • 6-Aminohexyl-Agarose (5 mL, 4% crosslinked beaded agarose, -5 ⁇ per mL) suspended in saline was centrifuged (3500 rpm for 5 min), then decanted to remove water. The resulting solid was suspended in DMF (4 x 15 mL), centrifuged (3500 rpm for 5 min) and decanted. The agarose was resuspended in DMF (1 mL), and treated with INT-2 (0.140 g, 0.40 mmol), followed by DIEA (0.21 mL, 1 .20 mmol), and HATU (0.152 g, 0.40 mmol).
  • Serum from immunized rabbits was diluted 2-fold in 2X PBS pH 7.4.
  • the solution was passaged over the solid supported a-L-rhamnose column (from Step a) by gravity flow followed by a wash step using 10 CV of 1 X PBS pH 7.4.
  • Protein was eluted using 20 mM Glycine Buffer pH 2.0 and immediately adjusted to a neutral pH by the addition of 1 M Tris pH 9.0.
  • the eluate was buffer exchanged with 1 X PBS pH 7.4 and concentrated in Amicon centrifugal concentrators (10K MWCO).
  • the presence of IgG was determined by reducing and non-reducing SDS-PAGE and quantitated using a NanoDrop 2000 Spectrophotometer.
  • the resultant purified antibodies can be used in place of serum adjusting for relative antibody titers.
  • Example 23 Efficacy of Compound 1 in a Mouse Candidiasis Model
  • Test articles Compound 1 , caspofungin acetate and purified rabbit anti-rhamnose antibodies (rAbs) were stored at 4 °C. Compound 1 was dissolved in 10% DMSO/1 % Tween 20 in water for injection (WFI) to generate five doses of 0.03, 0.1 , 0.3, 1 and 3 mg/kg and caspofungin at 0.1 mg/kg was dissolved in WFI before using. A pre-formulated solution of purified rabbit anti-Rha antibodies was injected 0.1 mL/mouse by intravenous (IV) injection. The dosing volume was 10 mL/kg by intraperitoneal (IP) administration for Compound 1 and caspofungin acetate in the study.
  • IV intravenous
  • IP intraperitoneal
  • Candida albicans (ATCC R303) was cryopreserved as single-use working stock cultures which stored at -80 S C. A 0.1 mL aliquot stock was transferred to a sabouraud agar (SA) plate and incubated at 35-37 S C overnight. The culture was re-suspended with 1 mL cold PBS (>3.0 x 10 9 CFU/mL, OD 6 2o 3.0-3.2) and diluted with PBS to 1 x 10 4 CFU/mL. The actual colony counts were determined by plating dilutions to sabouraud agar plates followed by 20 - 24 hr incubation. The actual inoculum count was 2.93 x 10 4 CFU/mL.
  • mice Male ICR mice weighing 22 ⁇ 2 g were acclimated for 3 days prior to use. All animals were maintained in a hygienic environment with controlled temperature (20 - 24 S C), humidity (30% - 70%) and 12 hours light/dark cycles. Free access to sterilized standard lab diet [MFG (Oriental Yeast Co., Ltd., Japan)] and autoclaved tap water were granted.
  • MFG Oriental Yeast Co., Ltd., Japan
  • Immune suppression was induced by two intraperitoneal injections of cyclophosphamide at 150 mg/kg 4 days (Day -4) and at 100 mg/kg 1 day before inoculation (Day -1 ). On Day 0, animals were inoculated intravenously (0.1 mL/mouse) with C. albicans (R303), 2.93 x 10 3 CFU per mouse.
  • Purified rabbit anti-Rha antibodies in PBS (pH 7.4) were injected once at 100 ⁇ / ⁇ by intravenous administration 1 day prior to C. albicans challenge. On day 0, Compound 1 was intraperitoneally administered at 0.03, 0.1 , 0.3, 1 and 3 mg/kg 2 hours post-inoculation to the rAbs untreated/treated animals. Caspogungin acetate at 0.1 mg/kg was administered IP 2 hours after inoculation. The dosing volume was 10 mL/kg for all groups, (see figure above)
  • the animals were euthanized by CO2 asphyxiation 2 or 72 hr post-inoculation. Paired kidneys were harvested and weighed. The harvested kidneys were homogenized in 1 mL of PBS, pH 7.4, with a Polytron homogenizer. A 0.1 mL aliquot of each homogenate was used for serial 10-fold dilutions and plated onto SA plates for fungal enumeration. The fungal counts (CFU/g) in kidneys were calculated and the percentage decrease in counts compared to the corresponding vehicle control was calculated with the following formula:
  • amphotericin B was dissolved in 0.9% saline and Compound 1 in 1 0% DMSO/1 % Tween 20/0.9% NaCI.
  • mice Female ICR mice weighing 22 ⁇ 2 g were maintained in a well-controlled temperature (20 - 24 °C) and humidity (30% - 70%) environment with 12 hours light/dark cycles. Free access to standard lab diet [MFG (Oriental Yeast Co., Ltd., Japan)] and autoclaved tap water were granted. Animals were immunosuppressed by three intraperitoneal injections of cyclophosphamide (the first injection was at 6 mg/mouse 3 days before inoculation, the second and third injections were at 2 mg/mouse 1 and 4 days after inoculation. On Day 0, animals were inoculated (0.1 mL/mouse IV) with A. fumigatus (ATCC 13073), 3.65 x 10 4 CFU per mouse.
  • MFG Oriental Yeast Co., Ltd., Japan
  • Example 25 Efficacy of Compound 1 in a Murine Model of Invasive Candidiasis
  • the objective of this study was to evaluate the in vivo efficacy of Compound 1 as therapy against invasive pulmonary candidiasis in a murine model.
  • mice were inoculated intravenously (IV) through the lateral tail vein with a susceptible Candida albicans isolate.
  • IV intravenously
  • AB polyclonal antibody
  • Treatment with each antifungal began one day post-challenge and continued through Day 7. Survival and fungal burden arms were included.
  • a placebo (vehicle) control was included in each arm.
  • Isolate A Candida albicans isolate, ATCC 90028, was utilized that is susceptible to antifungal agents. Isolates were sub-cultured at 37°C for 48 hours on Sabouraud dextrose agar twice. Prior to inoculation, isolates taken from the second subculture were placed into brain heart infusion broth and grown overnight at 37°C with shaking at 200 rpm. Cells were then collected by centrifugation and washed three times in sterile saline. Animal Model. Outbred ICR mice (Envigo) were housed 5 per cage and had access to food and water ad libitum. On Day 0, mice were infected intravenously with 0.2 ml_ of C.
  • the starting inoculum was determined by counting Candida cells using a hemocytometer and adjusting to the target number of cells for each isolate.
  • serial dilutions were prepared in saline and plated onto Sabouraud dextrose agar plates and incubated at 37°C in order to verify the number of viable Candida cells.
  • Antifungal Treatment experiments were used to evaluate the in vivo efficacy of Compound 1 against invasive candidiasis. Mice were administered the polyclonal antibody on Day -1 relative to inoculation. Treatment with antifungals began 24 hours following inoculation and were continued through Day 7 post-inoculation. Compound 1 was administered by intraperitoneal (IP) injection at doses of 3 mg/kg, 10 mg/kg, and 30 mg/kg once daily (QD). Survival and fungal burden arms were included in the study. Treatment groups and the number of animals in each group and each arm are shown in the Table 8.
  • IP intraperitoneal
  • mice were humanely euthanized on Day 8 post-inoculation.
  • Kidneys were harvested, weighed, and homogenized in sterile saline supplemented with antibiotics. Serial dilutions of the tissue homogenates were prepared and plated in duplicate onto Sabouraud dextrose agar. After 24 hours of incubation at 37°C, the colonies were counted and the numbers of colony forming units (CFU) per gram of tissue calculated. Fungal burden was also measured in mice as they succumb to infection in the survival arm and in those that survive to the study endpoint (Day 21 ). Blood was also collected by cardiac puncture on Day 8 in the fungal burden arm of mice administered Compound 1 . Plasma was separated and immediately frozen. Compound 1 concentrations were measured in plasma and kidney tissue samples.
  • Kidney fungal burden in the fungal arm is shown in Table 10.
  • Kidney fungal burden in the survival arm is shown in Table 1 1 .
  • Example 26 Efficacy of Compound 1 in a Murine Model of Invasive Pulmonary Aspergillosis
  • the objective of this study was to evaluate the in vivo efficacy of Compound 1 as therapy against invasive pulmonary aspergillosis in a murine model of invasive pulmonary aspergillosis.
  • mice immunosuppressed mice for seven days at two different doses (beginning two days after the administration of the polyclonal antibody).
  • Plasma and lung samples were collected at various time points after the last dose and concentrations of Compound 1 were measured. The tolerability of Compound 1 was also evaluated.
  • Compound 1 was administered as treatment against established pulmonary infection.
  • a single dose of the polyclonal antibody (AB) that is absent in mice was administered on Day -1 relative to infection.
  • Compound 1 was administered at different doses beginning one day after pulmonary inoculation with A. fumigatus.
  • a placebo (vehicle) control group was also included. Endpoints included survival and changes in pulmonary fungal burden.
  • Preliminary Pharmacokinetic / Dose Tolerability Study A preliminary pharmacokinetic / dose tolerability study was conducted with Compound 1 . Uninfected male ICR mice were immunosuppressed, as described below for the infection model. Mice were administered a single dose of the polyclonal antibody by intravenous injection.
  • mice were administered Compound 1 at the highest and lowest anticipated doses IV and IP doses for seven days. After the morning dose on Day 7, blood was collected by cardiac puncture from three mice per time point in each group, and the plasma was separated and frozen. Lung samples were also collected from the mice at these time points and stored frozen. Compound 1 concentrations were measured in the frozen plasma and lung samples. Mice were also monitored multiple times per day, including close observation following IV and IP administration. These observations, along with daily weights, were used to evaluate the tolerability of Compound 1 in immunosuppressed mice. The number of mice per time point for each dose of Compound 1 is shown in Table 12.
  • Compound 1 concentrations were measured in the frozen plasma and lung samples.
  • Compound 1 concentrations as measured in frozen plasma are shown in FIGs. 2A and 4A.
  • FIGs. 3A and 4A Compound 1 IV
  • FIGs.3B and 4B Compound 1 IP
  • the mean ratio of Compound 1 concentration in lung/plasma are shown in FIGs. 4A and 4B.
  • Compound 1 showed a sustained lung tissue/plasma ratio of 1 .

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Abstract

Compositions and methods for the treatment of fungal infections include compounds containing a β-1,3-glucan synthase inhibitor covalently conjugated to one or more monosaccharide or oligosaccharide moiety. In particular, compounds can be used in the treatment of fungal infections caused by a fungus in the genus Candida or Aspergillus.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF FUNGAL INFECTIONS
Background
The need for novel antifungal treatments is significant, and is especially critical in the medical field. Immunocompromised patients provide perhaps the greatest challenge to modern health care. During the last three decades there has been a dramatic increase in the frequency of fungal infections in these patients (Herbrecht, Eur. J. Haematol., 56:12, 1996; Cox et al., Curr. Opin. Infect. Dis., 6:422, 1993). Deep-seated mycoses are increasingly observed in patients undergoing organ transplants and in patients receiving aggressive cancer chemotherapy (Alexander et al., Drugs, 54:657, 1997). The most common pathogens associated with invasive fungal infections are the opportunistic yeast,
Candida albicans, and the filamentous fungus, Aspergillus fumigatus (Bow, Br. J. Haematol., 101 :1 , 1998; Wamock, J. Antimicrob. Chemother., 41 :95, 1998). There are an estimated 200,000 patients per year who acquire nosocomial fungal infections (Beck-Sague et al., J. Infect. Dis., 167:1247, 1993). Also adding to the increase in the numbers of fungal infections is the emergence of Acquired Immunodeficiency Syndrome (AIDS) where virtually all patients become affected with some form of mycoses during the course of the disease (Alexander et al., Drugs, 54:657, 1997; Hood et al., J. Antimicrob. Chemother., 37:71 , 1996). The most common organisms encountered in these patients are Cryptococcus neoformans, Pneumocystis carinii, and C. albicans (HIV/AIDS Surveillance Report, 1996, 7(2), Year-End Edition; Polis, M. A. et al., AIDS: Biology, Diagnosis, Treatment and Prevention, fourth edition, 1997). New opportunistic fungal pathogens such as Penicillium marneffei, C. krusei, C. glabrata, Histoplasma capsulatum, and Coccidioides immitis are being reported with regularity in immunocompromised patients throughout the world.
The development of antifungal treatment regimens has been a continuing challenge.
Currently available drugs for the treatment of fungal infections include amphotericin B, a macrolide polyene that interacts with fungal membrane sterols, flucytosine, a fluoropyrimidine that interferes with fungal protein and DNA biosynthesis, and a variety of azoles (e.g., ketoconazole, itraconazole, and fluconazole) that inhibit fungal membrane-sterol biosynthesis (Alexander et al., Drugs, 54:657, 1997).
For decades, the basis of most antifungal therapy has been the polyenes, specifically amphotericin B-based medications, the cytosine analogue 5-fluorocytosine, and triazole compounds. Polyene-based therapy is plagued by the problem of toxicity. Azoles and 5-fluorocytosine have the limitation of resistance emergence in yeast infections, especially problematic in therapy of Candida glabrata (Nguyen et al., Am. J. Med., 1 00:617 (1 996); Gumbo et al., Medicine (Baltimore), 78:220 (1999); Alexander et al., Transplantation, 80:868 (2005)). Indeed, even after apparent therapeutic success with these agents, recurrence of infection has been noted months to years later (Nasser et al., Am. J. Med., 103:25 (1997); Clancy et al., Eur. J. Clin Microbiol. Infect. Dis., 19:585 (2000);
Gumbo et al., Scand. J. Infect. Dis., 34:817 (2002)). Thus, development of new classes of antifungal agents is imperative. One class of new antifungal agents that have reached clinical use is that of echinocandins, of which anidulafungin is the latest member. The echinocandins have activity against Candida and Aspergillus species, but not C. neoformans. When the echinocandin caspofungin was approved for sale in 2001 , it represented the first new class of antifungal agents to be approved in over a decade. Since that time, two other echinocandin antifungals, micafungin and anidulafungin have been approved in various markets. Each agent in this class of compound acts by inhibition of β-1 ,3-D-glucan synthase, which is a key enzyme in the synthesis of glucan in the cell wall of many fungi. All three of these drugs are made semisynthetically, starting with natural products obtained through fermentation.
The echinocandins are a broad group of antifungal agents that typically are composed of a cyclic hexapeptide and lipophilic tail, the latter of which is attached to the hexapeptide core through an amide linkage. Although many echinocandins are natural products, the clinically relevant members of this class have all been semisynthetic derivatives. Although the naturally occurring echinocandins possess some degree of anti-fungal activity, they have not been suitable as therapeutics, primarily because of poor aqueous solubility, insufficient potency, and/or hemolytic action. The approved echinocandins are the products of intense efforts to generate derivatives that maintain or improve upon the glucan synthase inhibition, but do not cause the hemolytic effects. Unfortunately, the poor aqueous solubility and poor intestinal absorption of these compounds have relegated them to delivery by intravenous infusion. There is a need in the art for improved compounds and methods of treatment for fungal infections.
Summary
The disclosure relates to compounds, compositions, and methods for the treatment of fungal infections. In particular, such compounds include bifunctional molecules including a β-1 ,3-glucan synthase inhibitor and at least one monosaccharide or oligosaccharide moiety, β-1 ,3-glucan synthase inhibitors bind to and inhibit the function of β-1 ,3-glucan synthase, a glucosyltransferase enzyme involved in the generation of β-glucan in the cell wall of fungi, resulting in disrupting the integrity of the fungal cell well and leading to fungal cell death. Such compounds are useful in methods for the inhibition of fungal growth and in methods for the treatment of fungal infections, such as those caused by a fungus of the genus Candida.
In one aspect, the invention features a compound including a β-1 ,3-glucan synthase inhibitor conjugated to at least one monosaccharide or oligosaccharide moiety by way of a linker, wherein the
compound is described by formula (I):
Figure imgf000004_0001
wherein R1 is a lipophilic moiety; R2 is hydrogen or methyl ; each of R3 and R4 is, independently, hydrogen or hydroxyl; R5 is hydrogen, methyl, or optionally substituted C1 -C5 alkamino; R6 is hydrogen, hydroxyl, methyl, or amino; R7 is hydrogen or hydroxyl; R8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(0(CH2)a)bR', -(NH(CH2)a)bR', -(S(CH2)a)bR', -(0(CH2)a)bN(R')2, -(NH(CH2)a)bN(R')2, -(S(CH2)a)bN(R')2, -(0(CH2)a)bN+(R')3, -(NH(CH2)a)bN+(R')3, -(S(CH2)a)bN+(R')3, -(0(CH2)a)bOR', -(NH(CH2)a)bOR', -(S(CH2)a)bOR', -(OCH2CH2)a(NHCH2CH2)bN(R')2,
-(OCH2CH2)a(NHCH2CH2)bN+(R')3, -(OCH2CH2)a(NHCH2CH2)bOR', -(NHCH2CH2)a(OCH2CH2)bN(R')2, -(NHCH2CH2)a(OCH2CH2)bN+(R')3, or -(NHCH2CH2)a(OCH2CH2)bOR'; R9 is hydrogen, hydroxyl, or amino; n is 0 or 1 ; d is 1 , 2, 3, 4, 5, or 6; each of a and b is, independently, an integer from 1 to 5; each R' is, independently, hydrogen, optionally substituted C1 -C1 0 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyi, optionally substituted C3-C10 heterocycloalkyi, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1 -C1 0 heteroaryl; L is a linker; and each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
In some embodiments of the compound of formula (I), the compound is described by formula (I-1):
,
Figure imgf000005_0001
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, n, d, L, and E are as defined above, or a pharmaceutically acceptable salt thereof.
In some embodiments of the compound of formula (I), the compound is described by formula (I-2):
,
Figure imgf000005_0002
wherein R1 is a lipophilic moiety; R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2; R6 is hydrogen or methyl; R8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(O(CH2)a)bR’,
-(NH(CH2)a)bR’, -(S(CH2)a)bR’, -(O(CH2)a)bN(R’)2, -(NH(CH2)a)bN(R’)2, -(S(CH2)a)bN(R’)2,
-(O(CH2)a)bN+(R’)3, -(NH(CH2)a)bN+(R’)3, -(S(CH2)a)bN+(R’)3, -(O(CH2)a)bOR’, -(NH(CH2)a)bOR’, -(S(CH2)a)bOR’, -(OCH2CH2)a(NHCH2CH2)bN(R’)2, -(OCH2CH2)a(NHCH2CH2)bN+(R’)3,
-(OCH2CH2)a(NHCH2CH2)bOR’, -(NHCH2CH2)a(OCH2CH2)bN(R’)2, -(NHCH2CH2)a(OCH2CH2)bN+(R’)3, or -(NHCH2CH2)a(OCH2CH2)bOR’; each of a and b is, independently, an integer from 1 to 5; d is 1, 2, 3, 4, 5, or 6; each R’ is, independently, hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyi, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1 -C10 heteroaryl; L is a linker; and each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
In another aspect, the invention features a compound including a β-1 ,3-glucan synthase inhibitor conjugated to at least one monosaccharide or oligosaccharide moiety by way of a linker, wherein the compound is described by formula (II):
Figure imgf000006_0001
wherein R1 is a lipophilic moiety; R2 is hydrogen or methyl ; each of R3 and R4 is, independently, hydrogen or hydroxyl; R6 is hydrogen, hydroxyl, methyl, or amino; R7 is hydrogen or hydroxyl; R8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(0(CH2)a)bR', -(NH(CH2)a)bR',
-(S(CH2)a)bR\ -(0(CH2)a)bN(R')2, -(NH(CH2)a)bN(R")2, -(S(CH2)a)bN(R')2, -(0(CH2)a)bN+(R')3, -(NH(CH2)a)bN+(R')3, -(S(CH2)a)bN+(R')3, -(0(CH2)a)bOR', -(NH(CH2)a)bOR', -(S(CH2)a)bOR',
-(OCH2CH2)a(NHCH2CH2)bN(R')2, -(OCH2CH2)a(NHCH2CH2)bN+(R')3, -(OCH2CH2)a(NHCH2CH2)bOR', -(NHCH2CH2)a(OCH2CH2)bN(R')2, -(NHCH2CH2)a(OCH2CH2)bN+(R')3, or
-(NHCH2CH2)a(OCH2CH2)bOR'; R9 is hydrogen, hydroxyl, or amino; n is 0 or 1 ; each of a and b is, independently, an integer from 1 to 5; d is 1 , 2, 3, 4, 5, or 6; each R' is, independently, hydrogen, optionally substituted C1 -C10 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyi, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1 -C10 heteroaryl ; each R" is, independently, hydrogen or C1 -C10 alkyl; L is a linker; and each E is, independently, a monosaccharide or oligosaccharide moiety, or a
pharmaceutically acceptable salt thereof. In some embodiments of the compound of formula (II), the compound is described by formula
(11-1 ):
Figure imgf000007_0001
wherein R1 , R2, R3, R4, R6, R7, R8, R9, n, d, L, and E are as defined above, or a pharmaceutically acceptable salt thereof.
In some embodiments of the compound of formula (II), the compound is described by formula
(II-2):
Figure imgf000007_0002
wherein R1 is a lipophilic moiety; R6 is hydrogen or methyl ; R8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(0(CH2)a)bR', -(NH(CH2)a)bR', -(S(CH2)a)bR', -(0(CH2)a)bN(R')2,
-(NH(CH2)a)bN(R")2, -(S(CH2)a)bN(R')2, -(0(CH2)a)bN+(R')3, -(NH(CH2)a)bN+(R')3, -(S(CH2)a)bN+(R')3,
-(0(CH2)a)bOR', -(NH(CH2)a)bOR', -(S(CH2)a)bOR', -(OCH2CH2)a(NHCH2CH2)bN(R')2,
-(OCH2CH2)a(NHCH2CH2)bN+(R')3, -(OCH2CH2)a(NHCH2CH2)bOR', -(NHCH2CH2)a(OCH2CH2)bN(R')2,
-(NHCH2CH2)a(OCH2CH2)bN+(R')3, or -(NHCH2CH2)a(OCH2CH2)bOR'; each of a and b is,
independently, an integer from 1 to 5; d is 1 , 2, 3, 4, 5, or 6; each R' is, independently, hydrogen, optionally substituted C1 -C10 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1 -C10 heteroaryl ; each of R" is, independently, hydrogen or C1 -C10 alkyl; L is a linker; and each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
In another aspect, the invention features a compound including a β-1 ,3-glucan synthase inhibitor conjugated to at least one monosaccharide or oligosaccharide moiety by way of a linker, wherein the compound is described by formula (III):
Figure imgf000008_0001
wherein R1 is a lipophilic moiety; R2 is hydrogen or methyl ; each of R3 and R4 is, independently, hydrogen or hydroxyl; R5 is hydrogen, methyl, -CH2CH2NH2, or -CH2(CO)NH2; R6 is hydrogen, hydroxyl, methyl, or amino; R7 is hydrogen or hydroxyl; R9 is hydrogen, hydroxyl, or amino; X is O or NH; n is 0 or 1 ; d is 1 , 2, 3, 4, 5, or 6; L is a linker; and each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
In some embodiments of the compound of formula (III), the compound is described by formul
(111-1 ):
Figure imgf000009_0001
wherein R1 , R2, R3, R4, R5, R6, R7, R9, X, n, d, L, and E are as defined above, or a pharmaceutically acceptable salt thereof.
In some embodiments of the compound of formula (III), the compound is described by formul
(III-2):
Figure imgf000009_0002
wherein R1 is a lipophilic moiety; R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2; R6 is hydrogen or methyl; X is O or NH; d is 1 , 2, 3, 4, 5, or 6; L is a linker; and each E is, independently, a
monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
In some embodiments of the compound of formula (I), (1-1 ), or (I-2), R8 is -(0(CH2)a)bR', -(NH(CH2)a)bR', -(S(CH2)a)bR', -(0(CH2)a)bN(R')2, -(NH(CH2)a)bN(R')2, -(S(CH2)a)bN(R')2,
-(0(CH2)a)bOR', -(NH(CH2)a)bOR', -(S(CH2)a)bOR\ -(OCH2CH2)a(NHCH2CH2)bN(R')2, -(OCH2CH2)a(NHCH2CH2)bOR', -(NHCH2CH2)a(OCH2CH2)bN(R')2, or -(NHCH2CH2)a(OCH2CH2)bOR'; each of a and b is, independently, an integer from 1 to 5; and each R' is, independently, hydrogen or optionally substituted C1 -C5 alkyi, or a pharmaceutically acceptable salt thereof. In some embodiments, R8 is -OCH2CH2N(R')2, -NHCH2CH2N(R')2, -(NHCH2CH2)2N(R')2, -NHCH2CH2OR', -(NHCH2CH2)20R', -OCH2CH2NHCH2CH2N(R')2, -NHCH2CH2OCH2CH2N(R')2,
-NHCH2CH2(OCH2CH2)2N(R')2, -NHCH2CH2(OCH2CH2)3N(R')2, -OCH2CH2NHCH2CH2OR',
-NHCH2CH2OCH2CH2OR', or -NHCH2CH2(OCH2CH2)30R'; each R' is, independently, hydrogen or methyl; or a pharmaceutically acceptable salt thereof.
In some embodiments of the compound of formula (II), (11-1 ), or (II-2), R8 is -(0(CH2)a)bR', -(NH(CH2)a)bR', -(S(CH2)a)bR', -(0(CH2)a)bN(R')2, -(NH(CH2)a)bN(R")2, -(S(CH2)a)bN(R')2,
-(0(CH2)a)bOR', -(NH(CH2)a)bOR', -(S(CH2)a)bOR', -(OCH2CH2)a(NHCH2CH2)bN(R')2,
-(OCH2CH2)a(NHCH2CH2)bOR', -(NHCH2CH2)a(OCH2CH2)bN(R')2, or -(NHCH2CH2)a(OCH2CH2)bOR'; each of a and b is, independently, an integer from 1 to 5; and each R' is, independently, hydrogen or optionally substituted C1 -C5 alkyi; and each R" is, independently, hydrogen, or C1 -C10 alkyi, or a pharmaceutically acceptable salt thereof. In some embodiments, R8 is -OCH2CH2N(R')2,
-NHCH2CH2N(R")2, -(NHCH2CH2)2N(R")2, -NHCH2CH2OR', -(NHCH2CH2)20R',
-OCH2CH2NHCH2CH2N(R')2, -NHCH2CH2OCH2CH2N(R')2, -NHCH2CH2(OCH2CH2)2N(R')2,
-NHCH2CH2(OCH2CH2)3N(R')2, -OCH2CH2NHCH2CH2OR', -NHCH2CH2OCH2CH2OR', or
-NHCH2CH2(OCH2CH2)30R'; each R' is, independently, hydrogen or methyl; each R" is, independently, hydrogen or methyl; or a pharmaceutically acceptable salt thereof.
In some embodiments of the compound of formula (I), (1-1 ), (I-2), (II), (11-1 ), or (II-2), R8 is
Figure imgf000010_0001
In some embodiments of the compounds of formula (I), (1-1 ), (I-2), (II), (11-1 ), or (II-2), R8 is
-(0(CH2)a)bN+(R')3, -(NH(CH2)a)bN+(R')3, -(S(CH2)a)bN+(R')3, -(OCH2CH2)a(NHCH2CH2)bN+(R')3, or -(NHCH2CH2)a(OCH2CH2)bN+(R')3; each of a and b is, independently, an integer from 1 to 5; and each R' is, independently, hydrogen or optionally substituted C1 -C5 alkyl, or a pharmaceutically acceptable salt thereof. In some embodiments, R8 is -OCH2CH2N+(R')3, -(OCH2CH2)2N+(R')3, -NHCH2CH2N+(R')3, or -(NHCH2CH2)2N+(R')3; each R' is, independently, hydrogen or methyl, or a pharmaceutically acceptable salt thereof. In some embodiments, R8 is
Figure imgf000011_0001
In some embodiments of the compound of formula (I), (1-1 ), (I-2), (II), (11-1 ), or (II-2), R' is
Figure imgf000011_0002
wherein each RA is, independently, hydrogen or optionally substituted C1 -C1 0 alkyl. some embodiments of the compound of formula (I), the compound is described by formul (I-3):
Figure imgf000012_0001
wherein R1 is a lipophilic moiety; R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2;R6 is hydrogen or methyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (I-4) or (I-5):
Figure imgf000012_0002
wherein R1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof. In some embodiments of the compound of formula (I), the compound is described by formula
(1-6):
Figure imgf000013_0001
wherein R1 is a lipophilic moiety; R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2; R6 is hydrogen or methyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (I-7):
Figure imgf000013_0002
wherein R1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof. In some embodiments of the compound of formula (I), the compound is described by formula
(1-8):
Figure imgf000014_0001
wherein R1 is a lipophilic moiety; R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2; R6 is hydrogen or methyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (I-9) or (1-10):
Figure imgf000014_0002
wherein R1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof. In some embodiments of the compound of formula (II), the compound is described by formula
(II-3):
Figure imgf000015_0001
wherein R1 is a lipophilic moiety; R6 is hydrogen or methyl ; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (II-4):
Figure imgf000015_0002
wherein R1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof. In some embodiments of the compound of formula (II), the compound is described by formula
(11-5):
Figure imgf000016_0001
wherein R1 is a lipophilic moiety; R6 is hydrogen or methyl ; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (II-6):
Figure imgf000016_0002
wherein R1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof. In some embodiments of the compound of formula (II), the compound is described by formula
(11-7):
Figure imgf000017_0001
wherein R1 is a lipophilic moiety; R6 is hydrogen or methyl ; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (II-8):
Figure imgf000017_0002
wherein R1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof. In some embodiments of the compound of formula (III), the compound is described by formula
(111-3):
Figure imgf000018_0001
wherein R1 is a lipophilic moiety; R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2; R6 is hydrogen or methyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (III-4):
Figure imgf000018_0002
wherein R1 is a lipophilic moiety; or a pharmaceutically acceptable salt thereof.
In some embodiments of the compounds described herein, R1 is
Figure imgf000018_0003
each of X and Y is, independently, optionally substituted alkyl, optionally substituted heteroalkyi, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene, or is absent; Z is optionally substituted alkyl, optionally substituted heteroalkyi, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, or is absent;
at least one of X, Y, and Z is present; and wherein X and Y, when present, are joined by a direct bond, -0-, or -CH2=CH2- and Y and Z, when present, are joined by a direct bond, -0-, or
-CH2=CH2-,or a pharmaceutically acceptable salt thereof.
In some embodiments of the compounds described herein, R1 is
Figure imgf000019_0005
and X, Y, and Z,
together, form wherein RB is an optionally substituted C1 -C10 alkyl, or a
Figure imgf000019_0001
pharmaceutically acceptable salt thereof.
In some embodiments of the compounds described herein, R1 is
Figure imgf000019_0006
and X, Y, and Z,
together, form
Figure imgf000019_0002
wherein RB is optionally substituted C1 -C10 alkyl, or a
pharmaceutically acceptable salt thereof.
In some embodiments of the compounds described herein, R1 is
Figure imgf000019_0007
and X, Y, and Z,
together, form
Figure imgf000019_0003
wherein RB is optionally substituted C1 -C8 alkyl, or a pharmaceutically acceptable salt thereof.
In some embodiments of the compounds described herein, R1 is
Figure imgf000019_0008
and X, Y, and Z,
together, form
Figure imgf000019_0004
wherein RB is optionally substituted C1 -C6 alkyl, or a pharmaceutically acceptable salt thereof. In some embodiments of the compounds described herein, R1 is
Figure imgf000020_0001
In some embodiments of the compound of formula (I), the compound is described by formula (I-11) or (I-12):
Figure imgf000020_0002
wherein R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2; R6 is hydrogen or methyl; RB is optionally substituted C1 -C6 alkyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (1-13) or (1-14):
Figure imgf000021_0002
wherein RB is optionally substituted C1 -C6 alkyl, or a pharmaceutically acceptable salt thereof.
In some embodiments of the compound of formula (I), the compound is described by formula (I-15):
Figure imgf000021_0001
wherein R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2; R6 is hydrogen or methyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (1-16):
Figure imgf000022_0001
or a pharmaceutically acceptable salt thereof.
In some embodiments of the compound of formula (I), the compound is described by formula (1-17) or (1-18):
Figure imgf000022_0002
wherein R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2; R6 is hydrogen or methyl; RB is optionally substituted C1 -C6 alkyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (1-19) or (I-20):
Figure imgf000023_0001
wherein RB is optionally substituted C1 -C6 alkyl, or a pharmaceutically acceptable salt thereof.
In some embodiments of the compound of formula (II), the compound is described by formula (II-9) or (11-10):
Figure imgf000023_0002
wherein R6 is hydrogen or methyl; RB is optionally substituted C1 -C6 alkyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (11-1 1 ) or (11-12):
Figure imgf000024_0001
wherein RB is optionally substituted C1 -C6 alkyl, or a pharmaceutically acceptable salt thereof.
In some embodiments of the compound of formula (II), the compound is described by formula (11-13) or (11-14):
Figure imgf000024_0002
wherein R6 is hydrogen or methyl; RB is optionally substituted C1 -C6 alkyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (11-15) or (11-16):
Figure imgf000025_0001
wherein RB is optionally substituted C1 -C6 alkyl, or a pharmaceutically acceptable salt thereof.
In some embodiments of the compound of formula (II), the compound is described by formula (11-1 -18):
Figure imgf000025_0002
wherein R6 is hydrogen or methyl; and RB is optionally substituted C1 -C6 alkyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is described by formula (11-19) or (II-20):
Figure imgf000025_0003
In some embodiments of the compound of formula (III), the compound is described by formula -5) or (111-6):
Figure imgf000026_0001
wherein d is 1 , 2, 3, or 4; RB is optionally substituted C1 -C6 alkyl; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
In some embodiments of the compounds described herein, L is a bond.
In some embodiments of the compounds described herein, L is described by formula (L-l):
Figure imgf000026_0002
wherein I1 is a bond attached to the β-1 ,3-glucan synthase inhibitor; I2 is a bond attached to E; each of
U1 , U2, U3, and U4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -
C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C1 -C15 heteroarylene; each of V1 , V2, V3, V4, and V5 is, independently, O, S, NR.', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino; wherein R' is H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyi, optionally substituted C2-C20 alkenyl, optionally substituted
C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20
heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C5-C15 heteroaryl ; and each of f, g, h, i, j, k, I, m, and n is, independently, 0 or 1 .
In some embodiments of formula (L-l), each of U1 , U2, U3, and U4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C1 5 arylene, or optionally substituted C1 -C15 heteroarylene; each of V1 , V2, V3, V4, and V5 is,
independently, O, S, NR', P, carbonyl; R' is H or optionally substituted C1 -C20 alkyl; and each of f, g, h, i, j, k, I, m, and n is, independently, 0 or 1 .
In some embodiments, L is described by formula (L- II ):
Figure imgf000027_0001
wherein I1 is a bond attached to the β-1 ,3-glucan synthase inhibitor; I2 is a bond attached to E; each of U1 , U2, U3, and U4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C15 arylene, or optionally substituted C1 -C15 heteroarylene; each of V2, V3, V4, and V5 is, independently, O, S, NR', P, carbonyl; R' is H or optionally substituted C1 -C20 alkyl; and each of h, i, j, k, I, m, and n is, independently, 0 or 1 .
In some embodiments, L is described by formula (L-I2):
Figure imgf000027_0002
wherein I1 is a bond attached to the β-1 ,3-glucan synthase inhibitor; I2 is a bond attached to E; each of U1 , U2, U3, and U4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C15 arylene, or optionally substituted C1 -C15 heteroarylene; each of V2, V3, and V4 is, independently, O, S, NR', P, carbonyl ; R' is H or optionally substituted C1 -C20 alkyl; and each of h, i, j, k, I, and m is, independently, 0 or 1 .
In some embodiments, L is described by formula (L-I3):
Figure imgf000027_0003
wherein I1 is a bond attached to the β-1 ,3-glucan synthase inhibitor; I2 is a bond attached to E; each of U1 , U2, U3, and U4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C15 arylene, or optionally substituted C1 -C15 heteroarylene; each of V2, V3, and V4 is, independently, O, S, NR', P, carbonyl ; R' is H or optionally substituted C1 -C20 alkyl; and each of h, i, j, k, I, and m is, independently, 0 or 1 .
In some embodiments, L is described by formula (L-I4):
Figure imgf000028_0001
wherein I1 is a bond attached to the β-1 ,3-glucan synthase inhibitor; I2 is a bond attached to E;
each of U1 , U2, U3, and U4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C15 arylene, or optionally substituted C1 -C15 heteroarylene; each of V2, V3, and V4 is, independently, O, S, NR', P, carbonyl ; R' is H or optionally substituted C1 -C20 alkyl; and each of h, i, j, k, I, and m is, independently, 0 or 1 .
In some embodiments, L is
Figure imgf000028_0002
Figure imgf000029_0001
wherein each of p, q, r, and s is, independently, an integer from 1 to 10.
In some embodiments of the compounds described herein, L is described by formula (L-II):
Figure imgf000029_0002
Wherein LA is described by formula GA1-(ZA1)g1-(YA1)h1-(ZA2)i1-(YA2)j1-(ZA3)k1-(YA3)l1-(ZA4)m1-(YA4)n1- (ZA5)o1-GA2; LB is described by formula GB1-(ZB1)g2-(YB1)h2-(ZB2)i2-(YB2)j2-(ZB3)k2-(YB3)l2-(ZB4)m2-(YB4)n2- (ZB5)o2-GB2; LC is described by formula GC1-(ZC1)g3-(YC1)h3-(ZC2)i3-(YC2)j3-(ZC3)k3-(YC3)l3-(ZC4)m3-(YC4)n3- (ZC5)o3-GC2; GA1 is a bond attached to N in formula (L-II); GA2 is a bond attached to the β-1,3-glucan synthase inhibitor; GB1 is a bond attached to N in formula (L-II); GB2 is a bond attached to a first monosaccharide or oligosaccharide moiety, E1; GC1 is a bond attached to N in formula (L-II); GC2 is a bond attached to a second monosaccharide or oligosaccharide moiety, E2; each of YA1, YA2, YA3, YA4, YB1, YB2, YB3, YB4, YC1, YC2, YC3, and YC4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C1-C15 heteroarylene; each of ZA1, ZA2, ZA3, ZA4, ZA5, ZB1, ZB2, ZB3, ZB4, ZB5, ZC1, ZC2, ZC3, ZC4, and ZC5 is, independently, O, S, NRi, P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino;
wherein Ri is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C5-C15 heteroaryl; and each of g1, h1, i1, j1, k1, l1, m1, n1, o1, g2, h2, i2, j2, k2, l2, m2, n2, o2, g3, h3, i3, j3, k3, l3, m3, n3, and o3 is, independently, 0 or 1. In some embodiments, each of YA1, YA2, YA3, YA4, YB1, YB2, YB3, YB4, YC1, YC2, YC3, and YC4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C15 arylene, or optionally substituted C1-C15 heteroarylene; each of ZA1, ZA2, ZA3, ZA4, ZA5, ZB1, ZB2, ZB3, ZB4, ZB5, ZC1, ZC2, ZC3, ZC4, and ZC5 is, independently, O, S, NRi, P, carbonyl; Ri is H or optionally substituted C1-C20 alkyl; and each of g1, h1, i1, j1, k1, l1, m1, n1, o1, g2, h2, i2, j2, k2, l2, m2, n2, o2, g3, h3, i3, j3, k3, l3, m3, n3, and o3 is, independently, 0 or 1.
In some embodiments of the compounds described herein, L is
Figure imgf000030_0001
wherein each of p, q, r, s, and t is, independently, an integer from 1 to 10.
In some embodiments, L is
Figure imgf000030_0002
In some embodiments, L is
Figure imgf000030_0003
Figure imgf000031_0001
wherein each of p, q, r, s, t, and u is, independently, an integer from 1 to 10.
In some embodiments of the compounds described herein, L is described by formula (L-III):
Figure imgf000031_0002
wherein LA is described by formula GA1-(ZA1)g1-(YA1)h1-(ZA2)i1-(YA2)j1-(ZA3)k1-(YA3)l1-(ZA4)m1-(YA4)n1- (ZA5)o1-GA2; LB is described by formula GB1-(ZB1)g2-(YB1)h2-(ZB2)i2-(YB2)j2-(ZB3)k2-(YB3)l2-(ZB4)m2-(YB4)n2- (ZB5)o2-GB2; LC is described by formula GC1-(ZC1)g3-(YC1)h3-(ZC2)i3-(YC2)j3-(ZC3)k3-(YC3)l3-(ZC4)m3-(YC4)n3- (ZC5)o3-GC2; LD is described by formula GD1-(ZD1)g4-(YD1)h4-(ZD2)i4-(YD2)j4-(ZD3)k4-(YD3)l4-(ZD4)m4-(YD4)n4- (ZD5)o4-GD2; LE is described by formula GE1-(ZE1)g5-(YE1)h5-(ZE2)i5-(YE2)j5-(ZE3)k5-(YE3)l5-(ZE4)m5-(YE4)n5- (ZE5)o5-GE2, or is hydrogen; LF is described by formula GF1-(ZF1)g6-(YF1)h6-(ZF2)i6-(YF2)j6-(ZF3)k6-(YF3)l6- (ZF4)m6-(YF4)n6-(ZF5)o6-GF2; LG is described by formula GG1-(ZG1)g7-(YG1)h7-(ZG2)i7-(YG2)j7-(ZG3)k7-(YG3)l7- (ZG4)m7-(YG4)n7-(ZG5)o7-GG2, or is hydrogen; GA1 is a bond attached to NA in formula (L-III); GA2 is a bond attached to the β-1,3-glucan synthase inhibitor; GB1 is a bond attached to NA in formula (L-III); GB2 is a bond attached to NB in formula (L-III); GC1 is a bond attached to NA in formula (L-III); GC2 is a bond attached to NC in formula (L-III); GD1 is a bond attached to NB in formula (L-III); GD2 is a bond attached to a first monosaccharide or oligosaccharide moiety, E1; GE1 is a bond attached to NB in formula (L-III); GE2 is a bond attached to a second monosaccharide or oligosaccharide moiety, E2; GF1 is a bond attached to NC in formula (L-III); GF2 is a bond attached to a third monosaccharide or oligosaccharide moiety, E3; GG1 is a bond attached to NC in formula (L-III); GG2 is a bond attached to a fourth monosaccharide or oligosaccharide moiety, E4; each of YA1, YA2, YA3, YA4, YB1, YB2, YB3, YB4, YC1, YC2, YC3, YC4, YD1, YD2, YD3, YD4, YE1, YE2, YE3, YE4, YF1, YF2, YF3, YF4, YG1, YG2, YG3, and YG4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C1-C15 heteroarylene; each of ZA1, ZA2, ZA3, ZA4, ZA5, ZB1, ZB2, ZB3, ZB4, ZB5, ZC1, ZC2, ZC3, ZC4, ZC5, ZD1, ZD2, ZD3, ZD4, ZD5, ZE1, ZE2, ZE3, ZE4, ZE5, ZF1, ZF2, ZF3, ZF4, ZF5, ZG1, ZG2, ZG3, ZG4, and ZG5 is, independently, O, S, NRi, P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino; wherein Ri is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C5-C15 heteroaryl; each of g1, h1, i1, j1, k1, l1, m1, n1, o1, g2, h2, i2, j2, k2, l2, m2, n2, o2, g3, h3, i3, j3, k3, l3, m3, n3, o3, g4, h4, i4, j4, k4, l4, m4, n4, o4, g5, h5, i5, j5, k5, l5, m5, n5, o5, g6, h6, i6, j6, k6, l6, m6, n6, o6, g7, h7, i7, j7, k7, l7, m7, n7, and o7 is, independently, 0 or 1; and each of NA, NB, and NC is a nitrogen.
In some embodiments, each of YA1, YA2, YA3, YA4, YB1, YB2, YB3, YB4, YC1, YC2, YC3, YC4, YD1, YD2, YD3, YD4, YE1, YE2, YE3, YE4, YF1, YF2, YF3, YF4, YG1, YG2, YG3, and YG4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2- C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C15 arylene, or optionally substituted C1-C15 heteroarylene; each of ZA1, ZA2, ZA3, ZA4, ZA5, ZB1, ZB2, ZB3, ZB4, ZB5, ZC1, ZC2, ZC3, ZC4, ZC5, ZD1, ZD2, ZD3, ZD4, ZD5, ZE1, ZE2, ZE3, ZE4, ZE5, ZF1, ZF2, ZF3, ZF4, ZF5, ZG1, ZG2, ZG3, ZG4, and ZG5 is, independently, O, S, NRi, P, carbonyl; Ri is H or optionally substituted C1- C20 alkyl; and each of g1, h1, i1, j1, k1, l1, m1, n1, o1, g2, h2, i2, j2, k2, l2, m2, n2, o2, g3, h3, i3, j3, k3, l3, m3, n3, o3, g4, h4, i4, j4, k4, l4, m4, n4, o4, g5, h5, i5, j5, k5, l5, m5, n5, o5, g6, h6, i6, j6, k6, l6, m6, n6, o6, g7, h7, i7, j7, k7, l7, m7, n7, and o7 is, independently, 0 or 1.
In some embodiments, L is
Figure imgf000033_0001
wherein each of p, q, r, s, t, u, v, w, x, y, and z is, independently, an integer from 1 to 10.
In some embodiments, L is
Figure imgf000033_0002
In some embodiments of the compounds described herein, L is
Figure imgf000033_0003
,
wherein each of p, q, r, s, and t is, independently, an integer from 1 to 10.
In some embodiments of the compounds described herein, L is described by formula (L-IV):
Figure imgf000033_0004
wherein LA is described by formula GA1-(ZA1)g1-(YA1)h1-(ZA2)i1-(YA2)j1-(ZA3)k1-(YA3)l1-(ZA4)m1-(YA4)n1- (ZA5)o1-GA2; LB is described by formula GB1-(ZB1)g2-(YB1)h2-(ZB2)i2-(YB2)j2-(ZB3)k2-(YB3)l2-(ZB4)m2-(YB4)n2- (ZB5)o2-GB2; LC is described by formula GC1-(ZC1)g3-(YC1)h3-(ZC2)i3-(YC2)j3-(ZC3)k3-(YC3)l3-(ZC4)m3-(YC4)n3- (ZC5)o3-GC2; LD is described by formula GD1-(ZD1)g4-(YD1)h4-(ZD2)i4-(YD2)j4-(ZD3)k4-(YD3)l4-(ZD4)m4-(YD4)n4- (ZD5)o4-GD2, or is hydrogen; GA1 is a bond attached to N in formula (L-IV); GA2 is a bond attached to the β-1,3-glucan synthase inhibitor; GB1 is a bond attached to C in formula (L-IV); GB2 is a bond attached to a first monosaccharide or oligosaccharide moiety, E1; GC1 is a bond attached to C in formula (L-IV);
GC2 is a bond attached to a second monosaccharide or oligosaccharide moiety, E2; GD1 is a bond attached to C in formula (L-IV); GD2 is a bond attached to a third monosaccharide or oligosaccharide moiety, E3; each of YA1, YA2, YA3, YA4, YB1, YB2, YB3, YB4, YC1, YC2, YC3, YC4, YD1, YD2, YD3, and YD4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C2-C15 heteroarylene; each of ZA1, ZA2, ZA3, ZA4, ZA5, ZB1, ZB2, ZB3, ZB4, ZB5, ZC1, ZC2, ZC3, ZC4, ZC5, ZD1, ZD2, ZD3, ZD4, and ZD5 is, independently, O, S, NRi, P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino; Ri is H, optionally substituted C1- C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2- C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl; and each of g1, h1, i1, j1, k1, l1, m1, n1, o1, g2, h2, i2, j2, k2, l2, m2, n2, o2, g3, h3, i3, j3, k3, l3, m3, n3, o3, g4, h4, i4, j4, k4, l4, m4, n4, and o4 is, independently, 0 or 1; or a pharmaceutically acceptable salt thereof.
In some embodiments, L is
Figure imgf000035_0001
wherein each of p, q, r, s, and t is, independently, an integer from 1 to 10.
In some embodiments of the compounds descried herein, E is
Figure imgf000035_0002
In some embodiments, E is
Figure imgf000035_0003
In some embodiments of the compounds described herein, the monosaccharide moiety includes an optionally substituted C6-C9 monosaccharide residue. In some embodiments of the compounds described herein, the oligosaccharide moiety includes 2-18 optionally substituted C6-C9 monosaccharide residues.
In some embodiments, each of the optionally substituted C6-C9 monosaccharide residues is, independently, glucose (Glc), galactose (Gal), mannose (Man), allose (All), altrose (Alt), gulose (Gul), idose (Ido), talose (Tal), fucose (Fuc), rhamnose (Rha or L-Rha), thia-rhamnose (thia-Rha or thia-L- Rha), quinovose (Qui), 2-deoxyglucose (2-dGlc), glucosamine (GlcN), galactosamine (GaIN), mannosamine (ManN), fucosamine (FucN), quinovosamine (QuiN), N-Acetyl-glucosamine (GlcNAc), N-Acetyl-galactosamine (GalNAc), N-Acetyl-mannosamine (ManNAc), N-acetyl-fucosamine (FucNAc), N-acetyl-quinovosamine (QuiNAc), glucuronic acid (GIcA), galacturonic acid (GalA), mannuronic acid (ManA), iduronic acid (IdoA), sialic acid (Sia), neuraminic acid (Neu), N-Acetyl-neuraminic acid
(Neu5Ac), N-Glycolyl-neuraminic acid (Neu5Gc), glucitol (Glc-ol), galactitol (Gal-ol), mannitol (Man- ol), fructose (Fru), sorbose (Sor), tagatose (Tag), thevetose (The), acofriose (Aco), digitoxose (Dig), cymarose (Cym), abequose (Abe), colitose (Col), tyvelose (Tyv), ascarylose (Asc), paratose (Par), or N-acetyl-muramic acid (MurNAc). In some embodiments, each of the optionally substituted C6-C9 monosaccharide residues is, independently, an optionally substituted C6 monosaccharide residue
(e.g.,
Figure imgf000036_0001
In some embodiments, the optionally substituted C6 monosaccharide residue is
Figure imgf000036_0002
In some embodiments of the compounds described herein, the optionally substituted C6
monosaccharide residue is
Figure imgf000036_0003
In some embodiments of the compounds described herein, E is any one of the moieties in Tables 2A and 2B.
In some embodiments of the compounds described herein, E directly or indirectly activates an immune cell. In some embodiments of the compounds described herein, a concentration of the compound, or a pharmaceutically acceptable salt thereof, that activates an immune cell is less than or equal to 10,000 nM. In some embodiments, the concentration of the compound, or a pharmaceutically acceptable salt thereof, that activates an immune cell is less than or equal to equal to 1 ,000 nM. In some embodiments, the concentration of the compound, or a pharmaceutically acceptable salt thereof, that activates an immune cell is less than or equal to equal to 100 nM.
In some embodiments, E is a ligand to an innate immune receptor. In some embodiments, the innate immune receptor is AICL, BDCA2, CLEC2, Complement receptor 3, Complement receptor 4, DCIR, dectin-1 , dectin-2, DC-SIGN, a C-Type lectin receptor, MMR, langerin, TLR2, Mincle, MBL, or KCR.
In some embodiments of the compounds described herein, E binds to an antibody. In some embodiments, the antibody is a natural antibody (e.g., an antibody of the immunoglobulin M (IgM) isotype). In some embodiments, the antibody is anti-aGal antibody or anti-aRha antibody. In some embodiments, E binds to an antibody and is any one of the moieties in Tables 2A and 2B.
In another aspect, the invention features a compound selected from
Figure imgf000037_0001
Figure imgf000038_0001
or pharmaceutically acceptable salts thereof.
In some embodiments, the pharmaceutically acceptable salt of any one of Compounds 1 -3, 4a, 4b, 5a-5c, and 6 is a formate salt.
In some embodiments, the pharmaceutically acceptable salt of any one of Compounds 1 -3,
4a, 4b, 5a-5c, and 6 is an acetate salt. In some embodiments, the compound is Compound 1 ,
Figure imgf000039_0002
or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a formate salt. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is an acetate salt.
In some embodiments, the compound is Compound 4a
Figure imgf000039_0001
or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt of Compound 4a is a formate salt. In some embodiments, the pharmaceutically acceptable salt of Compound 4a is an acetate salt.
In another aspect, the invention features a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In another aspect, the invention features a method of treating a fungal infection in a subject by administering to the subject a pharmaceutical composition including a compound described herein in an amount sufficient to treat the infection.
In another aspect, the invention features a method of stabilizing or inhibiting a fungal infection in a subject by administering to the subject a pharmaceutical composition including a compound described herein in an amount sufficient to stabilize or inhibit the infection.
In some embodiments, the subject is immunocompromised.
In some embodiments of the methods described herein, the pharmaceutical composition is administered intravenously. In some embodiments, the pharmaceutical composition is administered subcutaneously. In some embodiments, the pharmaceutical composition is administered topically. In some embodiments, the pharmaceutical composition is administered orally.
In some embodiments, the pharmaceutical composition is administered to treat a blood stream infection or tissue infection in the subject.
In some embodiments of the methods described herein, the infection is selected from candidemia, invasive candidiasis, tinea capitis, tinea corporis, tinea pedis, onychomycosis, perionychomycosis, pityriasis versicolor, oral thrush, vaginal candidiasis, respiratory tract candidiasis, biliary candidiasis, eosophageal candidiasis, urinary tract candidiasis, systemic candidiasis, mucocutaneous candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, fungal sinusitis, or chronic sinusitis. In some embodiments, the infection is candidemia or invasive candidiasis.
In some embodiments of the methods described herein, the fungal infection is an infection of Candida albicans, C. parapsilosis, C. glabrata, C. guilliermondii, C. krusei, C. tropicalis, C. lusitaniae, Aspergillus fumigatus, A. flavus, A. terreus, A. niger, A. candidus, A. clavatus, or A. ochraceus.
In some embodiments of the methods described herein, the fungal infection is an infection of
Fusarium solani, Fusarium oxysporum, Fusarium verticillioides, Fusarium moniliforme, Scedosporium apiospermum, Scedosporium prolificans, Mucor circinelloides, Mucor azygosporus, Mucor circinelloides, Rhizopus oryzae, Rizomucor pusillus, Cunninghamella bertholletiae, Apophysomyces elegans, Absidia corymbifera, Saksenaea vasiformis, Acremonium strictum, Paecilomyces lilacinus, Paecilomyces variotii, Trichoderma longibrachiatum, Trichoderma harzianum, Trichoderma koningii, Trichoderma pseudokoningii, Trichoderma citrinovirde, Trichoderma viride, Stachybotrys chartarum, Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans, Trichophyton violaceum, Microsporum gypseum, Epidermophyton floccosum, Sporothrix schenckii, Histoplasma capsulatum, Coccidioides immitis, Coccidioides posadasii, Blastomyces dermatitidis,
Paracoccidioides brasiliensis, Cladosporium trichoides, Exophiala jeanselmei, Exserohilum rostratum,
Exserohilum longirostratum, or Exserohilum mcginnisii.
In some embodiments of the methods described herein, the fungal infection is a
dermatophyte infection.
In some embodiments of the methods described herein, the pharmaceutical composition includes any one of Compounds 1 -6, or a pharmaceutically acceptable salt thereof.
In another aspect, the invention also features a method of stabilizing or inhibiting the growth of fungi, or killing fungi, the method including contacting the fungi or a site susceptible to fungal growth with a compound described herein, or a pharmaceutically acceptable salt thereof. Definitions
The term "covalently attached" refers to two parts of a compound that are linked to each other by a covalent bond formed between two atoms in the two parts of the compound. For example, in the compound described herein (e.g., a compound of any one of formulas (l)-(lll)), L serves as a linker that covalently attaches a β-1 ,3-glucan synthase inhibitor to at least one monosaccharide or oligosaccharide moiety. An amine group in the β-1 ,3-glucan synthase inhibitor may for an amide bond with a carboxylic acid in the linker and a carbon atom in the monosaccharide or oligosaccharide moiety may form a C-0 bond with an oxygen atom in the linker.
The terms "linker" and "L," as used herein, refer to a covalent linkage or connection between two or more components in a compound (e.g., the β-1 ,3-glucan synthase inhibitor and one or more monosaccharide or oligosaccharide moieties in a compound described herein). In some
embodiments, a compound described herein may contain a linker that has a divalent structure (e.g., a divalent linker), in which one terminus of the linker is conjugated to the β-1 ,3-glucan synthase inhibitor and the other terminus of the linker is conjugated to a monosaccharide or oligosaccharide moiety. In some embodiments, a compound described herein may contain a linker that has a trivalent structure (e.g., a trivalent linker). A trivalent linker has three arms, in which each arm is conjugated to a component of the compound (e.g., a first arm conjugated to the β-1 ,3-glucan synthase inhibitor, a second arm conjugated to a first monosaccharide or oligosaccharide moiety, and a third arm conjugated to a second monosaccharide or oligosaccharide moiety).
Molecules that may be used as linkers include at least two functional groups, which may be the same or different, e.g., two carboxylic acid groups, two amine groups, two sulfonic acid groups, a carboxylic acid group and an amine group, or a carboxy group and a sulfonic acid group. The first functional group may form a covalent linkage with a first component in the compound and the second functional group may form a covalent linkage with the second component in the compound. In some embodiments of a trivalent linker, the first arm of the linker may contain a dicarboxylic acid that can form a form a covalent linkage (e.g., an amide bond) with the β-1 ,3-glucan synthase inhibitor, the second arm of the linker may for a covalent linkage (e.g., a C-0 bond) with a first monosaccharide or oligosaccharide moiety in the compound, and the third arm of the linker may for a covalent linkage (e.g., a C-0 bond) with a second monosaccharide or oligosaccharide moiety in the compound. In some embodiments of a divalent linker, the divalent linker may contain two carboxylic acids, in which the first carboxylic acid may form a covalent linkage with one component (e.g., the β-1 ,3-glucan synthase inhibitor) in the compound and the second carboxylic acid may form a covalent linkage with another component (e.g., the monosaccharide or oligosaccharide moiety) in the compound.
Examples of dicarboxylic acids are described further herein. In some embodiments, a molecule containing one or more sulfonic acid groups may be used as a linker, in which the sulfonic acid group may form a sulfonamide linkage with a component in the compound. In some embodiments, a molecule containing one or more isocyanate groups may be used as a linker, in which the isocyanate group may form a urea linkage with a component in the compound. In some embodiments, a molecule containing one or more haloalkyl groups may be used as a linker, in which the haloalkyl group may form a covalent linkage, e.g., C-N and C-0 linkages, with a component in the compound.
In some embodiments, a linker provides space, rigidity, and/or flexibility between the two or more components. In some embodiments, a linker may be a bond, e.g., a covalent bond. The term "bond" refers to a chemical bond, e.g., an amide bond, a disulfide bond, a C-0 bond, a C-S bond, a C-0 bond, a N-N bond, or any kind of bond created from a chemical reaction, e.g., chemical conjugation. In some embodiments, a linker includes no more than 250 atoms (e.g., no more than 225, 200, 175, 1 50, 125, 100, 50, 25, 20, 15, or 10 atoms). In some embodiments, a linker includes no more than 250 non-hydrogen atoms (e.g., no more than 225, 200, 1 75, 150, 125, 100, 50, 25, 20, 15, or 10 non-hydrogen atoms). In some embodiments, the backbone of a linker includes no more than 250 atoms (e.g., no more than 225, 200, 175, 1 50, 125, 1 00, 50, 25, 20, 15, or 10 atoms). The "backbone" of a linker refers to the atoms in the linker that together form the shortest path from one part of a compound to another part of the compound (e.g., the shortest path linking a β-1 ,3-glucan synthase inhibitor and a monosaccharide or oligosaccharide moiety). The atoms in the backbone of the linker are directly involved in linking one part of a compound to another part of the compound (e.g., linking a β-1 ,3-glucan synthase inhibitor and a monosaccharide or oligosaccharide moiety). For examples, hydrogen atoms attached to carbons in the backbone of the linker are not considered as directly involved in linking one part of the compound to another part of the compound.
In some embodiments, a linker may include a synthetic group derived from, e.g., a synthetic polymer (e.g., a polyethylene glycol (PEG) polymer). In some embodiments, a linker may include one or more amino acid residues, such as D- or L-amino acid residues. In some embodiments, a linker may be a residue of an amino acid sequence (e.g., a 1 -25 amino acid, 1 -10 amino acid, 1 -9 amino acid, 1 -8 amino acid, 1 -7 amino acid, 1 -6 amino acid, 1 -5 amino acid, 1 -4 amino acid, 1 -3 amino acid, 1 -2 amino acid, or 1 amino acid sequence). In some embodiments, a linker may include one or more, e.g., 1 -100, 1 -50, 1 -25, 1 -10, 1 -5, or 1 -3, optionally substituted alkylene, optionally substituted heteroalkylene (e.g., a PEG unit), optionally substituted alkenylene, optionally substituted
heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted cycloalkenylene, optionally substituted heterocycloalkenylene, optionally substituted cycloalkynylene, optionally substituted heterocycloalkynylene, optionally substituted arylene, optionally substituted heteroarylene (e.g., pyridine), O, S, NR' (R' is H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkenyl, optionally substituted cycloalkynyl, optionally substituted heterocycloalkynyl, optionally substituted aryl, or optionally substituted heteroaryl), P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino. For example, a linker may include one or more optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene (e.g., a PEG unit), optionally substituted C2-C20 alkenylene (e.g., C2 alkenylene), optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene (e.g., cyclopropylene, cyclobutylene), optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene (e.g., C6 arylene), optionally substituted C1 -C15 heteroarylene (e.g., imidazole, pyridine), O, S, NR' (R' is H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2- C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C1 -C15 heteroaryl), P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino.
The term "lipophilic moiety," as used herein, refers to a portion, substituent, or functional group of a compound that is, in general, hydrophobic and non-polar. A moiety is lipophilic if it has a hydrophobicity determined using a cLogP value of greater than 0, such as about 0.25 or greater, about 0.5 or greater, about 1 or greater, about 2 or greater, 0.25-5, 0.5-4 or 2-3. As used herein, the term "cLogP" refers to the calculated partition coefficient of a molecule or portion of a molecule. The partition coefficient is the ratio of concentrations of a compound in a mixture of two immiscible phases at equilibrium (e.g., octanol and water) and measures the hydrophobicity or hydrophilicity of a compound. A variety of methods are available in the art for determining cLogP. For example, in some embodiments, cLogP can be determined using quantitative structure-property relationship algorithms known in the art (e.g., using fragment based prediction methods that predict the logP of a compound by determining the sum of its non-overlapping molecular fragments). Several algorithms for calculating cLogP are known in the art including those used by molecular editing software such as CHEMDRAW® Pro, Version 12.0.2.1092 (Camrbridgesoft, Cambridge, MA) and MARVINSKETCH® (ChemAxon, Budapest, Hungary). A moiety is considered lipophilic if it has a cLogP value described above in at least one of the above methods. A lipophilic moiety having the stated cLogP value will be considered lipophilic, even though it may have a positive charge or a polar substituent.
In some embodiments, a lipophilic moiety contains entirely hydrocarbons. In some embodiments, a lipophilic moiety may contain one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms, wherein each heteroatom is, independently, selected from N, O, and S (e.g., an indolyl), or one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, halo groups, which, due to the structure of the moiety and/or small differences in electronegativity between the heteroatoms or halo groups and the hydrocarbons, do not induce significant chemical polarity into the lipophilic moiety. Thus, in some embodiments, a lipophilic moiety having, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms and/or, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, halo atoms may still be considered non-polar. In some embodiments, a lipophilic moiety may be optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted heteroalkynyl, or optionally substituted heteroaryl, or halo forms thereof, wherein the optional substituents are also lipophilic (such as alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
heteroalkynyl, aryl, or heteroaryl) or are not lipophilic but do not change the overall lipophilic character of the moiety, i.e., the moiety has a cLogP value of greater than 0. For example, octanol contains a polar group, OH, but is still a lipophilic moiety. In some embodiments, a lipophilic moiety may be benzyl, isobutyl, sec-butyl, isopropyl, n-propyl, methyl, biphenylmethyl, n-octyl, or substituted indolyl (e.g., alkyl substituted indolyl). In some embodiments, a lipophilic moiety may be the side chain of a hydrophobic amino acid residue, e.g., leucine, isoleucine, alanine, phenylalanine, valine, and proline, or groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and pyrrolidinyl. For example, R1 in a compound described herein may be a lipophilic moiety.
The terms "alkyl," "alkenyl," and "alkynyl," as used herein, include straight-chain and branched-chain monovalent substituents, as well as combinations of these, containing only C and H when unsubstituted. When the alkyl group includes at least one carbon-carbon double bond or carbon-carbon triple bond, the alkyl group can be referred to as an "alkenyl" or "alkynyl" group respectively. The monovalency of an alkyl, alkenyl, or alkynyl group does not include the optional substituents on the alkyl, alkenyl, or alkynyl group. For example, if an alkyl, alkenyl, or alkynyl group is attached to a compound, monovalency of the alkyl, alkenyl, or alkynyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl, alkenyl, or alkynyl group. In some embodiments, the alkyl or heteroalkyl group may contain, e.g.,
1 - 20. 1 -18, 1 -16, 1 -14, 1 -12, 1 -10, 1 -8, 1 -6, 1 -4, or 1 -2 carbon atoms (e.g., C1 -C20, C1 -C18, C1 -C16, C1 -C14, C1 -C12, C1 -C10, C1 -C8, C1 -C6, C1 -C4, or C1 -C2). In some embodiments, the alkenyl, heteroalkenyl, alkynyl, or heteroalkynyl group may contain, e.g., 2-20, 2-18, 2-16, 2-14, 2-12, 2-10,
2- 8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2- C6, or C2-C4). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, tert-butyl, 2-propenyl, and 3-butynyl.
The term "cycloalkyl," as used herein, represents a monovalent saturated or unsaturated non- aromatic cyclic alkyl group. A cycloalkyl may have, e.g., three to twenty carbons (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C1 1 , C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkyl).
Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. When the cycloalkyl group includes at least one carbon-carbon double bond, the cycloalkyl group can be referred to as a "cycloalkenyl" group. A cycloalkenyl may have, e.g., four to twenty carbons (e.g., a C4-C7, C4-C8, C4-C9, C4-C10, C4-C1 1 , C4-C12, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenyl). Exemplary cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl. When the cycloalkyl group includes at least one carbon-carbon triple bond, the cycloalkyl group can be referred to as a "cycloalkynyl" group. A cycloalkynyl may have, e.g., eight to twenty carbons (e.g., a C8-C9, C8-C10, C8-C1 1 , C8-C12, C8-C14, C8-C16, C8-C18, or C8-C20 cycloalkynyl). The term "cycloalkyl" also includes a cyclic compound having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.1 .]heptyl and adamantane. The term "cycloalkyl" also includes bicyclic, tricyclic, and tetracyclic fused ring structures, e.g., decalin and spiro cyclic compounds.
The term "aryl," as used herein, refers to any monocyclic or fused ring bicyclic or tricyclic system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system, e.g., phenyl, naphthyl, or phenanthrene. In some embodiments, a ring system contains 5-15 ring member atoms or 5-10 ring member atoms. An aryl group may have, e.g., five to fifteen carbons (e.g., a C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5-C1 1 , C5-C12, C5-C13, C5-C14, or C5-C15 aryl). The term "heteroaryl" also refers to such monocyclic or fused bicyclic ring systems containing one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms selected from O, S and N. A heteroaryl group may have, e.g., one to fifteen carbons (e.g., a C1 -C3, C1 -C4, C1 -C5, C1 -C6, C1 -C7, C1 -C8, C1 -C9.
C1 -C10, C1 -C1 1 , C1 -C12, C1 -C13, C1 -C14, or C1 -C15 heteroaryl). The inclusion of a heteroatom permits inclusion of 5-membered rings to be considered aromatic as well as 6-membered rings. Thus, typical heteroaryl systems include, e.g., pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzoisoxazolyl, and imidazolyl. Because tautomers are possible, a group such as phthalimido is also considered heteroaryl. In some embodiments, the aryl or heteroaryl group is a 5- or 6-membered aromatic rings system optionally containing 1 -2 nitrogen atoms. In some
embodiments, the aryl or heteroaryl group is an optionally substituted phenyl, pyridyl, indolyl, pyrimidyl, pyridazinyl, benzothiazolyl, benzimidazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, or imidazopyridinyl. In some embodiments, the aryl group is phenyl. In some embodiments, an aryl group may be optionally substituted with a substituent such an aryl substituent, e.g., biphenyl.
The term "alkaryl," refers to an aryl group that is connected to an alkylene, alkenylene, or alkynylene group. In general, if a compound is attached to an alkaryl group, the alkylene, alkenylene, or alkynylene portion of the alkaryl is attached to the compound. In some embodiments, an alkaryl is C6-C35 alkaryl (e.g., C6-C16, C6-C14, C6-C12, C6-C10, C6-C9, C6-C8, C7, or C6 alkaryl), in which the number of carbons indicates the total number of carbons in both the aryl portion and the alkylene, alkenylene, or alkynylene portion of the alkaryl. Examples of alkaryls include, but are not limited to, (C1 -C8)alkylene(C6-C12)aryl, (C2-C8)alkenylene(C6-C12)aryl, or (C2-C8)alkynylene(C6-C12)aryl. In some embodiments, an alkaryl is benzyl. In a heteroalkaryl, one or more heteroatoms selected from N, O, and S may be present in the alkylene, alkenylene, or alkynylene portion of the alkaryl group and/or may be present in the aryl portion of the alkaryl group. In an optionally substituted alkaryl, the substituent may be present on the alkylene, alkenylene, or alkynylene portion of the alkaryl group and/or may be present on the aryl portion of the alkaryl group.
The term "amino," as used herein, represents -N(RX)2 or -N+(RX)3, where each Rx is, independently, H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two Rx combine to form a heterocycloalkyl. In some embodiment, the amino group is -NH2.
The term "alkamino," as used herein, refers to an amino group, described herein, that is attached to an alkylene (e.g., C1 -C5 alkylene), alkenylene (e.g., C2-C5 alkenylene), or alkynylene group (e.g., C2-C5 alkenylene). In general, if a compound is attached to an alkamino group, the alkylene, alkenylene, or alkynylene portion of the alkamino is attached to the compound. The amino portion of an alkamino refers to -N(RX)2 or -N+(RX)3, where each Rx is, independently, H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two Rx combine to form a heterocycloalkyl. In some embodiment, the amino portion of an alkamino is -NH2. An example of an alkamino group is C1 -C5 alkamino, e.g., C2 alkamino (e.g., CH2CH2NH2 or CH2CH2N(CH3)2). In a heteroalkamino group, one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms selected from N, O, and S may be present in the alkylene, alkenylene, or alkynylene portion of the heteroalkamino group. In some embodiments, an alkamino group may be optionally substituted. In a substituted alkamino group, the substituent may be present on the alkylene, alkenylene, or alkynylene portion of the alkamino group and/or may be present on the amino portion of the alkamino group.
The term "alkamide," as used herein, refers to an amide group that is attached to an alkylene (e.g., C1 -C5 alkylene), alkenylene (e.g., C2-C5 alkenylene), or alkynylene (e.g., C2-C5 alkenylene) group. In general, if a compound is attached to an alkamide group, the alkylene, alkenylene, or alkynylene portion of the alkamide is attached to the compound. The amide portion of an alkamide refers to -C(0)-N(RX)2, where each Rx is, independently, H, alkyl, alkenyl, alkynyl, aryl, alkaryl, cycloalkyl, or two Rx combine to form a heterocycloalkyl. In some embodiment, the amide portion of an alkamide is -C(0)NH2. An alkamide group may be -(CH2)2-C(0)NH2 or -CH2-C(0)NH2. In a heteroalkamide group, one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms selected from N, O, and S may be present in the alkylene, alkenylene, or alkynylene portion of the heteroalkamide group. In some embodiments, an alkamide group may be optionally substituted. In a substituted alkamide group, the substituent may be present on the alkylene, alkenylene, or alkynylene portion of the alkamide group and/or may be present on the amide portion of the alkamide group.
The terms "alkylene," "alkenylene," and "alkynylene," as used herein, refer to divalent groups having a specified size. In some embodiments, an alkylene may contain, e.g., 1 -20, 1 -18, 1 -16, 1 -14, 1 -12, 1 -10, 1 -8, 1 -6, 1 -4, or 1 -2 carbon atoms (e.g., C1 -C20, C1 -C18, C1 -C1 6, C1 -C14, C1 -C12, C1 -C10, C1 -C8, C1 -C6, C1 -C4, or C1 -C2). In some embodiments, an alkenylene or alkynylene may contain, e.g., 2-20, 2-18, 2-16, 2-14, 2-12, 2-10, 2-8, 2-6, or 2-4 carbon atoms (e.g., C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4). Alkylene, alkenylene, and/or alkynylene includes straight-chain and branched-chain forms, as well as combinations of these. The divalency of an alkylene, alkenylene, or alkynylene group does not include the optional substituents on the alkylene, alkenylene, or alkynylene group. For example, a β-1 ,3-glucan synthase inhibitor and a monosaccharide or oligosaccharide moiety may be attached to each other by way of a linker that includes alkylene, alkenylene, and/or alkynylene, or combinations thereof. Each of the alkylene, alkenylene, and/or alkynylene groups in the linker is considered divalent with respect to the two attachments on either end of alkylene, alkenylene, and/or alkynylene group. For example, if a linker includes -(optionally substituted alkylene)-(optionally substituted alkenylene)-(optionally substituted alkylene)-, the alkenylene is considered divalent with respect to its attachments to the two alkylenes at the ends of the linker. The optional substituents on the alkenylene are not included in the divalency of the alkenylene. The divalent nature of an alkylene, alkenylene, or alkynylene group (e.g., an alkylene, alkenylene, or alkynylene group in a linker) refers to both of the ends of the group and does not include optional substituents that may be present in an alkylene, alkenylene, or alkynylene group. Because they are divalent, they can link together multiple (e.g., two) parts of a compound, e.g., a β- 1 ,3-glucan synthase inhibitor and a monosaccharide or oligosaccharide moiety. Alkylene, alkenylene, and/or alkynylene groups can be substituted by the groups typically suitable as substituents for alkyl, alkenyl and alkynyl groups as set forth herein. For example, C=0 is a C1 alkylene that is substituted by an oxo (=0). For example, -HCR-C≡C- may be considered as an optionally substituted alkynylene and is considered a divalent group even though it has an optional substituent, R. Heteroalkylene, heteroalkenylene, and/or heteroalkynylene groups refer to alkylene, alkenylene, and/or alkynylene groups including one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms, e.g., N, O, and S. For example, a polyethylene glycol (PEG) polymer or a PEG unit -(CH2)2-0- in a PEG polymer is considered a heteroalkylene containing one or more oxygen atoms.
The term "cycloalkylene," as used herein, refers to a divalent cyclic group linking together two parts of a compound. For example, one carbon within the cycloalkylene group may be linked to one part of the compound, while another carbon within the cycloalkylene group may be linked to another part of the compound. A cycloalkylene group may include saturated or unsaturated non-aromatic cyclic groups. A cycloalkylene may have, e.g., three to twenty carbons in the cyclic portion of the cycloalkylene (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C1 1 , C3-C12, C3-C14, C3-C16, C3-C1 8, or C3-C20 cycloalkylene). When the cycloalkylene group includes at least one carbon-carbon double bond, the cycloalkylene group can be referred to as a "cycloalkenylene" group. A cycloalkenylene may have, e.g., four to twenty carbons in the cyclic portion of the cycloalkenylene (e.g., a C4-C7, C4-C8, C4-C9. C4-C10, C4-C1 1 , C4-C12, C4-C14, C4-C16, C4-C18, or C4-C20 cycloalkenylene). When the cycloalkylene group includes at least one carbon-carbon triple bond, the cycloalkylene group can be referred to as a "cycloalkynylene" group. A cycloalkynylene may have, e.g., four to twenty carbons in the cyclic portion of the cycloalkynylene (e.g., a C4-C7, C4-C8, C4-C9, C4-C10, C4-C1 1 , C4-C12, C4-C14, C4-C16, C4-C1 8, or C8-C20 cycloalkynylene). A cycloalkylene group can be substituted by the groups typically suitable as substituents for alkyl, alkenyl and alkynyl groups as set forth herein. Heterocycloalkylene refers to a cycloalkylene group including one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms, e.g., N, O, and S. Examples of cycloalkylenes include, but are not limited to, cyclopropylene and cyclobutylene. A tetrahydrofuran may be considered as a
heterocycloalkylene.
The term "arylene," as used herein, refers to a multivalent (e.g., divalent or trivalent) aryl group linking together multiple (e.g., two or three) parts of a compound. For example, one carbon within the arylene group may be linked to one part of the compound, while another carbon within the arylene group may be linked to another part of the compound. An arylene may have, e.g., five to fifteen carbons in the aryl portion of the arylene (e.g., a C5-C6, C5-C7, C5-C8, C5-C9, C5-C10, C5- C1 1 , C5-C12, C5-C13, C5-C14, or C5-C15 arylene). An arylene group can be substituted by the groups typically suitable as substituents for alkyl, alkenyl and alkynyl groups as set forth herein. Heteroarylene refers to an aromatic group including one or more, e.g., 1 -4, 1 -3, 1 , 2, 3, or 4, heteroatoms, e.g., N, O, and S. A heteroarylene group may have, e.g., two to fifteen carbons (e.g., a C2-C3, C2-C4, C2-C5, C2-C6, C2-C7, C2-C8, C2-C9, C2-C10, C2-C1 1 , C2-C12, C2-C13, C2-C14, or C1 -C15 heteroarylene).
The term "optionally substituted," as used herein, refers to having 0, 1 , or more substituents, such as 0-25, 0-20, 0-10 or 0-5 substituents. Substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, alkaryl, acyl, heteroaryl, heteroalkyi, heteroalkenyl, heteroalkynyl, heteroalkaryl, halogen, oxo, cyano, nitro, amino, alkamino, hydroxy, alkoxy, alkanoyl, carbonyl, carbamoyl, guanidinyl, ureido, amidinyl, any of the groups or moieties described above, and hetero versions of any of the groups or moieties described above. Substituents include, but are not limited to, F, CI, methyl, phenyl, benzyl, OR, NR2, SR, SOR, SO2R, OCOR, NRCOR, NRCONR2, NRCOOR, OCONR2, RCO, COOR, alkyl-OOCR, SO3R, CONR2, SO2NR2, NRSO2NR2, CN, CF3, OCF3, S1R3, and NO2, wherein each R is, independently, H, alkyl, alkenyl, aryl, heteroalkyi, heteroalkenyl, or heteroaryl, and wherein two of the optional substituents on the same or adjacent atoms can be joined to form a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members, or two of the optional substituents on the same atom can be joined to form an optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members.
An optionally substituted group or moiety refers to a group or moiety (e.g., any one of the groups or moieties described above) in which one of the atoms (e.g., a hydrogen atom) is optionally replaced with another substituent. For example, an optionally substituted alkyl may be an optionally substituted methyl, in which a hydrogen atom of the methyl group is replaced by, e.g., OH. As another example, a substituent on a heteroalkyi or its divalent counterpart, heteroalkylene, may replace a hydrogen on a carbon or a hydrogen on a heteroatom such as N. For example, the hydrogen atom in the group -R-NH-R- may be substituted with an alkamide substituent, e.g., -R- N[(CH2C(0)N(CH3)2]-R. Generally, an optional substituent is a noninterfering substituent. A
"noninterfering substituent" refers to a substituent that leaves the ability of the compounds described herein (e.g., compounds of any one of formulas (l)-(lll)) to bind to β-1 ,3-glucan synthase and/or to kill or inhibit the growth of fungi qualitatively intact. Thus, in some embodiments, the substituent may alter the degree of such activity. However, as long as the compound retains the ability to bind to β- 1 ,3-glucan synthase and/or to kill or inhibit the growth of fungi, the substituent will be classified as "noninterfering." In some aspects, a noninterfering substituent leaves the ability of a compound described herein (e.g., a compound of any one of formulas (l)-(lll)) to kill or inhibit the growth of fungi qualitatively intact as determined by measuring the minimum inhibitory concentration (MIC) against at least one fungi as known in the art.
The term "hetero," when used to describe a chemical group or moiety, refers to having at least one heteroatom that is not a carbon or a hydrogen, e.g., N, O, and S. Any one of the groups or moieties described above may be referred to as hetero if it contains at least one heteroatom. For example, a heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl group refers to a cycloalkyl, cycloalkenyl, or cycloalkynyl group that has one or more heteroatoms, wherein each heteroatom is, independently, selected from, e.g., N, O, and S. An example of a heterocycloalkenyl group is a maleimido. For example, a heteroaryl group refers to an aromatic group that has one or more heteroatoms, wherein each heteroatom is, independently, selected from, e.g., N, O, and S. One or more heteroatoms may also be included in a substituent that replaced a hydrogen atom in a group or moiety as described herein. For example, in an optionally substituted heteroaryl group, if one of the hydrogen atoms in the heteroaryl group is replaced with a substituent (e.g., methyl), the substituent may also contain one or more heteroatoms (e.g., methanol). The term "acyl," as used herein, refers to a group having the structure:
Figure imgf000049_0001
wherein Rz is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyi, cycloalkenyl, cycloalkynyl, aryl, alkaryl, alkamino, heteroalkyi, heteroalkenyl, heteroalkynyl, heterocycloalkyi, heterocycloalkenyl, heterocycloalkynyl, heteroaryl, heteroalkaryl, or heteroalkamino.
The term "halo" or "halogen," as used herein, refers to any halogen atom, e.g., F, CI, Br, or I. Any one of the groups or moieties described herein may be referred to as a "halo moiety" if it contains at least one halogen atom, such as haloalkyl.
The term "hydroxyl," as used herein, represents an -OH group.
The term "oxo," as used herein, refers to a substituent having the structure =0, where there is a double bond between an atom and an oxygen atom.
The term "carbonyl," as used herein, refers to a group having the structure
Figure imgf000049_0002
The term "thiocarbonyl," as used herein, refers to a group having the structure
Figure imgf000049_0003
The term "phosphate," as used herein, represents the group having the structure:
Figure imgf000049_0004
The term "phosphoryl," as used herein, represents the group having the structure:
Figure imgf000049_0006
or
Figure imgf000049_0005
The term "sulfonyl," as used herein, represents the group having the structure
Figure imgf000049_0007
The term "imino," as used herein, represents the group having the structure:
Figure imgf000049_0008
wherein R is an optional substituent.
The term "/V-protecting group," as used herein, represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N- protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 5th Edition (John Wiley & Sons, New York, 2014), which is incorporated herein by reference. /V-protecting groups include, e.g., acyl, aryloyl, and carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t- butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, carboxybenzyl (CBz), 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D, L-amino acid residues such as alanine, leucine, phenylalanine; sulfonyl-containing groups such as benzenesulfonyl and p-toluenesulfonyl; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,
3,5-dimethoxybenzyl oxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-l - methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl (BOC), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, eth oxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2, -trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl; alkaryl groups such as benzyl, triphenylmethyl, and benzyloxymethyl; and silyl groups such as trimethylsilyl.
The term "amino acid," as used herein, means naturally occurring amino acids and non- naturally occurring amino acids.
The term "naturally occurring amino acids," as used herein, means amino acids including Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val.
The term "non-naturally occurring amino acid," as used herein, means an alpha amino acid that is not naturally produced or found in a mammal. Examples of non-naturally occurring amino acids include D-amino acids; an amino acid having an acetylaminomethyl group attached to a sulfur atom of a cysteine; a pegylated amino acid; the omega amino acids of the formula NH2(CH2)nCOOH where n is 2-6, neutral nonpolar amino acids, such as sarcosine, t-butyl alanine, t-butyl glycine, N- methyl isoleucine, and norleucine; oxymethionine; phenylglycine; citrulline; methionine sulfoxide; cysteic acid; ornithine; diaminobutyric acid; 3-aminoalanine; 3-hydroxy-D-proline; 2,4-diaminobutyric acid; 2-aminopentanoic acid; 2-aminooctanoic acid, 2-carboxy piperazine; piperazine-2-carboxylic acid, 2-amino-4-phenylbutanoic acid; 3-(2-naphthyl)alanine, and hydroxyproline. Other amino acids are a-aminobutyric acid, α-amino-a-methylbutyrate, aminocyclopropane-carboxylate, aminoisobutyric acid, aminonorbornyl-carboxylate, L-cyclohexylalanine, cyclopentylalanine, L-N-methylleucine, L-N-methylmethionine, L-N-methylnorvaline, L-N-methylphenylalanine, L-N-methylproline,
L-N-methylserine, L-N-methyltryptophan, D-ornithine, L-N-methylethylglycine, L-norleucine, a-methyl- aminoisobutyrate, a-methylcyclohexylalanine, D-a-methylalanine, D-a-methylarginine,
D-a-methylasparagine, D-a-methylaspartate, D-a-methylcysteine, D-a-methylglutamine,
D-a-methylhistidine, D-a-methylisoleucine, D-a-methylleucine, D-a-methyllysine,
D-a-methylmethionine, D-a-methylornithine, D-a-methylphenylalanine, D-a-methylproline,
D-a-methylserine, D-N-methylserine, D-a-methylthreonine, D-a-methyltryptophan, D-a-methyltyrosine, D-a-methylvaline, D-N-methylalanine, D-N-methylarginine, D-N-methylasparagine,
D-N-methylaspartate, D-N-methylcysteine, D-N-methylglutamine, D-N-methylglutamate,
D-N-methylhistidine, D-N-methylisoleucine, D-N-methylleucine, D-N-methyllysine, N-methylcyclohexylalanine, D-N-methylornithine, N-methylglycine, N-methylaminoisobutyrate, N-(1 -methylpropyl)glycine, N-(2-methylpropyl)glycine, D-N-methyltryptophan, D-N-methyltyrosine, D-N-methylvaline, γ-aminobutyric acid, L-t-butylglycine, L-ethylglycine, L-homophenylalanine, L-a-methylarginine, L-a-methylaspartate, L-a-methylcysteine, L-a-methylglutamine,
L-a-methylhistidine, L-a-methylisoleucine, L-a-methylleucine, L-a-methylmethionine,
L-a-methylnorvaline, L-a-methylphenylalanine, L-a-methylserine, L-a-methyltryptophan,
L-a-methylvaline, N-(N-(2,2-diphenylethyl) carbamylmethylglycine, 1 -carboxy-1 -(2,2-diphenyl- ethylamino) cyclopropane, 4-hydroxyproline, ornithine, 2-aminobenzoyl (anthraniloyl),
D-cyclohexylalanine, 4-phenyl-phenylalanine, L-citrulline, a-cyclohexylglycine, L-1 ,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, L-thiazolidine-4-carboxylic acid, L-homotyrosine,
L-2-furylalanine, L-histidine (3-methyl), N-(3-guanidinopropyl)glycine, O-methyl-L-tyrosine, O-glycan- serine, meta-tyrosine, nor-tyrosine, L-N,N',N"-trimethyllysine, homolysine, norlysine, N-glycan asparagine, 7-hydroxy-1 ,2,3,4-tetrahydro-4-fluorophenylalanine, 4-methylphenylalanine, bis-(2- picolyl)amine, pentafluorophenylalanine, indoline-2-carboxylic acid, 2-aminobenzoic acid, 3-amino-2- naphthoic acid, asymmetric dimethylarginine, L-tetrahydroisoquinoline-1 -carboxylic acid,
D-tetrahydroisoquinoline-1 -carboxylic acid, 1 -amino-cyclohexane acetic acid, D/L-allylglycine, 4-aminobenzoic acid, 1 -amino-cyclobutane carboxylic acid, 2 or 3 or 4-aminocyclohexane carboxylic acid, 1 -amino-1 -cyclopentane carboxylic acid, 1 -aminoindane-1 -carboxylic acid, 4-amino-pyrrolidine- 2-carboxylic acid, 2-aminotetraline-2-carboxylic acid, azetidine-3-carboxylic acid, 4-benzyl-pyrolidine- 2-carboxylic acid, tert-butylglycine, b-(benzothiazolyl-2-yl)-alanine, b-cyclopropyl alanine,
5,5-dimethyl-1 ,3-thiazolidine-4-carboxylic acid, (2R,4S)4-hydroxypiperidine-2-carboxylic acid, (2S,4S) and (2S,4R)-4-(2-naphthylmethoxy)-pyrolidine-2-carboxylic acid, (2S,4S) and (2S,4R)4-phenoxy- pyrrolidine-2-carboxylic acid, (2R,5S)and(2S,5R)-5-phenyl-pyrrolidine-2-carboxylic acid, (2S,4S)-4- amino-1 -benzoyl-pyrrolidine-2-carboxylic acid, t-butylalanine, (2S,5R)-5-phenyl-pyrrolidine-2- carboxylic acid, 1 -aminomethyl-cyclohexane-acetic acid, 3,5-bis-(2-amino)ethoxy-benzoic acid, 3,5- diamino-benzoic acid, 2-methylamino-benzoic acid, N-methylanthranylic acid, L-N-methylalanine, L-N-methylarginine, L-N-methylasparagine, L-N-methylaspartic acid, L-N-methylcysteine,
L-N-methylglutamine, L-N-methylglutamic acid, L-N-methylhistidine, L-N-methylisoleucine,
L-N-methyllysine, L-N-methylnorleucine, L-N-methylornithine, L-N-methylthreonine,
L-N-methyltyrosine, L-N-methylvaline, L-N-methyl-t-butylglycine, L-norvaline, a-methyl-γ- aminobutyrate, 4,4'-biphenylalanine, a-methylcylcopentylalanine, a-methyl-a-napthylalanine, a-methylpenicillamine, N-(4-aminobutyl)glycine, N-(2-aminoethyl)glycine, N-(3-aminopropyl)glycine, N-amino-a-methylbutyrate, a-napthylalanine, N-benzylglycine, N-(2-carbamylethyl)glycine,
N-(carbamylmethyl)glycine, N-(2-carboxyethyl)glycine, N-(carboxymethyl)glycine, N-cyclobutylglycine, N-cyclodecylglycine, N-cycloheptylglycine, N-cyclohexylglycine, N-cyclodecylglycine,
N-cylcododecylglycine, N-cyclooctylglycine, N-cyclopropylglycine, N-cycloundecylglycine, N-(2,2- diphenylethyl)glycine, N-(3,3-diphenylpropyl)glycine, N-(3-guanidinopropyl)glycine,
N-(1 -hydroxyethyl)glycine, N-(hydroxyethyl))glycine, N-(imidazolylethyl))glycine, N-(3- indolylyethyl)glycine, N-methyl-Y-aminobutyrate, D-N-methylmethionine, N-methylcyclopentylalanine, D-N-methylphenylalanine, D-N-methylproline, D-N-methylthreonine, N-(1 -methylethyl)glycine, N-methyl-napthylalanine, N-methylpenicillamine, N-(p-hydroxyphenyl)glycine, N-(thiomethyl)glycine, penicillamine, L-a-methylalanine, L-a-methylasparagine, L-a-methyl-t-butylglycine,
L-methylethylglycine, L-a-methylglutamate, L-a-methylhomophenylalanine,
N-(2-methylthioethyl)glycine, L-a-methyllysine, L-a-methylnorleucine, L-a-methylornithine,
L-a-methylproline, L-a-methylthreonine, L-a-methyltyrosine, L-N-methyl-homophenylalanine,
N-(N-(3,3-diphenylpropyl) carbamylmethylglycine, L-pyroglutamic acid, D-pyroglutamic acid,
0- methyl-L-serine, O-methyl-L-homoserine, 5-hydroxylysine, a-carboxyglutamate, phenylglycine, L-pipecolic acid (homoproline), L-homoleucine, L-lysine (dimethyl), L-2-naphthylalanine,
L-dimethyldopa or L-dimethoxy-phenylalanine, L-3-pyridylalanine, L-histidine (benzoyloxymethyl), N-cycloheptylglycine, L-diphenylalanine, O-methyl-L-homotyrosine, L-p-homolysine, O-glycan- threoine, Ortho-tyrosine, L-N,N'-dimethyllysine, L-homoarginine, neotryptophan,
3-benzothienylalanine, isoquinoline-3-carboxylic acid, diaminopropionic acid, homocysteine,
3,4-dimethoxyphenylalanine, 4-chlorophenylalanine, L-1 ,2,3,4-tetrahydronorharman-3-carboxylic acid, adamantylalanine, symmetrical dimethylarginine, 3-carboxythiomorpholine, D-1 ,2,3,4- tetrahydronorharman-3-carboxylic acid, 3-aminobenzoic acid, 3-amino-1 -carboxymethyl-pyridin-2-one,
1 - amino-1 -cyclohexane carboxylic acid, 2-aminocyclopentane carboxylic acid, 1 -amino-1 - cyclopropane carboxylic acid, 2-aminoindane-2-carboxylic acid, 4-amino-tetrahydrothiopyran-4- carboxylic acid, azetidine-2-carboxylic acid, b-(benzothiazol-2-yl)-alanine, neopentylglycine,
2-carboxymethyl piperidine, b-cyclobutyl alanine, allylglycine, diaminopropionic acid, homo-cyclohexyl alanine, (2S,4R)-4-hydroxypiperidine-2-carboxylic acid, octahydroindole-2-carboxylic acid, (2S,4R) and (2S,4R)-4-(2-naphthyl), pyrrolidine-2-carboxylic acid, nipecotic acid, (2S,4R)and (2S,4S)-4-(4- phenylbenzyl) pyrrolidine-2-carboxylic acid, (3S)-1 -pyrrolidine-3-carboxylic acid, (2S,4S)-4- tritylmercapto-pyrrolidine-2-carboxylic acid, (2S,4S)-4-mercaptoproline, t-butylglycine, N,N-bis(3- aminopropyl)glycine, 1 -amino-cyclohexane-1 -carboxylic acid, N-mercaptoethylglycine, and selenocysteine. In some embodiments, amino acid residues may be charged or polar. Charged amino acids include alanine, lysine, aspartic acid, or glutamic acid, or non-naturally occurring analogs thereof. Polar amino acids include glutamine, asparagine, histidine, serine, threonine, tyrosine, methionine, or tryptophan, or non-naturally occurring analogs thereof.
It is specifically contemplated that in some embodiments, a terminal amino group in the amino acid may be an amido group or a carbamate group.
The term "fungal infection," as used herein, refers to the invasion of a subject's cells, tissues, and/or organs by fungi (e.g., Candida spp. or Aspergillus spp.), thus, causing an infection. In some embodiments, the fungi may grow, multiply, and/or produce toxins in the subject's cells, tissues, and/or organs. In some embodiments, a fungal infection can be any situation in which the presence of a fungal population(s) is latent within or damaging to a host body. Thus, a subject is "suffering" from a fungal infection when a latent fungal population is detectable in or on the subject's body, an excessive amount of a fungal population is present in or on the subject's body, or when the presence of a fungal population(s) is damaging the cells, tissues, and/or organs of the subject. As used herein, the term "dermatophytosis" or "dermatophyte infection" refers to an infection caused by dermatophytes, which are fungi that require keratin for growth. Dermatophytes are fungi in the genus Microsporum, Epidermophyton, and Trichophyton. These fungi can cause superficial infections of the skin, hair, and/or nails. Dermatophytes are spread by direct contact from other people (anthropophilic organisms), animals (zoophilic organisms), and soil (geophilic organisms), as well as indirectly from fomites.
The term "protecting against a fungal infection" or "preventing a fungal infection" as used herein, refers to preventing a subject from developing a fungal infection or decreasing the risk that a subject may develop a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.). Prophylactic drugs used in methods of protecting against a fungal infection in a subject are often administered to the subject prior to any detection of the fungal infection. In some embodiments of methods of protecting against a fungal infection, a subject (e.g., a subject at risk of developing a fungal infection) may be administered a compound described herein (e.g., a compound having any one of formulas (l)-(lll)) to prevent the fungal infection development or decrease the risk of the fungal infection development.
The term "treating" or "to treat," as used herein, refers to a therapeutic treatment of a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.) in a subject. In some embodiments, a therapeutic treatment may slow the progression of the fungal infection, improve the subject's outcome, and/or eliminate the infection. In some embodiments, a therapeutic treatment of a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.) in a subject may alleviate or ameliorate of one or more symptoms or conditions associated with the fungal infection, diminish the extent of the fungal infection, stabilize (i.e., not worsening) the state of the fungal infection, prevent the spread of the fungal infection, and/or delay or slow the progress of the fungal infection, as compare the state and/or the condition of the fungal infection in the absence of therapeutic treatment.
As used herein, the term "immunocompromised" refers to a subject (e.g., a human) having a weakened immune system. The subject's immune system can be weakened or compromised by a disease (e.g., an HIV infection, an autoimmune disease, cancer), a medical procedure (e.g., an organ transplant (e.g., a solid organ transplant) or a bone marrow transplant), a drug (e.g., an
immunosuppressant), and/or a pathogen (e.g., bacteria, fungus, virus). The immune system of the host may also have a congenital defect that renders the host more susceptible to infection.
As used herein, the term "immunosuppression therapy" refers to a therapy that uses one or more immunosuppressants to reduce the activation and/or efficacy of the immune system of a subject (e.g., a human). In some embodiments, an immunosuppression therapy is used to prevent the body from rejecting a transplant (e.g., an organ transplant (e.g., a solid organ transplant) or a bone marrow transplant), to treat graft-versus-host disease after a bone marrow transplant, and/or to treat autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, multiple sclerosis, myasthenia gravis, Sarcoidosis, Behcet's disease). Immunosuppressants include, but are not limited to, calcineurin inhibitors, mTOR inhibitors, and tyrosine kinase inhibitors (e.g., cyclosporine A, cyclosporine G, voclosporin, tacrolimus, pimecrolimus, sirolimus, temsirolimus, deforolimus, everolimus, zotarolimus, biolimus, imatinib, dasatinib, nilotinib, erlotinib, sunitinib, gefitinib, bosutinib, neratinib, axitinib, crizotinib, lapatinib, toceranib and vatalanib).
The term "activating an immune cell," as used herein, refers to the ability of a compound to directly or indirectly bind to an immune cell to produce an effective immune response. The ability of a compound to directly or indirectly bind to an immune cell to produce an effective immune response may be quantified by measuring the concentration of the compound at which such immune response is produced. In some embodiments, the concentration of a compound that binds to an immune cell receptor such as dectin-1 or binds to an antibody (e.g., anti-aGal or anti-aRha antibody, which then binds to an immune cell) to trigger an effective immune response may be less than or equal to 10,000 nM as measured in accordance with, e.g., an enzyme-linked immunosorbent assay (ELISA). For instance, an aGal epitope, that binds to an antibody, such as an anti-aGal antibody, may be detected using an ELISA. In an ELISA, a compound containing a particular monosaccharide or
oligosaccharide moiety may be immobilized on a support or surface using conventional techniques in the art. After the compound is immobilized to the surface, an antibody that is specific for the particular monosaccharide or oligosaccharide moiety in the compound is applied over the surface so it is captured by the compound through binding to the monosaccharide or oligosaccharide moiety in the compound. The antibody is often linked to an enzyme (e.g., horseradish peroxidase) for subsequent signal amplification. During signal amplification, the enzyme's substrate (e.g., 3,3'-diaminobenzidine) is added to produce a measurable signal (e.g., color change). In some embodiments, the antibody itself can be detected using a secondary antibody, which is linked to an enzyme.
In some embodiments, the concentration of a compound that binds to an immune cell receptor such as dectin-1 or binds to an antibody (e.g., anti-aGal or anti-aRha antibody, which then binds to an immune cell) to trigger an effective immune response may be less than or equal to 1000 nM or less than or equal to 100 nM as measured in accordance with an ELISA.
The term "innate immune receptor," as used herein, refers to a natural receptor, such as a natural receptor on an immune cell, that binds to a carbohydrate (e.g., a monosaccharide or oligosaccharide moiety) or an optionally substituted carbohydrate and causes a response in the immune system. In some embodiments, an innate immune receptor binds to the monosaccharide or oligosaccharide moiety of the compounds described herein (e.g., compounds of any one of formulas (l)-(lll)). In some embodiments, an innate immune receptor binds to a moiety in Table 2A or 2B.
The term "natural antibody," as used herein, refers to a naturally existing antibody in the circulation of a mammal (e.g., a human) that has not been previously exposed to deliberate immunization. In some embodiments, a natural antibody is an antibody of the immunoglobulin M (IgM) isotype. In some embodiments, a natural antibody binds to the monosaccharide or
oligosaccharide moiety of the compounds described herein (e.g., compounds of any one of formulas (l)-(lll)). In some embodiments, a natural antibody binds to a moiety in Table 2A or 2B. In some embodiments, a natural antibody is anti-aGal antibobody or anti-aRha antibody. The term "subject," as used herein, can be a human, non-human primate, or other mammal, such as but not limited to dog, cat, horse, cow, pig, turkey, goat, fish, monkey, chicken, rat, mouse, and sheep.
The term "therapeutically effective amount," as used herein, refers to an amount, e.g., pharmaceutical dose, effective in inducing a desired effect in a subject or in treating a subject having a condition or disorder described herein (e.g., a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.)). It is also to be understood herein that a "therapeutically effective amount" may be interpreted as an amount giving a desired therapeutic and/or preventative effect, taken in one or more doses or in any dosage or route. For example, in the context of administering a compound described herein (e.g., a compound of any one of formulas (l)-(lll)) that is used for the treatment of a fungal infection, an effective amount of a compound is, for example, an amount sufficient to prevent, slow down, or reverse the progression of the fungal infection as compared to the response obtained without administration of the compound.
As used herein, the term "pharmaceutical composition" refers to a medicinal or
pharmaceutical formulation that contains at least one active ingredient (e.g., a compound of any one of formulas (l)-(lll)) as well as one or more excipients and diluents to enable the active ingredient suitable for the method of administration. The pharmaceutical composition of the present disclosure includes pharmaceutically acceptable components that are compatible with a compound described herein (e.g., a compound of any one of formulas (l)-(lll)).
As used herein, the term "pharmaceutically acceptable carrier" refers to an excipient or diluent in a pharmaceutical composition. For example, a pharmaceutically acceptable carrier may be a vehicle capable of suspending or dissolving the active compound (e.g., a compound of any one of formulas (l)-(lll)). The pharmaceutically acceptable carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient. In the present disclosure, the pharmaceutically acceptable carrier must provide adequate pharmaceutical stability to a compound described herein. The nature of the carrier differs with the mode of administration. For example, for oral administration, a solid carrier is preferred; for intravenous administration, an aqueous solution carrier (e.g., WFI, and/or a buffered solution) is generally used.
The term "pharmaceutically acceptable salt," as used herein, represents salts of the compounds described herein (e.g., compounds of any one of formulas (l)-(lll)) that are, within the scope of sound medical judgment, suitable for use in methods described herein without undue toxicity, irritation, and/or allergic response. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Pharmaceutical Salts:
Properties, Selection, and Use (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.
The term "about," as used herein, indicates a deviation of ±10%. For example, about 10% refers to from 9% to 1 1 %.
Definitions of abbreviations used in the disclosure are provided in Table 1 below: Table 1
Figure imgf000056_0001
Other features and advantages of the compounds described herein will be apparent from the following detailed description and the claims.
Description of the Drawings
FIGS. 1 A and 1 B are fluorescent images showing the binding of the secondary anti-rabbit lgG1 (red fluorescence) to rabbit anti-Rha antibodies, which in turn are bound to A. fumigatus hyphae treated with Compound 1 (FIG. 1 A) or CD101 acetate (FIG. 1 B).
FIGs. 2A and 2B are graphs, and corresponding tables, showing Compound 1 concentrations as measured in frozen plasma collected from mice treated with 3 mg/kg or 10 mg/kg Compound 1 IV (Fig. 2A) or mice treated with 3 mg/kg or 10 mg/kg Compound 1 IP (Fig. 2B).
FIGs. 3A and 3B are graphs, and corresponding tables, showing Compound 1 concentrations as measured in lung homogenates prepared from mice treated with 3 mg/kg or 10 mg/kg Compound 1 IV (Fig. 3A) or mice treated with 3 mg/kg or 10 mg/kg Compound 1 IP (Fig. 3B).
FIGs. 4A and 4B are tables summarzing Compound 1 concentrations as measured in lung homogenates or plasma isolated from mice treated with 3 mg/kg or 10 mg/kg Compound 1 IV (Fig. 4A) or mice treated with 3 mg/kg or 10 mg/kg Compound 1 IP (Fig. 4B).
Detailed Description
The disclosure features compounds, compositions, and methods for the treatment of fungal infections (e.g., fungal infections caused by Candida spp. or Aspergillus spp.J. The inventors have found that compounds disclosed herein have increased antifungal activity due to their ability to bind to the fungal cell wall through inhibition of β-1 ,3-glucan synthase, thereby driving a concentration gradient near the locus of infection. The compounds disclosed herein include a β-1 ,3-glucan synthase inhibitor covalently conjugated to a monosaccharide or oligosaccharide moiety by way of a linker.
I. Compounds of the Disclosure
Provided herein are synthetic compounds useful in the treatment of fungal infections (e.g., fungal infections caused by Candida spp.). The compounds disclosed herein include a β-1 ,3-glucan synthase inhibitor covalently conjugated to at least one monosaccharide or oligosaccharide moiety by way of a linker, β-1 ,3-glucan synthase is a glucosyltransferase enzyme involved in the generation of β-glucan in the cell wall of fungi. Inhibition of this enzyme results in disrupting the integrity of the fungal cell well and serves as a pharmacological target for antifungal drugs. In some embodiments, in addition to disrupting the fungal cell wall, the monosaccharide or oligosaccharide moiety in the compounds described herein serve as a gradient against which immune cells chemotax to the site of fungal infection and/or growth.
Compounds provided described herein are described by any one of formulas (l)-(lll).
Compounds described herein may be synthesized using available chemical synthesis techniques in the art. In some embodiments, available functional groups in the β-1 ,3-glucan synthase inhibitor, the linker, and the monosaccharide or oligosaccharide moiety, e.g., amines, carboxylic acids, and/or hydroxyl groups, may be used in making the compounds described herein. For example, the nitrogen atom in an amine group of the β-1 ,3-glucan synthase inhibitor may form an amide bond with the carbon in a carboxylic acid group of the linker. In cases where a functional group is not available for conjugation, a molecule may be derivatized using conventional chemical synthesis techniques that are well known in the art. In some embodiments, the compounds described herein contain one or more chiral centers. The compounds include each of the isolated stereoisomeric forms as well as mixtures of stereoisomers in varying degrees of chiral purity, including racemic mixtures. It also encompasses the various diastereomers, enantiomers, and tautomers that can be formed.
The disclosure provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (I):
Figure imgf000058_0001
In some embodiments of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R1 is a lipophilic moiety; R2 is hydrogen or methyl; each of R3 and R4 is, independently, hydrogen or hydroxyl; R5 is hydrogen, methyl, or optionally substituted C1-C5 alkamino; R6 is hydrogen, hydroxyl, methyl, or amino; R7 is hydrogen or hydroxyl; R8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(O(CH2)a)bR’, -(NH(CH2)a)bR’, -(S(CH2)a)bR’, -(O(CH2)a)bN(R’)2, -(NH(CH2)a)bN(R’)2, -(S(CH2)a)bN(R’)2, -(O(CH2)a)bN+(R’)3, -(NH(CH2)a)bN+(R’)3, -(S(CH2)a)bN+(R’)3, -(O(CH2)a)bOR’, -(NH(CH2)a)bOR’, -(S(CH2)a)bOR’, -(OCH2CH2)a(NHCH2CH2)bN(R’)2,
-(OCH2CH2)a(NHCH2CH2)bN+(R’)3, -(OCH2CH2)a(NHCH2CH2)bOR’, -(NHCH2CH2)a(OCH2CH2)bN(R’)2, -(NHCH2CH2)a(OCH2CH2)bN+(R’)3, or -(NHCH2CH2)a(OCH2CH2)bOR’; R9 is hydrogen, hydroxyl, or amino; n is 0 or 1; d is 1, 2, 3, 4, 5, or 6; each of a and b is, independently, an integer from 1 to 5; each R’ is, independently, hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-10 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1-C10 heteroaryl; L is a linker; and each E is, independently, a monosaccharide or oligosaccharide moiety.
The disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (1-1 ):
Figure imgf000059_0001
wherein R1 , R2, R3, R4, R5, R6, R7, R8, R9, n, d, L, and E are as described above.
The disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (I-2):
Figure imgf000059_0002
In some embodiments of the compound of formula (I-2), or a pharmaceutically acceptable salt thereof, R1 is a lipophilic moiety; R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2; R6 is hydrogen or methyl; R8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(0(CH2)a)bR',
-(NH(CH2)a)bR', -(S(CH2)a)bR', -(0(CH2)a)bN(R')2, -(NH(CH2)a)bN(R')2, -(S(CH2)a)bN(R')2,
-(0(CH2)a)bN+(R')3, -(NH(CH2)a)bN+(R')3, -(S(CH2)a)bN+(R')3, -(0(CH2)a)bOR', -(NH(CH2)a)bOR', -(S(CH2)a)bOR\ -(OCH2CH2)a(NHCH2CH2)bN(R')2, -(OCH2CH2)a(NHCH2CH2)bN+(R')3,
-(OCH2CH2)a(NHCH2CH2)bOR', -(NHCH2CH2)a(OCH2CH2)bN(R')2, -(NHCH2CH2)a(OCH2CH2)bN+(R')3, or -(NHCH2CH2)a(OCH2CH2)bOR'; each of a and b is, independently, an integer from 1 to 5; d is 1 , 2, 3, 4, 5, or 6; each R’ is, independently, hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-10 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1-C10 heteroaryl; L is a linker; and each E is, independently, a monosaccharide or oligosaccharide moiety.
In some embodiments of a compound of any one of formulas (I), (I-1), and (I-2), or a pharmaceutically acceptable salt thereof, R8 is -(O(CH2)a)bR’, -(NH(CH2)a)bR’, -(S(CH2)a)bR’, -(O(CH2)a)bN(R’)2, -(NH(CH2)a)bN(R’)2, -(S(CH2)a)bN(R’)2, -(O(CH2)a)bOR’, -(NH(CH2)a)bOR’,
-(S(CH2)a)bOR’, -(OCH2CH2)a(NHCH2CH2)bN(R’)2, -(OCH2CH2)a(NHCH2CH2)bOR’,
-(NHCH2CH2)a(OCH2CH2)bN(R’)2, or -(NHCH2CH2)a(OCH2CH2)bOR’; each of a and b is,
independently, an integer from 1 to 5; and each R’ is, independently, hydrogen or optionally substituted C1-C5 alkyl. In some embodiments, R8 is -OCH2CH2N(R’)2, -NHCH2CH2N(R’)2, -(NHCH2CH2)2N(R’)2, -NHCH2CH2OR’, -(NHCH2CH2)2OR’, -OCH2CH2NHCH2CH2N(R’)2,
-NHCH2CH2OCH2CH2N(R’)2, -NHCH2CH2(OCH2CH2)2N(R’)2, -NHCH2CH2(OCH2CH2)3N(R’)2, -OCH2CH2NHCH2CH2OR’, -NHCH2CH2OCH2CH2OR’, or -NHCH2CH2(OCH2CH2)3OR’.
The disclosure provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (II):
Figure imgf000060_0001
In some embodiments of the compound of formula (II), or a pharmaceutically acceptable salt thereof, R1 is a lipophilic moiety; R2 is hydrogen or methyl; each of R3 and R4 is, independently, hydrogen or hydroxyl; R6 is hydrogen, hydroxyl, methyl, or amino; R7 is hydrogen or hydroxyl; R8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(O(CH2)a)bR’, -(NH(CH2)a)bR’,
-(S(CH2)a)bR’, -(O(CH2)a)bN(R’)2, -(NH(CH2)a)bN(R’’)2, -(S(CH2)a)bN(R’)2, -(O(CH2)a)bN+(R’)3,
-(NH(CH2)a)bN+(R’)3, -(S(CH2)a)bN+(R’)3, -(O(CH2)a)bOR’, -(NH(CH2)a)bOR’, -(S(CH2)a)bOR’,
-(OCH2CH2)a(NHCH2CH2)bN(R’)2, -(OCH2CH2)a(NHCH2CH2)bN+(R’)3, -(OCH2CH2)a(NHCH2CH2)bOR’, -(NHCH2CH2)a(OCH2CH2)bN(R’)2, -(NHCH2CH2)a(OCH2CH2)bN+(R’)3, or -(NHCH2CH2)a(OCH2CH2)bOR'; R9 is hydrogen, hydroxyl, or amino; n is 0 or 1 ; each of a and b is, independently, an integer from 1 to 5; d is 1 , 2, 3, 4, 5, or 6; each R' is, independently, hydrogen, optionally substituted C1 -C10 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1 -C10 heteroaryl ; each R" is, independently, hydrogen or C1 -C10 alkyl; L is a linker; and each E is, independently, a monosaccharide or oligosaccharide moiety.
The disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (11-1 ):
Figure imgf000061_0001
wherein R1 , R2, R3, R4, R6, R7, R8, R9, n, d, L, and E are as defined above.
The disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (II-2):
Figure imgf000061_0002
In some embodiments of the compound of formula (II-2), or a pharmaceutically acceptable salt thereof, R1 is a lipophilic moiety; R6 is hydrogen or methyl; R8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(O(CH2)a)bR’, -(NH(CH2)a)bR’, -(S(CH2)a)bR’, -(O(CH2)a)bN(R’)2, -(NH(CH2)a)bN(R’’)2, -(S(CH2)a)bN(R’)2, -(O(CH2)a)bN+(R’)3, -(NH(CH2)a)bN+(R’)3, -(S(CH2)a)bN+(R’)3, -(O(CH2)a)bOR’, -(NH(CH2)a)bOR’, -(S(CH2)a)bOR’, -(OCH2CH2)a(NHCH2CH2)bN(R’)2,
-(OCH2CH2)a(NHCH2CH2)bN+(R’)3, -(OCH2CH2)a(NHCH2CH2)bOR’, -(NHCH2CH2)a(OCH2CH2)bN(R’)2, -(NHCH2CH2)a(OCH2CH2)bN+(R’)3, or -(NHCH2CH2)a(OCH2CH2)bOR’; each of a and b is, independently, an integer from 1 to 5; d is 1, 2, 3, 4, 5, or 6; each R’ is, independently, hydrogen, optionally substituted C1-C10 alkyl, optionally substituted C1-10 heteroalkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1-C10 heteroaryl; each of R’’ is, independently, hydrogen or C1-C10 alkyl; L is a linker; and each E is, independently, a monosaccharide or oligosaccharide moiety.
In some embodiments of a compound of any one of formulas (II), (II-1), and (II-2), or a pharmaceutically acceptable salt thereof, R8 is -(O(CH2)a)bR’, -(NH(CH2)a)bR’, -(S(CH2)a)bR’, -(O(CH2)a)bN(R’)2, -(NH(CH2)a)bN(R’’)2, -(S(CH2)a)bN(R’)2, -(O(CH2)a)bOR’, -(NH(CH2)a)bOR’,
-(S(CH2)a)bOR’, -(OCH2CH2)a(NHCH2CH2)bN(R’)2, -(OCH2CH2)a(NHCH2CH2)bOR’,
-(NHCH2CH2)a(OCH2CH2)bN(R’)2, or -(NHCH2CH2)a(OCH2CH2)bOR’; each of a and b is,
independently, an integer from 1 to 5; and each R’ is, independently, hydrogen or optionally substituted C1-C5 alkyl; and each R’’ is, independently, hydrogen, or C1-C10 alkyl, or a
pharmaceutically acceptable salt thereof. In some embodiments, R8 is -OCH2CH2N(R’)2,
-NHCH2CH2N(R’’)2, -(NHCH2CH2)2N(R’’)2, -NHCH2CH2OR’, -(NHCH2CH2)2OR’,
-OCH2CH2NHCH2CH2N(R’)2, -NHCH2CH2OCH2CH2N(R’)2, -NHCH2CH2(OCH2CH2)2N(R’)2,
-NHCH2CH2(OCH2CH2)3N(R’)2, -OCH2CH2NHCH2CH2OR’, -NHCH2CH2OCH2CH2OR’, or
-NHCH2CH2(OCH2CH2)3OR’; each R’ is, independently, hydrogen or methyl; each R’’ is,
independently, hydrogen or methyl.
In some embodiments of a compound of any one of formulas (I), (I-1), (I-2), (II), (II-1), and (II- 2), R8 is
Figure imgf000062_0001
Figure imgf000063_0001
In some embodiments of a compound of any one of formulas (I), (I-1), (I-2), (II), (II-1), and (II-2), R8 is -(O(CH2)a)bN+(R’)3, -(NH(CH2)a)bN+(R’)3, -(S(CH2)a)bN+(R’)3,
-(OCH2CH2)a(NHCH2CH2)bN+(R’)3, or -(NHCH2CH2)a(OCH2CH2)bN+(R’)3; each of a and b is, independently, an integer from 1 to 5; and each R’ is, independently, hydrogen or optionally substituted C1-C5 alkyl, or a pharmaceutically acceptable salt thereof. In some embodiments, R8 is -OCH2CH2N+(R’)3, -(OCH2CH2)2N+(R’)3, -NHCH2CH2N+(R’)3, or -(NHCH2CH2)2N+(R’)3; each R’ is, independently, hydrogen or methyl, or a pharmaceutically acceptable salt thereof. In certain embodiments, R8 is
Figure imgf000063_0002
In some embodiments of a compound of any one of formulas (I), (I-1), (I-2), (II), (II-1), and (II- 2), R’ is
Figure imgf000063_0003
Figure imgf000063_0004
wherein each RA is, independently, hydrogen or optionally substituted C1-C10 alkyl. The disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (III):
Figure imgf000064_0001
In some embodiments of the compound of formula (III), or a pharmaceutically acceptable salt thereof, R1 is a lipophilic moiety; R2 is hydrogen or methyl ; each of R3 and R4 is, independently, hydrogen or hydroxyl; R5 is hydrogen, methyl, -CH2CH2NH2, or -CH2(CO)NH2; R6 is hydrogen, hydroxyl, methyl, or amino; R7 is hydrogen or hydroxyl; R9 is hydrogen, hydroxyl, or amino; X is O or NH; n is 0 or 1 ; d is 1 , 2, 3, 4, 5, or 6; L is a linker; and each E is, independently, a monosaccharide or oligosaccharide moiety.
The disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (III-1 ):
Figure imgf000064_0002
wherein R1 , R2, R3, R4, R5, R6, R7, R9, X, n, d, L, and E are as defined above. The disclosure also provides a compound, or a pharmaceutically acceptable salt thereof, described by formula (111-2):
Figure imgf000065_0001
In some embodiments of the compound of formula (111-2), or a pharmaceutically acceptable salt thereof, R1 is a lipophilic moiety; R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2; R6 is hydrogen or methyl; X is O or NH; d is 1 , 2, 3, 4, 5, or 6; L is a linker; and each E is, independently, a monosaccharide or oligosaccharide moiety.
The disclosure also provides a compound of any one of the following formulas:
Figure imgf000065_0002
Figure imgf000066_0001
wherein R1 is a lipophilic moiety; R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2; R6 is hydrogen or methyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
The disclosure also provides a compound of any one of the following formulas:
Figure imgf000067_0001
wherein R1 is a lipophilic moiety; R6 is hydrogen or methyl ; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
The disclosure also provides a compound of any one of the following formulas:
Figure imgf000067_0002
wherein R1 is a lipophilic moiety; R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2; R6 is hydrogen or methyl; d is 1, 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
In some embodiments of the compounds described herein, R1 is
Figure imgf000068_0004
each of X and Y is, independently, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene, or is absent; Z is optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, or is absent; at least one of X, Y, and Z is present; and wherein X and Y, when present, are joined by a direct bond, -O-, or –CH2=CH2–, and Y and Z, when present, are joined by a direct bond, -O-, or–CH2=CH2–, or a pharmaceutically acceptable salt thereof.
In some embodiments, X, Y, and Z, together, form
Figure imgf000068_0001
wherein RB is an optionally substituted C1-C10 alkyl, or a pharmaceutically acceptable salt thereof. In some
embodiments, X, Y, and Z, together, form
Figure imgf000068_0002
wherein RB is optionally substituted C1- C10 alkyl, or a pharmaceutically acceptable salt thereof. In some embodiments, X, Y, and Z,
together, form
Figure imgf000068_0003
wherein RB is optionally substituted C1-C8 alkyl, or a pharmaceutically acceptable salt thereof. In some embodiments, X, Y, and Z, together, form
Figure imgf000069_0001
Figure imgf000069_0002
The disclosure also provides a compound of any one of the following formulas:
5
Figure imgf000070_0001
Figure imgf000071_0001
wherein R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2; R6 is hydrogen or methyl; RB is optionally substituted C1 -C6 alkyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
The disclosure also provides a compound of any one of the following formulas:
Figure imgf000072_0001
Figure imgf000073_0001
wherein R6 is hydrogen or methyl; RB is optionally substituted C1 -C6 alkyl; d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof. The disclosure also provides a compound of any one of the following formulas:
Figure imgf000074_0001
wherein d is 1 , 2, 3, or 4; each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
In the compounds described herein, the portion
Figure imgf000074_0002
in a compound described herein indicates that one or more (e.g., 1 , 2, 3, 4; 5, or 6; 1 -2, 1 -3, 1 -4, 1 -5, or 1 -6) monosaccharide or oligosaccharide moieties may be attached to L at any atom(s) within L. E represents a monosaccharide or oligosaccharide moiety. The portion
Figure imgf000074_0003
is not to be construed as a single bond between one or more monosaccharide or oligosaccharide moieties and an atom in L. In some embodiments, when d is 1 , one monosaccharide or oligosaccharide moiety may be attached to an atom in L. In some embodiments, when d is 2, two monosaccharide or oligosaccharide moieties may be attached to two atoms in L. As described further herein, a linker in a compound described herein (e.g., L) may be a branched structure. As described further herein, a linker in a compound described herein (e.g., L) may be a multivalent structure, e.g., divalent, trivalent, tetravalent, pentavalent, hexavalent, or heptavalent structure, containing two, three, four, five, six, or seven arms, respectively. For example, in some embodiments when the linker has two or more (e.g., three, four, five, six, or seven) arms, one arm may be attached to a β-1 ,3-glucan synthase inhibitor and the remaining arm(s) (e.g., the remaining one, two, three, four, five, or six arms) may each be attached to a monosaccaride or oligosaccharide moiety. Thus, L in the portion
Figure imgf000074_0004
may have multiple arms attached to multiple monosaccharide or oligosaccharide moieties.
Examples of other β-1 ,3-glucan synthase inhibitors that can be functionalized to covalently conjugate to at least one monosaccharide or oligosaccharide moiety by way of a linker are shown below.
Figure imgf000075_0001
Figure imgf000076_0001
The disclosure also features a compound selected from
Figure imgf000077_0001
Figure imgf000078_0001
or pharmaceutically acceptable salts thereof.
In some embodiments, the pharmaceutically acceptable salt of any one of Compounds 1 -3, 4a, 4b, 5a-5c, and 6 is a formate salt. In some embodiments, the pharmaceutically acceptable salt of any one of Compounds 1 -3, 4a, 4b, 5a-5c, and 6 is an acetate salt.
In some embodiments, the compound is Compound 1 ,
Figure imgf000078_0002
or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is a formate salt. In some embodiments, the pharmaceutically acceptable salt of Compound 1 is an acetate salt. In some embodiments, the compound is Compound 4a
Figure imgf000079_0001
or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt of Compound 4a is a formate salt. In some embodiments, the pharmaceutically acceptable salt of Compound 4a is an acetate salt.
II. Linkers
A linker refers to a linkage or connection between two or more components in a compound (e.g., between the β-1 ,3-glucan synthase inhibitor and the monosaccharide or oligosaccharide moiety in a compound described herein (e.g., a compound of any one of formulas (l)-(lll)). A linker in a compound described herein (e.g., L) may be a branched structure. As described further herein, a linker in a compound described herein (e.g., L) may be a multivalent structure, e.g., divalent, trivalent, tetravalent, pentavalent, hexavalent, or heptavalent structure, containing two, three, four, five, six, or seven arms, respectively, in which each arm is covalently conjugated to either a β-1 ,3-glucan synthase inhibitor or a monosaccharide or oligosaccharide moiety.
Divalent Linker
One terminus of a divalent linker may be covalently attached to a β-1 ,3-glucan synthase inhibitor and other terminus of the divalent linker may be covalently attached to a monosaccharide or oligosaccharide moiety (see, e.g., Compounds 1 -6). In some embodiments, a divalent linker L in the compound of any one of formulas (l)-(lll) is described by formula (L-l):
Figure imgf000079_0002
wherein I1 is a bond attached to the β-1 ,3-glucan synthase inhibitor; I2 is a bond attached to a monosaccharide or oligosaccharide moiety (E); each of U1 , U2, U3, and U4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C1 5 arylene, or optionally substituted C1 -C15 heteroarylene; each of V1 , V2, V3, V4, and V5 is, independently, O, S, NR', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino;
wherein R' is H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C5-C15 heteroaryl ; and each of f, g, h, i, j, k, I, m, and n is, independently, 0 or 1 .
In some embodiments of the linker of formula (L-l), each of U1 , U2, U3, and U4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C15 arylene, or optionally substituted C1 -C15 heteroarylene; each of V1 , V2, V3, V4, and V5 is, independently, O, S, NR', P, carbonyl; R' is H or optionally substituted C1 -C20 alkyl; and each of f, g, h, i, j, k, I, m, and n is, independently, 0 or 1 .
In some embodiments, a divalent linker is described by formula (L-11 ):
Figure imgf000080_0001
wherein I1 is a bond attached to the β-1 ,3-glucan synthase inhibitor; I2 is a bond attached to a monosaccharide or oligosaccharide moiety (E); each of U1 , U2, U3, and U4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C15 arylene, or optionally substituted C1 -C15 heteroarylene; each of V2, V3, V4, and V5 is, independently, O, S, NR', P, carbonyl; R' is H or optionally substituted C1 -C20 alkyl; and each of h, i, j, k, I, m, and n is, independently, 0 or 1 .
In some embodiments, a divalent linker is described by formula (L-I2), (L-I3), or (L-I4):
Figure imgf000080_0002
Figure imgf000081_0001
wherein I1 is a bond attached to the β-1 ,3-glucan synthase inhibitor; I2 is a bond attached to a monosaccharide or oligosaccharide moiety (E); each of U1 , U2, U3, and U4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4- C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5- C15 arylene, or optionally substituted C1 -C15 heteroarylene; each of V2, V3, and V4 is, independently, O, S, NR.', P, carbonyl ; RJ is H or optionally substituted C1 -C20 alkyl; and each of h, i, j, k, I, and m is, independently, 0 or 1 .
In some embodiments, a divalent linker is
Figure imgf000081_0002
Figure imgf000082_0001
wherein each of p, q, r, and s is, independently, an integer from 1 to 10. Trivalent Linker
One arm of a trivalent linker may be covalently attached to a β-1,3-glucan synthase inhibitor and each of the remaining two arms of the trivalent linker may be covalently attached to a monosaccharide or oligosaccharide moiety. In some embodiments, a trivalent linker L in the compound of any one of formulas (I)-(III) is described by formula (L-II):
Figure imgf000082_0002
wherein LA is described by formula GA1-(ZA1)g1-(YA1)h1-(ZA2)i1-(YA2)j1-(ZA3)k1-(YA3)l1-(ZA4)m1-(YA4)n1- (ZA5)o1-GA2; LB is described by formula GB1-(ZB1)g2-(YB1)h2-(ZB2)i2-(YB2)j2-(ZB3)k2-(YB3)l2-(ZB4)m2-(YB4)n2- (ZB5)o2-GB2; LC is described by formula GC1-(ZC1)g3-(YC1)h3-(ZC2)i3-(YC2)j3-(ZC3)k3-(YC3)l3-(ZC4)m3-(YC4)n3- (ZC5)o3-GC2; GA1 is a bond attached to N in formula (L-II); GA2 is a bond attached to the β-1,3-glucan synthase inhibitor; GB1 is a bond attached to N in formula (L-II); GB2 is a bond attached to a first monosaccharide or oligosaccharide moiety, E1; GC1 is a bond attached to N in formula (L-II); GC2 is a bond attached to a second monosaccharide or oligosaccharide moiety, E2; each of YA1, YA2, YA3, YA4, YB1, YB2, YB3, YB4, YC1, YC2, YC3, and YC4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C1-C15 heteroarylene; each of ZA1, ZA2, ZA3, ZA4, ZA5, ZB1, ZB2, ZB3, ZB4, ZB5, ZC1, ZC2, ZC3, ZC4, and ZC5 is, independently, O, S, NRi, P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino;
wherein Ri is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3- C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C5-C15 heteroaryl ; and each of g1 , hi , i1 , j1 , k1 , 11 , ml , n1 , o1 , g2, h2, i2, j2, k2, I2, m2, n2, o2, g3, h3, i3, j3, k3, I3, m3, n3, and o3 is, independently, 0 or 1 .
In some embodiments of the trivalent linker of formula (L-ll), each of YA1 , YA2, YA3, YM, YB1 , YB2, YB3, YB4, YC1 , YC2, YC3, and YC4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C1 5 arylene, or optionally substituted C1 -C15 heteroarylene; each of ZA1 , ZA2, ZA3, ZA4, ZA5, ZB1 , ZB2, ZB3, ZB4, ZB5, ZC1 , ZC2, ZC3, ZC4, and ZC5 is, independently, O, S, NR', P, carbonyl; R' is H or optionally substituted C1 -C20 alkyl; and each of g1 , hi , i1 , j1 , k1 , 11 , ml , n1 , o1 , g2, h2, i2, j2, k2, I2, m2, n2, o2, g3, h3, i3, j3, k3, 13, m3, n3, and o3 is, independently, 0 or 1 .
In some embodiments, a trivalent linker is
Figure imgf000083_0001
wherein each of p, q, r, s, and t is, independently, an integer from 1 to 10.
In some embodiments, a trivalent linker is
Figure imgf000083_0002
Figure imgf000084_0001
wherein each of p, q, r, s, t, and u is, independently, an integer from 1 to 10.
Linkers having four or more arms
A linker in a compound described herein may also have a tetravalent, pentavalent, hexavalent, or heptavalent structure, containing four, five, six, or seven arms, respectively. For example, in some embodiments when the linker has four or more (e.g., five, six, or seven) arms, one arm may be attached to a β-1 ,3-glucan synthase inhibitor and the remaining arms (e.g., remaining three, four, or five arms) may each be attached to a monosaccharide or oligosaccharide moiety. In some embodiments, a linker L in the compound of any one of formulas (I)-(III) is described by formula (L-III):
Figure imgf000085_0001
wherein LA is described by formula GA1-(ZA1)g1-(YA1)h1-(ZA2)i1-(YA2)j1-(ZA3)k1-(YA3)l1-(ZA4)m1-(YA4)n1- (ZA5)o1-GA2; LB is described by formula GB1-(ZB1)g2-(YB1)h2-(ZB2)i2-(YB2)j2-(ZB3)k2-(YB3)l2-(ZB4)m2-(YB4)n2- (ZB5)o2-GB2; LC is described by formula GC1-(ZC1)g3-(YC1)h3-(ZC2)i3-(YC2)j3-(ZC3)k3-(YC3)l3-(ZC4)m3-(YC4)n3- (ZC5)o3-GC2; LD is described by formula GD1-(ZD1)g4-(YD1)h4-(ZD2)i4-(YD2)j4-(ZD3)k4-(YD3)l4-(ZD4)m4-(YD4)n4- (ZD5)o4-GD2; LE is described by formula GE1-(ZE1)g5-(YE1)h5-(ZE2)i5-(YE2)j5-(ZE3)k5-(YE3)l5-(ZE4)m5-(YE4)n5- (ZE5)o5-GE2, or is hydrogen; LF is described by formula GF1-(ZF1)g6-(YF1)h6-(ZF2)i6-(YF2)j6-(ZF3)k6-(YF3)l6- (ZF4)m6-(YF4)n6-(ZF5)o6-GF2; LG is described by formula GG1-(ZG1)g7-(YG1)h7-(ZG2)i7-(YG2)j7-(ZG3)k7-(YG3)l7- (ZG4)m7-(YG4)n7-(ZG5)o7-GG2, or is hydrogen; GA1 is a bond attached to NA in formula (L-III); GA2 is a bond attached to the β-1,3-glucan synthase inhibitor; GB1 is a bond attached to NA in formula (L-III); GB2 is a bond attached to NB in formula (L-III); GC1 is a bond attached to NA in formula (L-III); GC2 is a bond attached to NC in formula (L-III); GD1 is a bond attached to NB in formula (L-III); GD2 is a bond attached to a first monosaccharide or oligosaccharide moiety, E1; GE1 is a bond attached to NB in formula (L-III); GE2 is a bond attached to a second monosaccharide or oligosaccharide moiety, E2; GF1 is a bond attached to NC in formula (L-III); GF2 is a bond attached to a third monosaccharide or oligosaccharide moiety, E3; GG1 is a bond attached to NC in formula (L-III); GG2 is a bond attached to a fourth monosaccharide or oligosaccharide moiety, E4; each of YA1, YA2, YA3, YA4, YB1, YB2, YB3, YB4, YC1, YC2, YC3, YC4, YD1, YD2, YD3, YD4, YE1, YE2, YE3, YE4, YF1, YF2, YF3, YF4, YG1, YG2, YG3, and YG4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C1-C15 heteroarylene; each of ZA1, ZA2, ZA3, ZA4, ZA5, ZB1, ZB2, ZB3, ZB4, ZB5, ZC1, ZC2, ZC3, ZC4, ZC5, ZD1, ZD2, ZD3, ZD4, ZD5, ZE1, ZE2, ZE3, ZE4, ZE5, ZF1, ZF2, ZF3, ZF4, ZF5, ZG1, ZG2, ZG3, ZG4, and ZG5 is, independently, O, S, NRi, P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino; wherein Ri is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C5-C15 heteroaryl; each of g1, h1, i1, j1, k1, l1, m1, n1, o1, g2, h2, i2, j2, k2, l2, m2, n2, o2, g3, h3, i3, j3, k3, l3, m3, n3, o3, g4, h4, i4, j4, k4, l4, m4, n4, o4, g5, h5, i5, j5, k5, l5, m5, n5, o5, g6, h6, i6, j6, k6, l6, m6, n6, o6, g7, h7, i7, j7, k7, l7, m7, n7, and o7 is, independently, 0 or 1; and each of NA, NB, and NC is a nitrogen.
In some embodiments of the linker of formula (L-III), each of YA1, YA2, YA3, YA4, YB1, YB2, YB3, YB4, YC1, YC2, YC3, YC4, YD1, YD2, YD3, YD4, YE1, YE2, YE3, YE4, YF1, YF2, YF3, YF4, YG1, YG2, YG3, and YG4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20
heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20
heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C15 arylene, or optionally substituted C1-C15 heteroarylene; each of ZA1, ZA2, ZA3, ZA4, ZA5, ZB1, ZB2, ZB3, ZB4, ZB5, ZC1, ZC2, ZC3, ZC4, ZC5, ZD1, ZD2, ZD3, ZD4, ZD5, ZE1, ZE2, ZE3, ZE4, ZE5, ZF1, ZF2, ZF3, ZF4, ZF5, ZG1, ZG2, ZG3, ZG4, and ZG5 is, independently, O, S, NRi, P, carbonyl; Ri is H or optionally substituted C1-C20 alkyl; and each of g1, h1, i1, j1, k1, l1, m1, n1, o1, g2, h2, i2, j2, k2, l2, m2, n2, o2, g3, h3, i3, j3, k3, l3, m3, n3, o3, g4, h4, i4, j4, k4, l4, m4, n4, o4, g5, h5, i5, j5, k5, l5, m5, n5, o5, g6, h6, i6, j6, k6, l6, m6, n6, o6, g7, h7, i7, j7, k7, l7, m7, n7, and o7 is, independently, 0 or 1.
In some embodiments, a multivalent linker in a compound described herein is
Figure imgf000086_0001
wherein each of p, q, r, s, t, u, v, w, x, y, and z is, independently, an integer from 1 to 10.
In some embodiments, a multivalent linker in a compound described herein is
Figure imgf000087_0001
wherein each of p, q, r, s, and t is, independently, an integer from 1 to 10.
In some embodiments, a linker L in the compound of any one of formulas (I)-(III) is described by formula (L-IV):
Figure imgf000087_0002
wherein LA is described by formula GA1-(ZA1)g1-(YA1)h1-(ZA2)i1-(YA2)j1-(ZA3)k1-(YA3)l1-(ZA4)m1-(YA4)n1- (ZA5)o1-GA2; LB is described by formula GB1-(ZB1)g2-(YB1)h2-(ZB2)i2-(YB2)j2-(ZB3)k2-(YB3)l2-(ZB4)m2-(YB4)n2- (ZB5)o2-GB2; LC is described by formula GC1-(ZC1)g3-(YC1)h3-(ZC2)i3-(YC2)j3-(ZC3)k3-(YC3)l3-(ZC4)m3-(YC4)n3- (ZC5)o3-GC2; LD is described by formula GD1-(ZD1)g4-(YD1)h4-(ZD2)i4-(YD2)j4-(ZD3)k4-(YD3)l4-(ZD4)m4-(YD4)n4- (ZD5)o4-GD2, or is hydrogen; GA1 is a bond attached to N in formula (L-IV); GA2 is a bond attached to the β-1,3-glucan synthase inhibitor; GB1 is a bond attached to C in formula (L-IV); GB2 is a bond attached to a first monosaccharide or oligosaccharide moiety, E1; GC1 is a bond attached to C in formula (L-IV); GC2 is a bond attached to a second monosaccharide or oligosaccharide moiety, E2; GD1 is a bond attached to C in formula (L-IV); GD2 is a bond attached to a third monosaccharide or oligosaccharide moiety, E3; each of YA1, YA2, YA3, YA4, YB1, YB2, YB3, YB4, YC1, YC2, YC3, YC4, YD1, YD2, YD3, and YD4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20
heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C2-C15 heteroarylene; each of ZA1, ZA2, ZA3, ZA4, ZA5, ZB1, ZB2, ZB3, ZB4, ZB5, ZC1, ZC2, ZC3, ZC4, ZC5, ZD1, ZD2, ZD3, ZD4, and ZD5 is, independently, O, S, NR', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino; R' is H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl; and each of g1 , hi , i1 , j1 , k1 , 11 , ml , n1 , o1 , g2, h2, i2, j2, k2, I2, m2, n2, o2, g3, h3, i3, j3, k3, I3, m3, n3, o3, g4, h4, i4, j4, k4, I4, m4, n4, and o4 is, independently, 0 or 1 ; or a pharmaceutically acceptable salt thereof.
In some embodiments, a multivalent linker in a compound described herein is
Figure imgf000088_0001
wherein each of p, q, r, s, and t is, independently, an integer from 1 to 10.
In some embodiments, a linker provides space, rigidity, and/or flexibility between the β-1 ,3- glucan synthase inhibitor and the monosaccharide or oligosaccharide moiety. In some embodiments, a linker may be a bond, e.g., a covalent bond, e.g., an amide bond, a disulfide bond, a C-N bond, a N- N bond, or any kind of bond created from a chemical reaction, e.g., chemical conjugation. In some embodiments, a linker includes no more than 250 atoms (e.g., 1-2, 1-4, 1-6, 1-8, 1-10, 1-12, 1-14, 1- 16, 1-18, 1-20, 1-25, 1-30, 1-35, 1-40, 1-45, 1-50, 1-55, 1-60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95, 1-100, 1-110, 1-120, 1-130, 1-140, 1-150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-210, 1-220, 1-230, 1- 240, or 1-250 atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 atom(s)). In some embodiments, a linker includes no more than 250 non- hydrogen atoms (e.g., 1-2, 1-4, 1-6, 1-8, 1-10, 1-12, 1-14, 1-16, 1-18, 1-20, 1-25, 1-30, 1-35, 1-40, 1- 45, 1 -50, 1 -55, 1 -60, 1 -65, 1 -70, 1 -75, 1 -80, 1 -85, 1 -90, 1 -95, 1 -100, 1-110, 1-120, 1 -130, 1 -140, 1 - 150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-210, 1-220, 1-230, 1-240, or 1-250 non-hydrogen atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 non- hydrogen atom(s)). In some embodiments, the backbone of a linker includes no more than 250 atoms (e.g., 1-2, 1-4, 1-6, 1-8, 1-10, 1-12, 1-14, 1-16, 1-18, 1-20, 1-25, 1-30, 1-35, 1-40, 1-45, 1-50, 1-55, 1- 60, 1-65, 1-70, 1-75, 1-80, 1-85, 1-90, 1-95, 1-100, 1-110, 1-120, 1-130, 1-140, 1-150, 1-160, 1-170, 1-180, 1-190, 1-200, 1-210, 1-220, 1-230, 1-240, or 1-250 atom(s); 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 28, 26, 24, 22, 20, 18, 16, 14, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 atom(s)). The "backbone" of a linker refers to the atoms in the linker that together form the shortest path from one part of the compound to another part of the compound. The atoms in the backbone of the linker are directly involved in linking one part of the compound to another part of the compound. For examples, hydrogen atoms attached to carbons in the backbone of the linker are not considered as directly involved in linking one part of the compound to another part of the compound.
Molecules that may be used to make linkers include at least two functional groups. In some embodiments, a divalent linker may contain two carboxylic acids, in which the first carboxylic acid may form a covalent linkage with one component (e.g., a β-1 ,3-glucan synthase inhibitor) in the compound and the second carboxylic acid may form a covalent linkage with another component (e.g., a monosaccharide or oligosaccharide moiety) in the compound. In other embodiments, one end of the linker may form a covalent linkage with the β-1 ,3-glucan synthase inhibitor in the compound and the other end of the linker may form a covalent linkage (e.g., a C-0 bond, a C-S bond, or a C-N bond) with the monosaccharide or oligosaccharide moiety.
In some embodiments, dicarboxylic acid molecules may be used as linkers (e.g., a dicarboxylic acid linker). For example, the first carboxylic acid in a dicarboxylic acid molecule may form a covalent linkage with the β-1 ,3-glucan synthase inhibitor and the second carboxylic acid may form a covalent linkage with the monosaccharide or oligosaccharide moiety. Examples of dicarboxylic acids molecules that may be used to serve as linkers in compounds disclosed herein (e.g., compounds of formulas (l)-(lll)) include, but are not limited to,
Figure imgf000089_0001
Figure imgf000090_0001
In some embodiments, dicarboxylic acid molecules, such as the ones described herein, may be further functionalized to contain one or more additional functional groups, which may be used to conjugate to one or more monosaccharide or oligosaccharide moieties.
In some embodiments, a molecule containing one or more sulfonic acid groups may be used to form a linker, in which the sulfonic acid group may form a sulfonamide linkage with a nitrogen in a β-1 ,3-glucan synthase inhibitor . In some embodiments, a molecule containing one or more isocyanate groups may be used to form a linker, in which the isocyanate group may form a urea linkage with a nitrogen in a β-1 ,3-glucan synthase inhibitor. In some embodiments, a molecule containing one or more haloalkyl groups may be used to form a linker, in which the haloalkyl group may form a covalent linkage, e.g., C-N and C-0 linkages, with a β-1 ,3-glucan synthase inhibitor.
In some embodiments, a linker may include a synthetic group derived from, e.g., a synthetic polymer (e.g., a polyethylene glycol (PEG) polymer). In some embodiments, a linker may include one or more amino acid residues. In some embodiments, a linker may be an amino acid sequence (e.g., a 1 -25 amino acid, 1 -10 amino acid, 1 -9 amino acid, 1 -8 amino acid, 1 -7 amino acid, 1 -6 amino acid, 1 -5 amino acid, 1 -4 amino acid, 1 -3 amino acid, or 1 -2 amino acid sequence). In some embodiments, a linker may include one or more optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene (e.g., a PEG unit), optionally substituted C2-C20 alkenylene (e.g., C2 alkenylene), optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene (e.g., cyclopropylene, cyclobutylene), optionally substituted C3-C20
heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene (e.g., C6 arylene), optionally substituted C1 -C15 heteroarylene (e.g., imidazole, pyridine), O, S, NR' (R' is H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C1 -C15 heteroaryl), P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino.
In some embodiments, L in a compound of any one of formulas (l)-(lll) may have a formula of (L-l), (L-ll), (L-lll), or (L-IV).
Covalent conjugation of two or more components in a compound using a linker may be accomplished using well-known organic chemical synthesis techniques and methods.
Complementary functional groups on two components may react with each other to form a covalent bond. Examples of complementary reactive functional groups include, but are not limited to, e.g., amine and activated carboxylic acid, thiol and maleimide, activated sulfonic acid and amine, isocyanate and amine, azide and alkyne, and alkene and tetrazine. Other examples of functional groups capable of reacting with amino groups include, e.g., alkylating and acylating agents. Representative alkylating agents include: (i) an a-haloacetyl group, e.g., XCH2CO- (where X=Br, CI, or I); (ii) a N-maleimide group, which may react with amino groups either through a Michael type reaction or through acylation by addition to the ring carbonyl group; (iii) an aryl halide, e.g., a nitrohaloaromatic group; (iv) an alkyl halide; (v) an aldehyde or ketone capable of Schiff's base formation with amino groups; (vi) an epoxide, e.g., an epichlorohydrin and a bisoxirane, which may react with amino, sulfhydryl, or phenolic hydroxyl groups; (vii) a chlorine- containing of s-triazine, which is reactive towards nucleophiles such as amino, sufhydryl, and hydroxyl groups; (viii) an aziridine, which is reactive towards nucleophiles such as amino groups by ring opening; (ix) a squaric acid diethyl ester; and (x) an a-haloalkyl ether.
Examples of amino-reactive acylating groups include, e.g., (i) an isocyanate and an isothiocyanate; (ii) a sulfonyl chloride; (iii) an acid halide; (iv) an active ester, e.g., a nitrophenylester or N-hydroxysuccinimidyl ester; (v) an acid anhydride, e.g., a mixed, symmetrical, or N- carboxyanhydride; (vi) an acylazide; and (vii) an imidoester. Aldehydes and ketones may be reacted with amines to form Schiff's bases, which may be stabilized through reductive amination.
It will be appreciated that certain functional groups may be converted to other functional groups prior to reaction, for example, to confer additional reactivity or selectivity. Examples of methods useful for this purpose include conversion of amines to carboxyls using reagents such as dicarboxylic anhydrides; conversion of amines to thiols using reagents such as N-acetylhomocysteine thiolactone, S-acetylmercaptosuccinic anhydride, 2-iminothiolane, or thiol-containing succinimidyl derivatives; conversion of thiols to carboxyls using reagents such as a -haloacetates; conversion of thiols to amines using reagents such as ethylenimine or 2-bromoethylamine; conversion of carboxyls to amines using reagents such as carbodiimides followed by diamines; and conversion of alcohols to thiols using reagents such as tosyl chloride followed by transesterification with thioacetate and hydrolysis to the thiol with sodium acetate.
III. Monosaccharide or Oligosaccharide Moieties
A monosaccharide moiety is a molecular moiety that has one optionally substituted C6-C9 (exclusive of the substituents) monosaccharide residue. An oligosaccharide moiety is a molecular moiety that includes at least two, e.g., 2-150 (e.g., 2-149, 2-140, 2-130, 2-120, 2-1 10, 2-100, 2-90,
2-80, 2-70, 2-60, 2-50, 2-40, 2-30, 2-20, 2-18, 2-16, 2-14, 2-12, 2-1 0, 2-9, 2-8, 2-7, 2-6, 2-5, 2-4, 2-3, or 2)) optionally substituted C6-C9 (exclusive of the substituents) monosaccharide residues. In some embodiments, an oligosaccharide moiety includes 2-18 optionally substituted C6-C9 (exclusive of the substituents) monosaccharide residues. In some embodiments, an oligosaccharide moiety includes 2-12 optionally substituted C6-C9 (exclusive of the substituents) monosaccharide residues. In some embodiments, an oligosaccharide moiety has a molecule weight that does not exceed 30 kDa, 25 kDa, 24 kDa, 23 kDa, 22 kDa, 21 kDa, 20 kDa, 19 kDa, 18 kDa, 17 kDa, 16 kDa, 1 5 kDa, 14 kDa, 13 kDa, 12 kDa, 1 1 kDa, 10 kDa, 9 kDa, 8 kDa, 7 kDa, 6 kDa, 5 kDa or 3 kDa. In some embodiments, a monosaccharide moiety has an optionally substituted C6-C9 monosaccharide residue selected from glucose (Glc), galactose (Gal), mannose (Man), allose (All), altrose (Alt), gulose (Gul), idose (Ido), talose (Tal), fucose (Fuc), rhamnose (Rha; also called
L-rhamnose or L-Rha), thia-rhamnose (thia-Rha; also called thia-L-rhamnose or thia-L-Rha), quinovose (Qui), 2-deoxyglucose (2-dGlc), glucosamine (GlcN), galactosamine (GaIN), mannosamine (ManN), fucosamine (FucN), quinovosamine (QuiN), N-Acetyl-glucosamine (GlcNAc); N-Acetyl- galactosamine (GalNAc), N-Acetyl-mannosamine (ManNAc), N-acetyl-fucosamine (FucNAc), N-acetyl-quinovosamine (QuiNAc), glucuronic acid (GlcA), galacturonic acid (GalA), mannuronic acid (ManA), iduronic acid (IdoA), sialic acid (Sia), neuraminic acid (Neu), N-Acetyl-neuraminic acid (Neu5Ac), N-Glycolyl-neuraminic acid (Neu5Gc), glucitol (Glc-ol), galactitol (Gal-ol), mannitol (Man- ol), fructose (Fru), sorbose (Sor), tagatose (Tag), thevetose (The), acofriose (Aco), digitoxose (Dig), cymarose (Cym), abequose (Abe), colitose (Col), tyvelose (Tyv), ascarylose (Asc), paratose (Par), or N-acetyl-muramic acid (MurNAc).
In some embodiments, a monosaccharide moiety has an optionally substituted C6-C9 monosaccharide residue selected from Rha, Gal, Glc, GlcA (Glucuronic acid), GlcNAc, GalNAc, GlcN(Gc) (N-Glycolyl-Glucosamine), Neu5Ac, Neu5Gc (N-Glycolyl-neuraminic acid), Fuc, Man, -htePOsMan (mannose phosphate), 6-H2PO3GIC (glucose phosphate), Mur (muramoyl), Mur-L-Ala-D-i- Gln-Lys, (Mur)-3-0-GlcNAc, sulfate-galactose (Su-Gal), disulfate-galactose (Su2-Gal), sulfate-glucose (Su-Glc), sulfate-GlcNAc (Su-GlcNAc), or sulfate-GalNAc (Su-GalNAc).
Rhamnose (Rha) occurs in nature in its L-form, thus, rhamnose is also referred to as
L-rhamnose or L-Rha. Rhamnose may be in a form (also called a-Rha or a-L-Rha) or β form (also called β-Rha or β-L-Rha). Thia-rhamnose has -SH attached at the anomeric carbon instead of -OH. Thia-rhamnose is also referred to as thia-Rha or thia-L-Rha. Thia-rhamnose may be in a form (also called thia-a-Rha or thia-a-L-Rha) or in β form (also called thia^-Rha or thia^-L-Rha). The structures of Rha, a-Rha, and β-Rha are shown below. In some embodiments, the monosaccharide moiety is an optionally substituted a-Rha or an optionally substituted thia-a-Rha. In some
embodiments, a compounds described herein (e.g., a compound of any one of formulas (l)-(lll)) may contain a-Rha.
Figure imgf000093_0001
In some embodiments, in an oligosaccharide moiety, each of the optionally substituted C6-C9 monosaccharide residues may, independently, joined to an adjacent monosaccharide residue through an O-glycosidic, S-glycosidic, N-glycosidic linkage, or C-glycosidic. The binding at an O-glycosidic, S- glycosidic, N-glycosidic, or C-glycosidic linkage may be an a- or β-configuration, for example, through 1 ,2-, 1 ,3-, 1 ,4-, 1 ,6-, 2,3-, 2,6-, or 2,8-linkage, or a linkage such as 3-0, for example, a1 -2, a1 -3, a1 -4, α1 -6, α2-3, α2-6, α2-8, β1 -2, β1 -3, β1 -4, or β1 -6. In some embodiments, each of the optionally substituted C6-C9 monosaccharide residues is, independently, glucose (Glc), galactose (Gal), mannose (Man), allose (All), altrose (alt), gulose (Gul), idose (ido), talose (Tal), fucose (Fuc), rhamnose (Rha), quinovose (Qui), 2-deoxyglucose (2-dGlc), glucosamine (GlcN), galactosamine (GaIN), mannosamine (ManN), fucosamine (FucN), quinovosamine (QuiN), N-Acetyl-glucosamine (GlcNAc); N-Acetyl-galactosamine (GalNAc), N-Acetyl-mannosamine (ManNAc), N-acetyl-fucosamine (FucNAc), N-acetyl-quinovosamine (QuiNAc), glucuronic acid (GlcA), galacturonic acid (GalA), mannuronic acid (ManA), iduronic acid (IdoA), sialic acid (Sia), neuraminic acid (Neu), N-Acetyl- neuraminic acid (Neu5Ac), N-Glycolyl-neuraminic acid (Neu5Gc), glucitol (Glc-ol), galactitol (Gal-ol), mannitol (Man-ol), fructose (Fru), sorbose (Sor), tagatose (Tag), thevetose (The), acofriose (Aco), digitoxose (Dig), cymarose (Cym), abequose (Abe), colitose (Col), tyvelose (Tyv), ascarylose (Asc), paratose (Par), or N-acetyl-muramic acid (MurNAc). In some embodiments, each of the optionally substituted C6-C9 monosaccharide residues is, independently, Rha, Gal, Glc, GlcA (Glucuronic acid), GlcNAc, GalNAc, GlcN(Gc) (N-Glycolyl-Glucosamine), Neu5Ac, Neu5Gc (N-Glycolyl-neuraminic acid), Fuc, Man, -FtePCbMan (mannose phosphate), 6-H2PO3GIC (glucose phosphate), Mur
(muramoyi), Mur-L-Ala-D-i-Gln-Lys, (Mur)-3-0-GlcNAc, sulfate-galactose (Su-Gal), disulfate-galactose (Su2-Gal), sulfate-glucose (Su-Glc), sulfate-GlcNAc (Su-GlcNAc), or sulfate-GalNAc (Su-GalNAc). In some embodiments, an oligosaccharide moiety may be straight or branched.
In some embodiments, the optionally substituted monosaccharide residue(s) (i.e., at least one monosaccharide residue) in the monosaccharide or oligosaccharide moiety is substituted with one or more, such as 1 -3, substituents independently selected from sulfate, phosphate, methyl, acetyl, naturally amino acids, and non-naturally occurring amino acids.
In some embodiments, the optionally substituted monosaccharide residue(s) (i.e., at least one monosaccharide residue) in the monosaccharide or oligosaccharide moiety is substituted with one or more, such as 1 -3, substituents, wherein each substituent is, independently, selected from sulfate, phosphate, methyl, acetyl.
In some embodiments, the optionally substituted monosaccharide residue(s) (i.e., at least one monosaccharide residue) in the monosaccharide or oligosaccharide moiety is substituted with one or more, such as 1 -3, substituents, wherein each substituent is, independently, selected from naturally occurring amino acids and non-naturally occurring amino acids. If the monosaccharide residue is linked to an amino acid, such as serine, the linkage may be, for example, a a1 -0 linkage. If the linkage is through a sulfate, the linkage may be through a hydroxyl group, for example, a 2-0, 3-0 , 4-0, or 6-0 linkage, such as 3-0-Su-Gal, (6-0-Su)Gal, (6-0-Su)Glc, 6-0-Su-GlcNAc, (6-0- Su)GalNAc, 3,6-0-Su2-Gal, 3,4-0-Su2-Gal, or 4-0-Su-Gal.
Naturally occurring amino acids include Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, He, Leu,
Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val. A non-naturally occurring amino acid is an amino acid that is not naturally produced or found in a mammal. Examples of non-naturally occurring amino acids include D-amino acids; an amino acid having an acetylaminomethyl group attached to a sulfur atom of a cysteine; a pegylated amino acid; the omega amino acids of the formula NH2(CH2)nCOOH where n is 2-6, neutral nonpolar amino acids, such as sarcosine, t-butyl alanine, t-butyl glycine, N- methyl isoleucine, and norleucine; oxymethionine; phenylglycine; citrulline; methionine sulfoxide; cysteic acid; ornithine; diaminobutyric acid; and hydroxyproline. Other amino acids are a- aminobutyric acid, α-amino-a-methylbutyrate, aminocyclopropane-carboxylate, aminoisobutyric acid, aminonorbornyl-carboxylate, L-cyclohexylalanine, cyclopentylalanine, L-N-methylleucine,
L-N-methylmethionine, L-N-methylnorvaline, L-N-methylphenylalanine, L-N-methylproline,
L-N-methylserine, L-N-methyltryptophan, D-ornithine, L-N-methylethylglycine, L-norleucine, a-methyl- aminoisobutyrate, a-methylcyclohexylalanine, D-a-methylalanine, D-a-methylarginine,
D-a-methylasparagine, D-a-methylaspartate, D-a-methylcysteine, D-a-methylglutamine,
D-a-methylhistidine, D-a-methylisoleucine, D-a-methylleucine, D-a-methyllysine,
D-a-methylmethionine, D-a-methylornithine, D-a-methylphenylalanine, D-a-methylproline,
D-a-methylserine, D-N-methylserine, D-a-methylthreonine, D-a-methyltryptophan, D-a-methyltyrosine, D-a-methylvaline, D-N-methylalanine, D-N-methylarginine, D-N-methylasparagine,
D-N-methylaspartate, D-N-methylcysteine, D-N-methylglutamine, D-N-methylglutamate,
D-N-methylhistidine, D-N-methylisoleucine, D-N-methylleucine, D-N-methyllysine,
N-methylcyclohexylalanine, D-N-methylornithine, N-methylglycine, N-methylaminoisobutyrate, N-(1 -methylpropyl)glycine, N-(2-methylpropyl)glycine, D-N-methyltryptophan, D-N-methyltyrosine, D- N-methylvaline, γ-aminobutyric acid, L-t-butylglycine, L-ethylglycine, L-homophenylalanine,
L-a-methylarginine, L-a-methylaspartate, L-a-methylcysteine, L-a-methylglutamine,
L-a-methylhistidine, L-a-methylisoleucine, L-a-methylleucine, L-a-methylmethionine,
L-a-methylnorvaline, L-a-methylphenylalanine, L-a-methylserine, L-a-methyltryptophan,
L-a-methylvaline, N-(N-(2,2-diphenylethyl) carbamylmethylglycine, 1 -carboxy-1 -(2,2-diphenyl- ethylamino) cyclopropane, 4-hydroxyproline, ornithine, 2-aminobenzoyl (anthraniloyl),
D-cyclohexylalanine, 4-phenyl-phenylalanine, L-citrulline, a-cyclohexylglycine, L-1 ,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, L-thiazolidine-4-carboxylic acid, L-homotyrosine,
L-2-furylalanine, L-histidine (3-methyl), N-(3-guanidinopropyl)glycine, O-methyl-L-tyrosine, O-glycan- serine, meta-tyrosine, nor-tyrosine, L-N,N',N"-trimethyllysine, homolysine, norlysine, N-glycan asparagine, 7-hydroxy-1 ,2,3,4-tetrahydro-4-fluorophenylalanine, 4-methylphenylalanine, bis-(2- picolyl)amine, pentafluorophenylalanine, indoline-2-carboxylic acid, 2-aminobenzoic acid, 3-amino-2- naphthoic acid, asymmetric dimethylarginine, L-tetrahydroisoquinoline-1 -carboxylic acid,
D-tetrahydroisoquinoline-1 -carboxylic acid, 1 -amino-cyclohexane acetic acid, D/L-allylglycine, 4-aminobenzoic acid, 1 -amino-cyclobutane carboxylic acid, 2 or 3 or 4-aminocyclohexane carboxylic acid, 1 -amino-1 -cyclopentane carboxylic acid, 1 -aminoindane-1 -carboxylic acid, 4-amino-pyrrolidine- 2-carboxylic acid, 2-aminotetraline-2-carboxylic acid, azetidine-3-carboxylic acid, 4-benzyl-pyrolidine- 2-carboxylic acid, tert-butylglycine, b-(benzothiazolyl-2-yl)-alanine, b-cyclopropyl alanine, 5,5- dimethyl-1 ,3-thiazolidine-4-carboxylic acid, (2R,4S)4-hydroxypiperidine-2-carboxylic acid, (2S,4S) and (2S,4R)-4-(2-naphthylmethoxy)-pyrolidine-2-carboxylic acid, (2S.4S) and (2S,4R)4-phenoxy- pyrrolidine-2-carboxylic acid, (2R,5S)and(2S,5R)-5-phenyl-pyrrolidine-2-carboxylic acid, (2S,4S)-4- amino-1 -benzoyl-pyrrolidine-2-carboxylic acid, t-butylalanine, (2S,5R)-5-phenyl-pyrrolidine-2- carboxylic acid, 1 -aminomethyl-cyclohexane-acetic acid, 3,5-bis-(2-amino)ethoxy-benzoic acid, 3,5-diamino-benzoic acid, 2-methylamino-benzoic acid, N-methylanthranylic acid, L-N-methylalanine, L-N-methylarginine, L-N-methylasparagine, L-N-methylaspartic acid, L-N-methylcysteine,
L-N-methylglutamine, L-N-methylglutamic acid, L-N-methylhistidine, L-N-methylisoleucine,
L-N-methyllysine, L-N-methylnorleucine, L-N-methylornithine, L-N-methylthreonine,
L-N-methyltyrosine, L-N-methylvaline, L-N-methyl-t-butylglycine, L-norvaline, a-methyl-γ- aminobutyrate, 4,4'-biphenylalanine, a-methylcylcopentylalanine, a-methyl-a-napthylalanine, a-methylpenicillamine, N-(4-aminobutyl)glycine, N-(2-aminoethyl)glycine, N-(3-aminopropyl)glycine, N-amino-a-methylbutyrate, a-napthylalanine, N-benzylglycine, N-(2-carbamylethyl)glycine,
N-(carbamylmethyl)glycine, N-(2-carboxyethyl)glycine, N-(carboxymethyl)glycine, N-cyclobutylglycine, N-cyclodecylglycine, N-cycloheptylglycine, N-cyclohexylglycine, N-cyclodecylglycine,
N-cylcododecylglycine, N-cyclooctylglycine, N-cyclopropylglycine, N-cycloundecylglycine, N-(2,2- diphenylethyl)glycine, N-(3,3-diphenylpropyl)glycine, N-(3-guanidinopropyl)glycine,
N-(1 -hydroxyethyl)glycine, N-(hydroxyethyl))glycine, N-(imidazolylethyl))glycine,
N-(3-indolylyethyl)glycine, N-methyl-Y-aminobutyrate, D-N-methylmethionine,
N-methylcyclopentylalanine, D-N-methylphenylalanine, D-N-methylproline, D-N-methylthreonine, N-(1 -methylethyl)glycine, N-methyl-napthylalanine, N-methylpenicillamine,
N-(p-hydroxyphenyl)glycine, N-(thiomethyl)glycine, penicillamine, L-a-methylalanine,
L-a-methylasparagine, L-a-methyl-t-butylglycine, L-methylethylglycine, L-a-methylglutamate,
L-a-methylhomophenylalanine, N-(2-methylthioethyl)glycine, L-a-methyllysine, L-a-methylnorleucine, L-a-methylornithine, L-a-methylproline, L-a-methylthreonine, L-a-methyltyrosine, L-N-methyl- homophenylalanine, N-(N-(3,3-diphenylpropyl) carbamylmethylglycine, L-pyroglutamic acid,
D-pyroglutamic acid, O-methyl-L-serine, O-methyl-L-homoserine, 5-hydroxylysine,
a-carboxyglutamate, phenylglycine, L-pipecolic acid (homoproline), L-homoleucine, L-lysine
(dimethyl), L-2-naphthylalanine, L-dimethyldopa or L-dimethoxy-phenylalanine, L-3-pyridylalanine, L-histidine (benzoyloxymethyl), N-cycloheptylglycine, L-diphenylalanine, O-methyl-L-homotyrosine, L-p-homolysine, O-glycan-threoine, Ortho-tyrosine, L-N.N'-dimethyllysine, L-homoarginine, neotryptophan, 3-benzothienylalanine, isoquinoline-3-carboxylic acid, diaminopropionic acid, homocysteine, 3,4-dimethoxyphenylalanine, 4-chlorophenylalanine, L-1 ,2,3,4-tetrahydronorharman-3- carboxylic acid, adamantylalanine, symmetrical dimethylarginine, 3-carboxythiomorpholine, D-1 ,2,3,4- tetrahydronorharman-3-carboxylic acid, 3-aminobenzoic acid, 3-amino-1 -carboxymethyl-pyridin-2-one, 1 -amino-1 -cyclohexane carboxylic acid, 2-aminocyclopentane carboxylic acid, 1 -amino-1 - cyclopropane carboxylic acid, 2-aminoindane-2-carboxylic acid, 4-amino-tetrahydrothiopyran-4- carboxylic acid, azetidine-2-carboxylic acid, b-(benzothiazol-2-yl)-alanine, neopentylglycine,
2-carboxymethyl piperidine, b-cyclobutyl alanine, allylglycine, diaminopropionic acid, homo-cyclohexyl alanine, (2S,4R)- 4-hydroxypiperidine-2-carboxylic acid, octahydroindole-2-carboxylic acid, (2S,4R) and (2S,4R)-4-(2-naphthyl), pyrrolidine-2-carboxylic acid, nipecotic acid, (2S,4R)and (2S,4S)-4-(4- phenylbenzyl) pyrrolidine-2-carboxylic acid, (3S)-1 -pyrrolidine-3-carboxylic acid, (2S,4S)-4- tritylmercapto-pyrrolidine-2-carboxylic acid, (2S,4S)-4-mercaptoproline, t-butylglycine, N,N-bis(3- aminopropyl)glycine, 1 -amino-cyclohexane-1 -carboxylic acid, N-mercaptoethylglycine, and selenocysteine. In some embodiments, amino acid residues may be charged or polar. Charged amino acids include alanine, lysine, aspartic acid, or glutamic acid, or non-naturally occurring analogs thereof. Polar amino acids include glutamine, asparagine, histidine, serine, threonine, tyrosine, methionine, or tryptophan, or non-naturally occurring analogs thereof.
In some embodiments, non-natural amino acids that may be included in a compound described herein (e.g., a compound of any one of formulas (l)-(lll)), for example, in the linker portion of the compound, include, but are not limited to, D-Ser, D-Pro, D-Leu, D-Nle (D-norleucine), D-Thr, D-Val, L-Abu (L-2-aminobutyric acid), 3-(2H-tetrazol-5-yl)alanine, 3-aminoalanine, piperazine-2- carboxylic acid, 2,4-diaminobutyric acid, 3-hydroxyproline, 2-amino-4-phenylbutyric acid,
3- (2-naphthyl)alanine, 2-piperazinecarboxylic acid, 2-aminooctanoic acid, 2-aminohexanoic acid,
4- amino-4-piperidinyl carboxylic acid, methionine sulfoxide, methionine sulfone, S-methylcysteine,
5- ethylcysteine, S-propylhomocysteine, cyclopropylalanine, 3-fluoroalanine, 2-amino-5- methylhexanoic acid, 2-amino-5-methylhex-4-enoic acid, alpha-t-butylglycine, and alpha- neopentylglycine.
In some embodiments, the optionally substituted monosaccharide residue(s) (i.e., at least one monosaccharide residue) in the monosaccharide or oligosaccharide moiety may be in a closed ring form (i.e., where the aldehyde/ketone carbonyl carbon (C=0) and hydroxyl group (-OH) in the open- chain monosaccharide residue reacts to form a hemiacetal with a new C-O-C bridge) or an open ring form.
In some embodiments, the optionally substituted monosaccharide residue(s) (i.e., at least one monosaccharide residue) in the monosaccharide or oligosaccharide moiety is an optionally substituted C6 monosaccharide residue. In some embodiments, the optionally substituted C6 monosaccharide residue is optionally substituted Gal or optionally substituted Glc. In some embodiments, the optionally substituted Gal is optionally substituted a1 -3Gal. In some embodiments, the optionally substituted Glc is an optionally substituted β-glucan having 1 -6 Glc moieties.
In some embodiments, the optionally substituted monosaccharide residue(s) (i.e., at least one monosaccharide residue) in the monosaccharide or oligosaccharide moiety is an optionally substituted C9 monosaccharide residue, e.g., sialic acid (Sia), Neuraminic acid (Neu), N-Acetyl- neuraminic acid (Neu5Ac), or N-Glycolyl-neuraminic acid (Neu5Gc).
In some embodiments, the optionally substituted monosaccharide residue(s) (i.e., at least one monosaccharide residue) in the monosaccharide or oligosaccharide moiety may include a hexose residue, e.g., glucose (Glc), galactose (Gal), mannose (Man), allose (All), altrose (alt), gulose (Gul), idose (ido), or talose (Tal).
In some embodiments, the optionally substituted monosaccharide residue(s) (i.e., at least one monosaccharide residue) in the monosaccharide or oligosaccharide moiety may include a deoxyhexose residue, e.g., a hexose residue without the hydroxyl group at the 6-position or the 2-position, e.g., fucose (Fuc), rhamnose (Rha), quinovose (Qui), or 2-deoxyglucose (2-dGlc). In some embodiments, the optionally substituted monosaccharide residue(s) (i.e., at least one monosaccharide residue) in the monosaccharide or oligosaccharide moiety may also include an aminohexose residue, e.g., a hexose residue with an amino group or an N-acetylated amino group at the 2 -position, e.g., glucosamine (GlcN), galactosamine (GaIN), mannosamine (ManN), fucosamine (FucN), quinovosamine (QuiN), N-Acetyl-glucosamine (GlcNAc), N-Acetyl-galactosamine (GalNAc), N-Acetyl-mannosamine (ManNAc), N-acetyl-fucosamine (FucNAc), or N-acetyl-quinovosamine (QuiNAc).
In some embodiments, the optionally substituted monosaccharide residue(s) (i.e., at least one monosaccharide residue) in the monosaccharide or oligosaccharide moiety may include a uronic acid residue, e.g., a hexose residue with a negatively charged carboxylate at the 6-position, e.g., glucuronic acid (GlcA), galacturonic acid (GalA), mannuronic acid (ManA), or iduronic acid (IdoA).
In addition to hexose residues, the optionally substituted monosaccharide residue(s) (i.e., at least one monosaccharide residue) in the monosaccharide or oligosaccharide moiety may include a sialic acid residue, e.g., a residue of a nine-carbon acidic sugar, e.g., a residue of. Sialic acid (Sia), Neuraminic acid (Neu), N-Acetyl-neuraminic acid (Neu5Ac), or N-Glycolyl-neuraminic acid (Neu5Gc).
In some embodiments, the optionally substituted monosaccharide residue(s) (i.e., at least one monosaccharide residue) in the monosaccharide or oligosaccharide moiety may include a sugar alcohol, e.g., glucitol (Glc-ol), galactitol (Gal-ol), or mannitol (Man-ol).
In some embodiments, the optionally substituted monosaccharide residue(s) (i.e., at least one monosaccharide residue) in the monosaccharide or oligosaccharide moiety may include other compounds, e.g., thevetose (The), acofriose (Aco), digitoxose (Dig), cymarose (Cym), abequose (Abe), colitose (Col), tyvelose (Tyv), ascarylose (Asc), paratose (Par), and N-acetyl-muramic acid (MurNAc).
In some embodiments, the optionally substituted monosaccharide residue(s) (i.e., at least one monosaccharide residue) in the monosaccharide or oligosaccharide moiety is Gal, such as aGal (for example, a1 -3Gal). An aGal epitope, i.e., an oligosaccharide moiety that exhibits specific binding to an anti-aGal antibody, may also include a moiety including an a-D-galactopyranoside moiety, Gal, Galal-3Gal, Galal-4Gal, Galal-6Gal, Galal-3Gala1 -3GlcNAc, Galal-3Gala1 -4Gal, Galal-3Gala1 - 4GlcNAc, Galal-3Gala1 -4Glc, Galal-3Gala1 -4[3-deoxy]GlcNAc, Galal-3Gala1 -4[6-deoxy]GlcNAc, Galal-3Gala1 -4Gala1 -3Gal, Galal-3Gala1 -4GlcNAca1 -3Gala1 -4Glc, and any multimers and combinations thereof. Galal-3Gal 1 -4GlcNAc-R (aGal epitope) glyconjugates have been reported in Macher, et al. Biochim Biophys Acta 1780: 75-88, 2008.
Exemplary aGal epitopes that may be included in a compound described here (e.g., a compound of any one of formulas (l)-(lll)) are shown below:
Figure imgf000098_0001
If present, optional substituents may include 1 -3 substituents, wherein each substituent is, independently, selected from sulfate, phosphate, methyl, acetyl, naturally occurring amino acid residues, and non-naturally occurring amino acid residues on each monosaccharide residue. These may be linked through an O, S, or N, such as a sulfamate linkage through an S. The amino acid residues may be charged or polar and includes isomers thereof. Charged amino acids include alanine, lysine, aspartic acid, or glutamic acid. Polar amino acids include glutamine, asparagine, histidine, serine, threonine, tyrosine, methionine, or tryptophan. For example, the amino acid substituent, if present, may be alanine, lysine, serine, glutamine, or i-glutamine, or asparagine.
In some embodiments, the optionally substituted monosaccharide residue(s) (i.e., at least one monosaccharide residue) in the monosaccharide or oligosaccharide moiety may contain at least one (such as 1 -12) of the following optionally substituted monosaccharide residues: Rha, Gal, Glc, GlcA (Glucuronic acid), GlcNAc, GalNAc, GlcN(Gc) (N-Glycolyl-Glucosamine), Neu5Ac, Neu5Gc
(N- phosphate), Mur (muramoyl), Mur-L-Ala-D-i-Gln-Lys, (Mur)-3-0-GlcNAc, sulfate-galactose (Su- Gal), disulfate-galactose (Su2-Gal), sulfate-glucose (Su-GIc), sulfate-GlcNAc (Su-GlcNAc), or sulfate- GalNAc (Su-GalNAc).
In some embodiments, the 1 -12 optionally substituted C6-C9 monosaccharide residues in the monosaccharide or oligosaccharide moiety may be β-glucan residues. In some embodiments, the β-Glucan residue includes 2-12 optionally substituted glucopyranosyl monosaccharide residues, wherein each residue is, independently, joined to an adjacent glucopyranosyl monosaccharide residue via an O-glycosidic, S-glycosidic, N-glycosidic, or C-glycosidic linkage to form β-linked chains, which retain the ability to bind dectin-1 . Optional substituents may include, e.g., 1 -3 substituents, such as with acetyl, sulfate, phosphate, or a natural or non-natural amino acid. Some examples of β-glucan residues include thia^-glucan residues such as the structures shown below:
Figure imgf000099_0001
In some embodiments, an oligosaccharide moiety may be a β-glucan having more than 10 monosaccharides and/or a molecular weight of at least 3 kDa (e.g., 3-30 kDa; e.g., 3-29, 3-25, 3-20, 3-15, 3-10, 3-8, 3-6, 3-5, or 3-4 kDa). For example, an oligosaccharide moiety may be a β(1→3, 1→6)-glucan, e.g., laminarin, or a β(1→6)-glucan, e.g., pustulan. In some embodiments, a monosaccharide or oligosaccharide moiety directly or indirectly activates an immune cell. In some embodiments, the monosaccharide or oligosaccharide moiety directly binds an immune cell. For example, β-glucans bind dectin-1 receptors. When bound to dectin-1 , which internalizes the β-glucan, β-glucan mediates the production of reactive oxygen species (ROS), activation of NF-κΒ, and subsequent secretion of proinflammatory cytokines. The β- glucan receptor, dectin-1 , is predominantly expressed on the surface of cells of
monocytes/macrophages and neutrophils. In some embodiments, the monosaccharide or oligosaccharide moiety indirectly binds an immune cell. For example, without being bound by theory, the monosaccharide or oligosaccharide moiety may bind to an antibody. The antibody in turn may bind to Fc receptors found on the surface of certain on immune cells including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, and mast cells. For example, aGal or aRha will bind to anti-aGal or anti-aRha antibody, respectively, thereby indirectly activating immune cells.
In some embodiments, a monosaccharide or oligosaccharide moiety is a ligand to an innate immune receptor. In some embodiments, the innate immune receptor is AICL, BDCA2, CLEC2,
Complement receptor 3, Complement receptor 4, DCIR, dectin-1 , dectin-2, DC-SIGN, a C-Type lectin receptor, MMR, langerin, TLR2, Mincle, MBL, or KCR. In some embodiments, the monosaccharide or oligosaccharide moiety binds to an antibody. In some embodiments, the antibody is a natural antibody. In some embodiments, the natural antibody is an antibody of the immunoglobulin M (IgM) isotype. Glycans bound by antibodies contained in intravenous immunoglobulin (IVIG) are studied by Gunten et al., J. Allergy Clin Immunol. 123:1268, 2009, e.g., see Tables I and E1 of Gunten et al., which is incorporated herein by reference in its entirety. In some embodiments, a monosaccharide or oligosaccharide moiety in a compound described herein (e.g., a compound of any one of formulas (I)- (III)) may be any one of the glycans listed in Tables I and E1 of Gunten et al. Examples of glycans studied by Gunten et al. are shown in Table 2A. Anti-carbohydrate antibodies found in normal sera have been studied by Huflejt et al., Molecular Immunology 46:3037-3049, 2009, using a library of glycans shown in Table 2B.
Table 2A
Figure imgf000100_0001
Figure imgf000101_0002
Table 2B
(Gc: glycolyl; GIcA: glucuronic acid; Mur: muramoyi; OS: oligosaccharide; P: phosphate; Ser. Sia: Neu5Ac; Su. Sulfate.)
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0002
Parameter that describe properties of immunoprofiles of carbohydrate-binding antibodies are median and median absolute deviation. A low median indicates that most donors show low intensities of antibodies bound to the given glycan, while a large median suggests that there is a significant number of donors with large antibody binding intensities to the given glycan. Any of the glycan moieties in Tables 2A and 2B may be used as the monosaccharide or oligosaccharide moiety herein, such as a glycan moiety with a relatively larger median.
In some embodiments, a compounds described herein (e.g., a compound of any one of formulas (l)-(lll)) may contain one or more monosaccharide or oligosaccharide moieties having the structures shown below:
Figure imgf000104_0001
IV. Methods
Methods of the invention include, e.g., methods of protecting against or treating a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.) in a subject and methods of stabilizing or inhibiting the growth of fungi, or killing fungi. A method of treating a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp.) in a subject includes administering to the subject a compound described herein (e.g., a compound of any one of formulas (l)-(lll)) or a pharmaceutical composition thereof. A method of stabilizing or inhibiting the growth of fungi, or killing fungi includes contacting the fungi or a site susceptible to fungal growth with a compound described herein (e.g., a compound of any one of formulas (l)-(lll)) or a pharmaceutical composition thereof).
In some embodiments of the methods described herein, a compound described herein (e.g., a compound of any one of formulas (l)-(lll)), or a pharmaceutical composition thereof, may be administered to the subject intravenously, subcutaneously, topically, or orally. In some embodiments, a compound described herein (e.g., a compound of any one of formulas (l)-(lll)), or a pharmaceutical composition thereof, is administered to treat a blood stream infection or tissue infection in the subject.
In some embodiments, the subject may be immunocompromised, and thus, is at a higher risk for developing a fungal infection. In some embodiments, the subject is being prepared for an invasive medical procedure or undergoing long term antibiotic therapy. In some embodiments, the subject has been diagnosed with humoral immune deficiency, T cell deficiency, neutropenia, asplenia, or complement deficiency. In some embodiments, the subject is being treated or is about to be treated with immunosuppresive drugs. In some embodiments, the subject has been diagnosed with a disease which causes immunosuppression (e.g., cancer or acquired immunodeficiency syndrome). In some embodiments, the subject has cancer (e.g., leukemia, lymphoma, or multiple myeloma). In some embodiments, the subject has undergone or is about to undergo immunosuppression therapy. In some embodiments, the subject has undergone or is about to undergo hematopoietic stem cell transplantation. In some embodiments, the subject has undergone or is about to undergo an organ transplant.
In some embodiments of the methods described herein, the fungal infection is selected from candidemia, invasive candidiasis, tinea capitis, tinea corporis, tinea pedis, onychomycosis, perionychomycosis, pityriasis versicolor, oral thrush, vaginal candidiasis, respiratory tract candidiasis, biliary candidiasis, eosophageal candidiasis, urinary tract candidiasis, systemic candidiasis, mucocutaneous candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, fungal sinusitis, or chronic sinusitis.
In some embodiments of the methods described herein, the fungal infection is candidemia or invasive candidiasis.
In some embodiments of the methods described herein, the fungal infection is an infection of Candida albicans, C. glabrata, C. dubliniensis, C. krusei, C. parapsilosis, C. tropicalis, C.
orthopsilosis, C. guilliermondii, C. rugosa, C. auris, C. lusitaniae, Aspergillus fumigatus, A. flavus, A. terreus, A. niger, A. candidus, A. clavatus, or A. ochraceus.
In some embodiments of the methods described herein, the fungal infection is an infection of Fusarium spp., Scedosporium spp., Mucor spp., Rhizopus spp., Rizomucor spp., Cunninghamella spp., Apophysomyces spp., Absidia spp., Saksenaea spp., Acremonium spp., Paecilomyces spp., Trichoderma spp., Stachybotrys spp., Trichophyton spp., Microsporum spp., Epidermophyton spp., Sporothrix spp., Histoplasma spp., Coccidioides spp., Blastomyces spp., Paracoccidioides spp., the
Cladosporium spp., Exophiala spp., or Exserohilum spp..
In some embodiments, the Fusarium spp. is F. solani, F. oxysporum, F. verticillioides, or F. moniliforme. In some embodiments, the Scedosporium spp. is S. apiospermum or S. prolificans. In some embodiments, ffte Mt/cor spp. is M circinelloides, M. azygosporus, or M. circinelloides. In some embodiments, the Rhizopus spp. is ft oryzae. In some embodiments, the Rizomucor spp. is ft pusillus. In some embodiments, the Cunninghamella spp. is £ bertholletiae. In some embodiments, the Apophysomyces spp. is /A. elegans. In some embodiments, the Absidia spp. is /A. corymbifera. In some embodiments, the Saksenaea spp. is S. vasiformis. In some embodiments, the Acremonium spp. is /A. strictum. In some embodiments, the Paecilomyces spp. is P. Iilacinus or P. variotii. In some embodiments, the Trichoderma spp. is Γ. longibrachiatum, T. harzianum, T. koningii, T.
pseudokoningii, T. citrinovirde, or T. viride. In some embodiments, the Stachybotrys spp. is S.
chartarum. In some embodiments, the Trichophyton spp. is Γ. rubrum, T. mentagrophytes, T.
tonsurans, or T. violaceum. In some embodiments, the Microsporum spp. is M gypseum. In some embodiments, the Epidermophyton spp. is E. floccosum. In some embodiments, the Sporothrix spp. is S. schenckii. In some embodiments, the Histoplasma spp. is -/. capsulatum. In some
embodiments, the Coccidioides spp. is £ immitis or £ posadasii. In some embodiments, the
Blastomyces spp. is B. dermatitidis. In some embodiments, the Paracoccidioides spp. is P.
brasiliensis. In some embodiments, the Cladosporium spp. is C trichoides. In some embodiments, the Exophiala spp. is E. jeanselmei. In some embodiments, the Exserohilum spp. is E. rostratum, E. longirostratum, or E. mcginnisii.
V. Pharmaceutical Compositions and Preparations
A compound described herein may be formulated in a pharmaceutical composition for use in the methods described herein. In some embodiments, a compound described herein may be formulated in a pharmaceutical composition. In some embodiments, the pharmaceutical composition includes a compound described herein (e.g., a compound described by any one of formulas (l)-(lll)) and pharmaceutically acceptable carriers and excipients.
Acceptable carriers and excipients in the pharmaceutical compositions are nontoxic to recipients at the dosages and concentrations employed. Acceptable carriers and excipients may include buffers such as phosphate, citrate, HEPES, and TAE, antioxidants such as ascorbic acid and methionine, preservatives such as hexamethonium chloride, octadecyldimethylbenzyl ammonium chloride, resorcinol, and benzalkonium chloride, proteins such as human serum albumin, gelatin, dextran, and immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acid residues such as glycine, glutamine, histidine, and lysine, and carbohydrates such as glucose, mannose, sucrose, and sorbitol.
Examples of other excipients include, but are not limited to, antiadherents, binders, coatings, compression aids, disintegrants, dyes, emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, sorbents, suspensing or dispersing agents, or sweeteners. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.
The compounds herein may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds herein be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.
Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulphuric, hydrobromic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like for forming basic salts. Methods for preparation of the appropriate salts are well-established in the art.
Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative alkali or alkaline earth metal salts include, but are not limited to, sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium,
tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
Depending on the route of administration and the dosage, a compound herein or a pharmaceutical composition thereof used in the methods described herein will be formulated into suitable pharmaceutical compositions to permit facile delivery. A compound (e.g., a compound of any one of formulas (l)-(lll)) or a pharmaceutical composition thereof may be formulated to be
administered intramuscularly, intravenously (e.g., as a sterile solution and in a solvent system suitable for intravenous use), intradermal^, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally,
intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally (e.g., a tablet, capsule, caplet, gelcap, or syrup), topically (e.g., as a cream, gel, lotion, or ointment), locally, by inhalation, by injection, or by infusion (e.g., continuous infusion, localized perfusion bathing target cells directly, catheter, lavage, in cremes, or lipid compositions). Depending on the route of administration, a compound herein or a pharmaceutical composition thereof may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, preparations suitable for iontophoretic delivery, or aerosols. The compositions may be formulated according to conventional pharmaceutical practice.
A compound described herein may be formulated in a variety of ways that are known in the art. For use as treatment of human and animal subjects, a compound described herein can be formulated as pharmaceutical or veterinary compositions. Depending on the subject (e.g., a human) to be treated, the mode of administration, and the type of treatment desired, e.g., prophylaxis or therapy, a compound described herein is formulated in ways consonant with these parameters. A summary of such techniques is found in Remington: The Science and Practice of Pharmacy, 22nd Edition, Lippincott Williams & Wilkins (2012); and Encyclopedia of Pharmaceutical Technology, 4th Edition, J. Swarbrick and J. C. Boylan, Marcel Dekker, New York (2013), each of which is
incorporated herein by reference.
Formulations may be prepared in a manner suitable for systemic administration or topical or local administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration. The formulation will generally include a diluent as well as, in some cases, adjuvants, buffers, and preservatives. The compounds can be administered also in liposomal compositions or as microemulsions. Systemic administration may also include relatively noninvasive methods such as the use of suppositories, transdermal patches, transmucosal delivery and intranasal administration. Oral administration is also suitable for compounds herein. Suitable forms include syrups, capsules, and tablets, as is understood in the art.
The pharmaceutical compositions can be administered parenterally in the form of an injectable formulation. Pharmaceutical compositions for injection can be formulated using a sterile solution or any pharmaceutically acceptable liquid as a vehicle. Formulations may be prepared as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions.
Pharmaceutically acceptable vehicles include, but are not limited to, sterile water, physiological saline, and cell culture media (e.g., Dulbecco's Modified Eagle Medium (DMEM), a-Modified Eagles Medium (a-MEM), F-12 medium). Such injectable compositions may also contain amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, such as sodium acetate and sorbitan monolaurate. Formulation methods are known in the art, see e.g.,
Pharmaceutical Preformulation and Formulation, 2nd Edition, M. Gibson, Taylor & Francis Group, CRC Press (2009). The pharmaceutical compositions can be prepared in the form of an oral formulation.
Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including
microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc).
Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
Other pharmaceutically acceptable excipients for oral formulations include, but are not limited to, colorants, flavoring agents, plasticizers, humectants, and buffering agents. Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
Dissolution or diffusion controlled release of a compound described herein (e.g., a compound of any one of formulas (l)-(lll)) or a pharmaceutical composition thereof can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of the compound, or by incorporating the compound into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol
palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2- hydroxymethacrylate, methacrylate hydrogels, 1 ,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax, and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.
The pharmaceutical composition may be formed in a unit dose form as needed. The amount of active component, e.g., a compound described herein (e.g., a compound of any one of formulas (I)- (III)), included in the pharmaceutical compositions are such that a suitable dose within the designated range is provided (e.g., a dose within the range of 0.01 -100 mg/kg of body weight).
VI. Routes of Administration and Dosages
In any of the methods described herein, compounds herein may be administered by any appropriate route for treating or protecting against a fungal infection (e.g., a fungal infection caused by Candida spp. or Aspergillus spp), or for preventing, stabilizing, or inhibiting the growth of fungi, or killing fungi (e.g., Candida spp. or Aspergillus spp). Compounds described herein may be administered to humans, domestic pets, livestock, or other animals with a pharmaceutically acceptable diluent, carrier, or excipient. In some embodiments, administering includes administration of any of the compounds described herein (e.g., compounds of any one of formulas (l)-(lll)) or compositions intramuscularly, intravenously (e.g., as a sterile solution and in a solvent system suitable for intravenous use), intradermal^, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally,
intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularally, orally (e.g., a tablet, capsule, caplet, gelcap, or syrup), topically (e.g., as a cream, gel, lotion, or ointment), locally, by inhalation, by injection, or by infusion (e.g., continuous infusion, localized perfusion bathing target cells directly, catheter, lavage, in cremes, or lipid compositions).
The dosage of a compound described herein (e.g., a compound of any one of formulas
(l)-(lll)) or a pharmaceutical compositions thereof depends on factors including the route of administration, the disease to be treated (e.g., the extent and/or condition of the fungal infection), and physical characteristics, e.g., age, weight, general health, of the subject. Typically, the amount of the compound or the pharmaceutical composition thereof contained within a single dose may be an amount that effectively prevents, delays, or treats the fungal infection without inducing significant toxicity. A pharmaceutical composition may include a dosage of a compound described herein ranging from 0.01 to 500 mg/kg (e.g., 0.01 , 0.1 , 0.2, 0.3, 0.4, 0.5, 1 , 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg/kg) and, in a more specific
embodiment, about 0.1 to about 30 mg/kg and, in a more specific embodiment, about 1 to about 30 mg/kg.
A compound described herein (e.g., a compound of any one of formulas (l)-(lll)) or a pharmaceutical composition thereof may be administered to a subject in need thereof, for example, one or more times (e.g., 1 -10 times or more; 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 times) daily, weekly, monthly, biannually, annually, or as medically necessary. Dosages may be provided in either a single or multiple dosage regimens. The timing between administrations may decrease as the medical condition improves or increase as the health of the patient declines. The dosage and frequency of administration may be adapted by the physician in accordance with conventional factors such as the extent of the infection and different parameters of the subject. EXAMPLES
General Methods
Analytical HPLC was performed using the following column and conditions: Atlantis T3, 3 micron, 3.0 x 75 mm ; 50°C, water/CH3CN + 0.1 % formic acid, 5 to 95% CH3CN over 1 1 min + 2 min hold. Preparative HPLC was performed using the following column: Agilent ZORBAX SB-CN, 7 μιτι, 21 .2 x 250 mm, CH3CN/H2O/0.1 % Acetic Acid various linear gradients as necessary at 20 mL/min.
Rapid LC: A Waters BEH C18, 3.0 x 30 mm, 1 .7 μιτι, was used at a temperature of 50 °C and at a flow rate of 1 .5 mL/min, 2 μί injection, mobile phase: (A) water with 0.1 % formic acid and 1 % acetonitrile, mobile phase (B) methanol with 0.1 % formic acid; retention time given in minutes.
Method details: (I) runs on a Binary Pump G1312B with UV/Vis diode array detector G1315C and Agilent 6130 mass spectrometer in positive and negative ion electrospray mode with UV PDA detection with a gradient of 15-95% (B) in a 2.2 min linear gradient, (II) hold for 0.8 min at 95% (B), (III) decrease from 95-15% (B) in a 0.1 min linear gradient, and (IV) hold for 0.29 min at 15% (B).
Polar Stop-Gap: An Agilent Zorbax Bonus RP, 2.1 x 50mm, 3.5 μιη, was used at a temperature of 50°C and at a flow rate of 0.8 mL/min, 2 μί injection, mobile phase: (A) water with 0.1 % formic acid and 1 % acetonitrile, mobile phase (B) methanol with 0.1 % formic acid; retention time given in minutes. Method details: (I) runs on a Binary Pump G1312Bwith UV/Vis diode array detector G1315C and Agilent 6130 mass spectrometer in positive and negative ion electrospray mode with UV-detection at 220 and 254 nm with a gradient of 5-95% (B) in a 2.5 min linear gradient, (II) hold for 0.5 min at 95% (B), (III) decrease from 95-5% (B) in a 0.1 min linear gradient, and (IV) hold for 0.29 min at 5% (B).
NMR Spectra were acquired on either of two instruments: (1 ) Agilent (formerly Varian) Unitylnova 400 MHz NMR spectrometer equipped with a 5mm Automation Triple Broadband (ATB) probe. The ATB probe was simultaneously tuned to 1 H, 19F and 13C. (2) Agilent (formerly Varian) Unitylnova 500 MHz NMR spectrometer. Several NMR probes are available for use with the 500 MHz NMR spectrometer, including both 3 mm and 5 mm 1 H13C1 5N probes and a 3 mm X1 H19F NMR probe (usually X is tuned to 13C). For typical 1 H NMR spectra, the pulse angle was 45 degrees, 8 scans were summed and the spectral width was 16 ppm (-2 ppm to 14 ppm). A total of 32768 complex points were collected during the 5.1 second acquisition time, and the recycle delay was set to 1 second. Spectra were collected at 25SC. 1 H NMR Spectra are typically processed with 0.3 Hz line broadening and zero-filling to 131072 points prior to Fourier transformation.
Compounds of the invention may be made using synthetic methods known in the art, including procedures analogous to those disclosed below. Example 1 : Synthesis of L-Rhamnose-PEG1-NH2 (INT-1 )
Figure imgf000112_0001
Step a. Synthesis of benzyl (2-(2-hydroxyethoxy)ethyl)carbamate
To a solution of 2-(2-aminoethoxy)ethanol (10.5 g, 0.1 mol) in 200 mL THF was added
Hunig's base (28 mL, 0.2mol) under the ice-water bath, then CBz-CI (18g, 0.1 mol) in 50 mL THF was added dropwise to the above cooled solution. The resultant solution was stirred for overnight and then concentrated to remove solvent, the residue was partitioned by ethyl acetate (300mL) and water 150 mL, the organic layer was washed by 5% sodium bicarbonate (100 mL), brine (100 mL), and 1 N HCI (100 mL) and then brine, respectively. The organic layer was dried and concentrated for next step. Yield of products 18 g, 75%. 1 H NMR (300 MHz, DMSO-afe) δ 7.34 (d, J = 3.2 Hz, 5H), 5.01 (d, J = 2.5 Hz, 2H), 3.40 (m, 8H).
Step b. Synthesis of (2R,3R,4R,5S,6S)-2-(2-(2- (((benzyloxy)carbonyl)amino)ethoxy)ethoxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate
To a solution of benzyl (2-(2-hydroxyethoxy)ethyl)carbamate (14g, 56 mmol) and per-acetyl-L- rhamnose (20 g, 56 mmol) in 200 mL dry DCM under the ice-water bath, then BF3-Et20 (15 mL, 1 10 mmol) was added dropwise to the above cooled solution. After stirring overnight, the reaction was quenched with saturated NaHCCb (aq) and diluted with EtOAc. The organic phase was washed sat. NaHCOe (aq) and brine. The combined organic layers were dried over anhydrous Na2S04. The resultant solution was concentrated and purified by reversed phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 5% to 100% acetonitrile and water, using 0.1 % trifluoroacetic acid as the modifier. The product was isolated as an oil, 18 g (63%). LC/MS [M]+1 512.2.
Step c. Synthesis of benzyl (2-(2-(((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)carbamate
A solution of (2R,3R,4R,5S,6S)-2-(2-(2-(((benzyloxy)carbonyl)amino)ethoxy)ethoxy)-6- methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (26 g, 50 mmol) and hydrazine (25 mL) in anhydrous methanol was stirred overnight, The resultant solution was concentrated and purified by reversed phase liquid chromatography (RPLC) using an Isco CombiFlash liquid chromatograph eluted with 5% to 100% acetonitrile and water, using 0.1 % trifluoroacetic acid as the modifier. The product was obtained as an oil, 18.5 g (95%). LC/MS [M+H]+ 386.2. The material was subjected to high vacuum to remove excess hydrazine. Step d. Synthesis of (2R,3R,4R,5R,6S)-2-(2-(2-aminoethoxy)ethoxy)-6- methyltetrahydro-2H-pyran-3,4,5-triol (L-Rhamnose-PEG1-NH2, INT-1)
Benzyl (2-(2-(((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2- yl)oxy)ethoxy)ethyl)carbamate (14.6 mg, 38 mmol) was dissolved into 30 mL MeOH and 30 mL ethyl acetate, then 5 mg of 5% Pd on charcoal was added above solution, and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The palladium on charcoal was removed by filtration after completion of the reaction by LCMS. The filtrate was concentrated and used in the next step without any purification. 1 H NMR (300 MHz, methanol-ck) δ 4.75(s, 1 H) 3.84 (ddt, J = 8.5, 3.3, 1 .6 Hz, 2H), 3.76 - 3.52 (m, 7H), 3.47 - 3.28 (m, 4H), 3.1 5 (t, J = 5.1 Hz, 2H), 1 .28 (d, J = 6.2 Hz, 3H). 13C NMR (75 MHz, methanol-ck) δ 100.36, 72.52, 70.93, 70.72, 70.1 1 , 68.45, 66.60, 66.27, 39.29, 16.61 . LCMS 252.2 [M+H]+
Example 2: Synthesis of 4-[(2-{2-[(6-deoxy-alpha-L-mannopyranosyl)oxy]ethoxy}ethyl)amino]- 4-oxobutanoic acid (INT-2)
Procedu e A
Succinic anhydride (156 mg, 1 .57 mmol) was added to a stirring mixture of INT-1 (375 mg, 1 .49 mmol) and DIEA (193 mg, 1 .49 mmol) in MeOH (7 mL) and the reaction was stirred at RT for 3 hours at room temperature. The solvent was reduced by 80% on the rotary evaporator and the mixture was applied to reversed phase HPLC (5 to 50% acetonitrile in Dl water containing 0.1 % formic acid: 20 minute gradient). The pure fractions were pooled and lyophilized to afford 4-[(2-{2-[(6- deoxy-alpha-L-mannopyranosyl)oxy]ethoxy}ethyl)amino]-4-oxobutanoic acid (INT-2) as a clear vicous oil. Yield: 75%. LC/MS [M-H-]- 350.2.
Procedure B
Figure imgf000113_0001
Step a. Synthesis of benzyl (2-(2-hydroxyethoxy)ethyl)carbamate
To the solution of 2-(2-aminoethoxy)ethanol (301 .0 g, 2.863mol, 1 .Oeq) in 1500ml_ DCM was added Et3N (343. Og, 3.390mol, 1 .2eq) under the ice-water bath (control the temperature below 20°C), then CBz-CI (488. Og, 2.863mol, 1 .Oeq) was added dropwise to the above cooled solution (control inside temperature below 20°C). The resultant solution was stirred overnight (>16 hrs) and then washed with water 1500 mL, sat. NaHCOs (1500 mL), 1 N HCI (1500 mL) and brine (1500 mL), respectively. The organic layer was dried (200 g of Na2S04) and concentrated for next step directly. Yield of product 639 g, 92%. Colorless oil. Step b. Per-acetylation of L-rhamnose
To a solution of L-rhamnose (69.0 g, 0.3799 mol, 1 .0 eq) and DMAP (1 .40 g, 0.02x) in pyridine (280 mL, 4V/M) was added acetic anhydride (232.0 g, 2.273 mol, 6.0 equiv) dropwise under the ice-water bath (to control the temperature of the reaction below 20°C), The mixture was stirred at ambient temperature (>12 hrs), and volatiles were removed under reduced pressure (toluene azeotrope). The crude product was dissolved in EtOAc (800 mL), washed with hydrochloric acid (1 N, 800 mL*2), sat. NaHC03 (800 mL), brine (800 mL), and dried with sodium sulfate (100 g). Volatiles were removed under reduced pressure, and crude per-acetyl-L-rhamnose (131 .0 g, yield: 100%) was used directly for the next step. Step c. Synthesis of (2R,3R,4R,5S,6S)-2-(2-(2-
(((benzyloxy)carbonyl)amino)ethoxy)ethoxy)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate
Figure imgf000114_0001
To the solution of benzyl (2-(2-hydroxyethoxy)ethyl)carbamate (48.8 g, 0.204 mol, 1 .20 eq) and per-acetyl-L-rhamnose (56.6 g, 0.170 mol, 1 .00 eq) in 500 mL dry DCM under the ice-water bath, then BF3-Et20 (52.5 mL, 0.416 mol, 2.5 eq) was added dropwise to the above cooled solution (control the temperature below 20°C). After stirring overnight, the reaction was quenched by 700 mL of sat. NaHC03 (aq), concentrated and purified by chromatography on silica gel (90g/500g), eluent:PE (1 L), PE/EA=5/1 (10.8L), PE/EA=3/1 (20L). Yield: 50.0 g, 57%, of a colorless oil. Step d. Synthesis of benzyl (2-(2-(((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6- methyltetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethyl)carbamate
Figure imgf000115_0001
To a solution of (2R,3R,4R,5S,6S)-2-(2-(2-(((benzyloxy)carbonyl)amino)ethoxy)ethoxy)-6- methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (33.7 g, 0.066 mol, 1 .0 eq) in methanol (200 mL) was added NaOMe (1 .14 g in 50 mL of MeOH, 0.050 mol, 0.75 eq) and stirred overnight. The resultant solution was concentrated and dissolved in 800 mL of THF, then filtered through a pad of silica gel (20 g), and washed with THF (400 mL*3) and concentrated to give a colorless oil (23.4 g, 92%).
Step e. Synthesis of (2R,3R,4R,5R,6S)-2-(2-(2-aminoethoxy)ethoxy)-6- methyltetrahydro-2H-pyran-3,4,5-triol (L-Rhamnose-PEG1-NH2) (INT-1)
Figure imgf000115_0002
Benzyl (2-(2-(((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2- yl)oxy)ethoxy)ethyl)carbamate (21 .2 g, 0.066 mol, 1 .0 eq) was dissolved into 300 mL MeOH, then 2.2 g of 5% palladium on charcoal (0.1 x) was added to the above solution and the mixture was stirred at room temperature under the hydrogen atmosphere for overnight. The palladium on charcoal was removed by filtration after the reaction was complete as judged by TLC. The filtrate was concentrated to give INT-1 as a colorless oil (13.4 g, 97%). LCMS 252.2[M+H]+
Step f. Synthesis of 4-[(2-{2-[(6-deoxy-alpha-L- mannopyranosyl)oxy]ethoxy}ethyl)amino]-4-oxobutanoic acid (INT-2)
Figure imgf000115_0003
A solution of INT-1 (10.93 g, 0.043 mol, 1 .0 eq) and succinic anhydride (4.35 g, 0.043 mol, 1 .0 eq) in anhydrous MeOH (100 mL) was stirred at RT for overnight (>12 hrs). Then the solvent was removed and the residue was purified by flash silica gel column chromatography (18 g/100 g), eluent: DCM/MeOH=10/1 (1 .8L), DCM/MeOH=6/1 (1 .6L) to give INT-2 (12.1 g, 82 %) as a colorless oil. 1 HNMR (400 MHz, methanol-ck): 4.72 (s, 1 H); 3.82-3.75 (m, 2H); 3.67-3.53 (m, 7H); 3.39-3.35 (m, 2H); 3.31 (m, 1 H); 2.61 -2.47 (m, 4H); 1 .26 (d, 6.4 Hz, 3H). Example 3: Synthesis of 2-aminoethyl 2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl-(1->3)- 2,4,6-tri-0-acetyl-3-thio-beta-D-glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-1 ,3-dithio-beta-D- glucopyranoside (INT-3)
Figure imgf000116_0001
Step a. Synthesis of (3aR,5R,6R,6aR)-5-((R)-2,2-dimethyl-1 ,3-dioxolan-4-yl)-2,2- dimethyltetrahydro-2H-furo[2,3-d][1 ,3]dioxol-6-yl trifluoromethanesulfonate
Triflic anhydride (7.8 mL, 46.39 mmol) was added over 30 minutes to a cold (0°C) solution of the diacetone allofuranose (10.50 g, 40.34 mmol) in pyridine (100 mL). After stirring in the ice-bath for 1 hour, the reaction was diluted with ethyl acetate (250 mL) and the organic layer was washed with a mixture of saturated sodium bicarbonate and brine (50 mL + 50 mL), dried (Na2S04) and concentrated under reduced pressure to provide the crude triflate. The crude residue was purified using a normal phase flash column (0-1 0% EA/Hex) to give the title compound (14.1 5 g, 89%) as a colorless oil. 1 HNMR (300 MHz, Chloroform-d): 5.85 (d, 1 H); 4.93 (dd, 1 H); 4.79 (dd, 1 H); 4.21 (dd, 1 H); 4.1 1 -4.1 7 (dt, 1 H); 3.90-3.95 (dt, 1 H); 1 .61 (s, 3H); 1 .47 (s, 3H); 1 .41 (s, 3H); 0.3 (s, 3H).
Step b. Synthesis of Thio-linked Disaccharide: ((2R,3R,4S,5R,6S)-2-[(acetyloxy)methyl]- 6-{[(3aR,5R,6S,6aS)-5-(2,2-dimethyl-1 dioxolan-4-yl)-2,2-dimethyltetrahydro-2H-furo[2,3- d][1 ,3]dioxol-6-yl]sulfanyl}oxane-3,4,5-triyl triacetate)
Sodium hydride was added to a solution of 2,3,4,6-tetra-O-acetyl-l-thio-p-D-glucopyranose (14.00 g, 38.42 mmol) in dry THF (450 ml_ in a 2000-mL RB Flask) at 0 °C. The suspension was stirred under nitrogen until hydrogen formation had ceased. To this solution, 1 ,7,10-trioxa-4,13- diazacyclopentadecane (Kryptofix 21 , 4,10-diaza-16-crown-5-ether, 1 .53 g, 9.92 mmol) and a solution of (3aR,5R,6R,6aR)-5-((R)-2,2-dimethyl-1 ,3-dioxolan-4-yl)-2,2-dimethyltetrahydro-2H-furo[2,3- d][1 ,3]dioxol-6-yl trifluoromethanesulfonate (13.09 g, 46.39 mmol) in THF (200 ml_) was added via cannula transfer and the mixture was stirred for 2 h at 0 °C under nitrogen, then at room temperature for overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (400 mL), washed with water (200 mL), dried (Na2S04), and concentrated. Added 40 mL of EtOH to the residue to dissolve the foam followed by swirling the flask. The foam slowly turn to white solid. After standing still for 5 minutes, breaking down the solid cake and filtering and washing with 20% aq. EtOH (100 mL). After drying, 1 0.28 g of the title compound was obtained (44%). Check TLC of the mother liquor and some of the product remained in the mother liquor which was purified with normal phase flash column. 1 HNMR (300 MHz, Chloroform-d): 5.86 (d, H), 5.25 (dd, 1 H), 5.10 (m, 2H), 4.86 (d, H), 4.76 (d, H), 3.95_4.42 (m, 6H), 3.64-3.78 (m, H), 3.58 (d, H), 2.1 1 (s, 3H), 2.09 (s,3H), 2.06 (s, 3H), 2.03 (s, 3H), 1 .54 (s, 3H), 1 .45 (s, 3H), 1 .35 (s, 3H), 1 .35 (s, 3H)
Step c. Synthesis of 1 ,2,4,6-tetra-0-acetyl-3-S-(2,3,4,6-tetra-0-acetyl-beta-D- glucopyranosyl)-3-thio-D-glucopyranose
A solution of ((2R,3R,4S,5R,6S)-2-[(acetyloxy)methyl]-6-{[(3aR,5R,6S,6aS)-5-(2,2-dimethyl- 1 ,3-dioxolan-4-yl)-2,2-dimethyltetrahydro-2H-furo[2,3-d][1 ,3]dioxol-6-yl]sulfanyl}oxane-3,4,5-triyl triacetate) (10.28 g) in 60% aq. AcOH/TFA (20:1 , 105 mL) was heated for 5 hours at 70 °C, then concentrated under reduced pressure and the residue dissolved in water and freeze-dried.
Conventional acetylation of the resulting solid (1 :1 Ac20/pyridine, 200 mL) yielded the product.
Rotovaped to remove most of Ac20/Py, diluted with DCM (400 mL) and washed with 0.5 N HCI 200 mL. 200 mL of DCM extracted the aqueous layer once. Combined DCM extract and dried with Na2S04. DCM was removed under reduced pressure. The residue was precipitated with 30% EA/Hex to give a white solid. Filtration and 30%EA/Hex wash and dry. Check TLC of mother liquor, the impurities and the desired product have almost equal amount. Purification was not performed due to the small amount in the mother liquor. The precipitation gave peracetylated (1 -3>)-thiodisaccharide (1 ,2,4,6-tetra-0-acetyl-3-S-(2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl)-3-thio-D-glucopyranose) 9.770 g (83.0%) and a column purification gave 1 .384 g (1 1 .8%). 1 HNMR showed alpha/beta ratio 1 :1 (from ~H NMR integration of H-1 signals). Step d. Synthesis of (1->3)-Thiodisaccharide Bromide: 2,4,6-tri-0-acetyl-3-S-(2,3,4,6- tetra-O-acetyl-beta-D-g lucopyranosyl)-3-th io-alpha-D-g lucopyranosyl brom ide
To a solution of 1 ,2,4,6-tetra-0-acetyl-3-S-(2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl)-3- thio-D-glucopyranose (1 1 .15 g, 16.06 mmol) in dry DCM (160 mL) at 0 °C was added dropwise commercial 33% HBr in AcOH (34.9 mL, 12 equiv.). After the mixture was stirred for 3 hours in an ice- bath, TLC (1 :1 EtOAc-hexane) showed complete conversion of the SM into a single product. DCM was added (240 mL), and the solution was washed with cold water (2 x 100 mL) and dried with Na2S04. DCM was removed under reduced pressure. The residue was precipitated with 30% EA/Hex to give a white solid. Filtration and 30% EA/Hex wash and dry to give the title compound (10.50 g, 91 .4%) as white a powder. 1 HNMR spectrum was identical with literature data for the compound [B. Sylla, et al.; J. Med. Chem., 2014, 57 (20), pp 8280-8292].
Step e. Synthesis of (1->3)-Thiodisaccharide Thiol: 2,4,6-tri-0-acetyl-3-S-(2,3,4,6-tetra- 0-acetyl-beta-D-glucopyranosyl)-1 ,3-dithio-beta-D-glucopyranose
Thiourea (5.56 g, 73.4 mmol, 5 equiv.) was added into a solution of the 2,4,6-tri-0-acetyl-3-S- (2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl)-3-thio-alpha-D-glucopyranosyl bromide (10.5 g, 14.6 mmol) from Step d. in dry acetone (1 00 mL). The reaction mixture was refluxed with TLC monitoring. After 10 minutes, the reaction mixture became a clear solution. After 2hrs, another 5 equiv. of thiourea was added and the mixture was refluxed for another 2 hours. After completion of conversion of starting material (checked by TLC), the reaction mixture was cooled to room temperature. Acetone was removed by reduced pressure. To the residue solid was added Chloroform and water (1 :1 , 300 mL) and stirred at 85 °C for 1 hour with condenser. The mixture was cooled to room temperature and extracted with DCM (3 x 200 mL). Dried and remove solvent. Crystallization in EtOH gave the title compound as a white solid (9.01 g, 92%). H NMR (300 MHz, Chloroform-d): 5.17 (dd, 1 H), 4.95-5.12 (m, 2H), 4.85-4.98 (m, 2H), 4.67 (d, 1 H), 4.43 (dd, 1 H), 4.27 (ddd, 1 H), 4.18 (m, 1 H), 4.06-4.16 (2H), 3.64-3.76 (m, 2H), 2.96 (dd, 1 H), 2.35 (d, 1 H, SH), 2.1 6 (s, 3H), 2.09 (s, 3H), 2.08 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 1 .00 (s, 3H). 13C NMR (75 MHz, Chloroform-d): 170.6 (CO), 170.5 (CO), 170.2 (CO), 169.4 (CO), 169.3 (CO), 169.1 (2CO), 84.1 (CH), 80.5 (CH), 78.5 (CH), 75.7 (CH), 75.4 (CH), 73.6 (CH), 70.1 (CH), 68.2 (CH), 66.5 (CH), 52.5 (CH), 61 .9 (CH), 52.0 (CH), 21 .0 (CH3), 20.8 (CH3), 20.7 (CH3), 20.5 (3 CH3), 20.4 (CH3).
Step f. Synthesis of Thio-linked Trisaccharide: 2,4,6-tri-0-acetyl-3-S-(2,3,4,6-tetra-0- acetyl-beta-D-glucopyranosyl)-1 ,3-dithio-beta-D-glucopyranose
Sodium hydride (0.808 g, 29.2 mmol) was added to a solution of 2,4,6-tri-0-acetyl-3-S-
(2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl)-1 ,3-dithio-beta-D-glucopyranose (9.01 g, 13.47 mmol) in dry THF (450 mL in a 2000-mL RB Flask) at 0 °C. The suspension was stirred under nitrogen until hydrogen formation had ceased. To this solution, 1 ,7,1 0-trioxa-4,13-diazacyclopentadecane (Kryptofix 21 , 4,10-diaza-1 6-crown-5-ether, 0.535 g, 2.43 mmol) and a solution of (3aR,5R,6R,6aR)-5-((R)-2,2- dimethyl-1 ,3-dioxolan-4-yl)-2,2-dimethyltetrahydro-2H-furo[2,3-d][1 ,3]dioxol-6-yl
trifluoromethanesulfonate (5.551 g, 14.15 mmol) in THF (200 mL) was added via cannula transfer and the mixture was stirred for 2 hours at 0 °C under Nitrogen, then at room temperature for overnight. The reaction mixture was concentrated under reduced pressure. A solution of the residue was dissolved in DCM (400 mL), washed with water (200 mL), dried (Na2S04), and concentrated. Added 40 mL of EtOH to the crude product to dissolve the foam followed by swirling the flask. The white precipitate was formed. Filtration and wash with 30% EtOAc/Hex and drying gave the title compound 6.55 g (53.4%). Check TLC of the mother liquor and some of the product remained in the mother liquor which was purified with normal phase flash column. 1 H NMR (300 MHz, Chloroform-d): δ 5.83 (d, J = 3.5 Hz, 1 H), 5.18 (dd, J = 9.3 Hz, 1 H), 5.07 (dd, J = 1 0.2 Hz, 1 H), 5.06 (dd, J = 9.6 Hz, 1 H), 4.88 (ddd, J = 9.7, 9.7, 9.9 Hz, 1 H), 4.83 (d, J = 3.6 Hz, 1 H), 4.63 (dd, J = 14.2, 10.0 Hz, 2H), 4.37 - 4.21 (m, 3H), 4.21 - 4.05 (m, 5H), 4.04 - 3.96 (m, 1 H), 3.76 - 3.61 (m, 2H), 3.54 (d, J = 3.7 Hz, 1 H), 3.00 (dd, J = 10.8 Hz, 1 H), 2.15 (s, 3H), 2.10 (s, 3H), 2.08 (s, 3H), 2.08 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 1 .99 (s, 3H), 1 .51 (s, 3H), 1 .42 (s, 3H), 1 .34 (s, 3H), 1 .32 (s, 3H). 13C NMR (75 MHz,
Chloroform-d): δ 170.53 (e), 170.48(e), 170.16(e), 169.42(e), 1 69.26(e), 169.09(e), 168.47(e),
1 1 1 .92(e), 109.45(e), 1 04.82(o), 86.04(o), 84.52(o), 84.31 (o), 80.1 1 (o), 78.43(o), 75.59(o), 73.72(o), 73.62(0), 71 .74(0), 70.02(o), 68.1 5(o), 67.31 (e), 66.62(o), 62.51 (e), 61 .92(e), 52.18(o), 50.07(o), 26.87(0, CH3), 26.59(0, CH3), 26.32(o, CH3), 25.33(o, CH3), 20.83(o, CH3), 20.73(o, CH3), 20.68(o, CH3), 20.53(0, 3CH3), 20.39(o, CH3).
Step g. Synthesis of Peracetylated (1->3)-Thiotrisaccharide: 2,3,4,6-tetra-O-acetyl-beta- D-glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-3-thio-beta-D-glucopyranosyl-(1->3)-1 ,2,4,6-tetra-0- acetyl-3-thio-D-glucopyranose
A solution of 2,4,6-tri-0-acetyl-3-S-(2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl)-1 ,3-dithio- beta-D-glucopyranose 6.55 g, 7.19 mmol) in 60% aq. AcOH/TFA (10:0.5, 105 mL) was heated for 5 hours at 70 °C, then concentrated under reduced pressure and the residue dissolved in water and freeze-dried. Conventional acetylation of the resulting solid (1 :1 Ac20/pyridine, 100 mL) yielded the desired product. Rotovaped to remove most of Ac20/Py, diluted with DCM (400 mL) and washed with 0.5N HCI 200 mL. 200 mL of DCM extracted the aqueous layer once. Combined DCM extract and dried with Na2S04. DCM was removed by reduced pressure. Normal phase silica column purification (0-70% EtOAc/Hex) gave the title compound (6.51 g, 90.6%) as a white solid.
Step h. Synthesis of (1->3)-Thiotrisaccharide Bromide: 2,3,4,6-tetra-O-acetyl-beta-D- glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-3-thio-beta-D-glucopyranosyl-(1->3)-1 ,2,4,6-tetra-0- acetyl-3-thio-D-glucopyranose
To a solution of the 2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl-(1 ->3)-2,4,6-tri-0-acetyl-3- thio-beta-D-glucopyranosyl-(1 ->3)-1 ,2,4,6-tetra-0-acetyl-3-thio-D-glucopyranose (6.51 g, 6.52 mmol) in dry CH2CI2 (70 mL) at 0 °C was added dropwise commercial 33% HBr in AcOH (14.2 mL, 12 equiv.). After the mixture was stirred for 3 hours at ice-bath, TLC (1 :1 EtOAc-hexane) showed complete conversion of the starting material into a single product. DCM was added (200ml_), and the solution was washed with cold water (1 00 mL). DCM was used to extract on the aqueous layer.
Combined DCM layers were washed with water (1 00 mL). Dried and removed solvent. Ethanol (Hot, 50 mL) dissolved the residue to precipitate the title compound (4.43 g, 67%). 1 H NMR (300 MHz, chloroform-d): 6.65 (d, J = 3.63, 1 H), δ 5.18 (dd, J = 9.3 Hz, 1 H), 5.02 - 5.13 (m, 2H), 4.80 - 5.01 (m, 4H), 4.72 (d, J = 9.7, 1 H), 4.65 (d, J = 1 0.2, 1 H), 4.07 - 4.35 (m, 7H), 3.67 - 3.78 (m, 2H), δ 3.32 (dd, J = 1 1 .1 Hz, 1 H), 3.00 (dd, J = 10.5 Hz, 1 H), 2.16 (s, 3H), 2.14 (s, 3H), 2.12 (s, 6H), 2.1 1 (s, 3H), 2.10 (s, 3H), 2.08 (s, 3H), 2.04 (s, 3H), 2.02 (s, 3H), 2.00 (s, 3H).
13C NMR (75 MHz, Chloroform-d): δ 170.55 (e), 170.53 (e), 170.50 (e), 1 70.21 (e), 169.43 (e), 169.40(e), 169.38 (e), 169.30 (e), 169.10 (e), 168.53 (e), 89.00 (o), 84.23 (o), 77.82 (o), 75.58 (o), 73.61 (o), 73.61 (o), 73.00 (o), 71 .83 (o, 2C), 71 .48 (o), 69.96 (o), 68.01 (o), 66.41 (o), 64.65 (o), 62.32 (e), 61 .86 (e), 61 .51 (e), 52.17 (o), 46.83 (o), 20.78 (o), 20.74 (o, 2C), 20.67 (o), 20.64 (o), 20.60 (o, 3C), 20.54 (o), 20.44 (o).
Step i. Synthesis of (1->3)-Thiotrisaccharide Thiol: 2,3,4,6-tetra-O-acetyl-beta-D- glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-3-thio-beta-D-glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl- 1 ,3-dithio-beta-D-glucopyranose
A similar procedure was used as that in Example 3, Step e. Crystallization from EtOH gave 3.50 g of the title compound as a white solid. Column purification of mother liquor gave a white solid (0.55 g). The yield was 95.9%. Ή NMR (300 MHz, Chloroform-d): δ 5.16 (dd, J = 9.3 Hz, 1 H), 4.99 - 5.12 (m, 2H), 4.79 - 4.80 (m, 4H), 4.64 (d, J = 9.9, 1 H), 4.61 (d, J = 4.0, 1 H), 4.41 (t, J = 4.5 Hz, 1 H), 4.30 - 4.04 (m, 6H), 3.60 - 3.75 (m, 3H), 2.85 - 3.00 (m, 2H), 2.38 (d, J = 9.9 Hz, 1 H), 2.14 (s, 3H), 2.10 (s, 3H), 2.08 (s, 9H), 2.07 (s, 6H), 2.01 (s, 3H), 1 .99 (s, 3H), 1 .98 (s, 3H). 13C NMR (75 MHz, Chloroform-d): δ 170.68 (e), 170.64 (e), 170.55 (e), 170.17 (e), 169.50 (e), 169.39 (e), 169.29 (e), 169.10 (e), 168.95 (e), 168.56 (e), 84.87 (o), 84.10 (o), 80.73 (o), 78.45 (o), 77.84 (o), 75.55 (o), 74.99 (o), 73.60 (o), 71 .84 (o), 69.96 (o), 68.04 (o), 66.65 (o), 66.14 (o), 62.49 (e, 2C), 61 .84 (e), 52.12 (o), 51 .84 (o), 20.98 (o), 20.88 (o), 20.77 (o), 20.74 (o), 20.65 (o), 20.59 (o), 20.55 (o, 3C), 20.41 (o). Step j. Synthesis of Peracetylated (1->3)-Thiotrisaccharide ethyleneamine: 2- aminoethyl 2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-3-thio-beta-D- glucopyranosyl-(1->3)-2,4,6-tri-0-acetyl-1 ,3-dithio-beta-D-glucopyranoside (INT-3)
Part 1 (Mitsunobu Reaction). Trimethylphosphine (TMP, 1 .0M in THF, 2.1 mL, 2.06 mmol) was added to a solution of 1 ,1 '-(azodicarbonyl)dipiperidine (ADDP, 0.519 g, 2.06 mmol) in 25 mL of THF at 0°C and stirred for 30 min. N-Cbz-ethanolamine (0.201 g, 1 .03 mmol) and 2,3,4,6-tetra-O- acetyl-beta-D-glucopyranosyl-(1 ->3)-2,4,6-tri-0-acetyl-3-thio-beta-D-glucopyranosyl-(1 ->3)-2,4,6-tri-0- acetyl-1 ,3-dithio-beta-D-glucopyranose (0.54 mmol in 5 mL of THF) were added sequentially to the solution, with further stirring at room temperature for 2 hours. Any precipitate was then filtered off and the solution evaporated to dryness. Normal phase silica gel column purification (0-70% EtOAc/Hex) gave the desired product as a white foam (0.946 g, 80%). 13C NMR (75 MHz, Chloroform-d): δ 170.70 (e), 170.59 (e), 170.57 (e), 170.20 (e), 169.46 (e), 169.36 (e), 169.30 (e), 1 69.12 (e), 1 68.66 (e), 168.57 (e), 156.27 (e), 136.44 (e), 128.54 (o, 2C), 128.19 (o, 3C), 86.05 (o), 85.16 (o), 84.10 (o), 78.1 1 (o), 77.75 (o), 75.56 (o), 73.60 (o), 71 .73 (o), 71 .23 (o), 69.95 (o), 68.04 (o), 66.70 (e), 66.59 (o), 66.29 (o), 62.46 (e), 61 .85 (e), 52.1 8 (o), 51 .81 (o), 41 .13 (e), 31 .35 (e), 20.94 (o), 20.85 (o), 20.77 (o), 20.67 (o, 2C), 20.61 (o), 20.58 (o, 2C), 20.55 (o), 20.44 (o).
Part 2 (Hydrogenolysis). The compound from Example 3, Step j, Part 1 (0.500 g, 0.435 mmol) and 30% Pd/C (0.463 g, 1 .30 mmol) were in the flask with 20 ml_ of EtOH and 5 ml_ of CHC . Under H2, the reaction mixture was stirred overnight. Check TLC and mass. Celite filtration and wash with EtOH gave the title compound 0.44 g (100%). Mass showed a strong detectable positive charge signal at tr=3 min with 8 min (5~95%)/highMW method (found M+H+: 1016.2).
Example 4: Synthesis of INT-4
Figure imgf000121_0002
INT-3 (1 eq) is dissolved in methanol and excess NaOMe (10 eq) is added. The reaction is stirred until LCMS shows substantial formation of the desired product (INT-4) with an exact mass of 595.14.
Example 5: Synthesis of (1->3)-Thiotrisaccharide ethyleneamine: 4-[(2-{[beta-D- glucopyranosyl-(1->3)-3-thio-beta-D-glucopyranosyl-(1->3)-3-thio-beta-D- glucopyranosyl]thio}ethyl)amino]-4-oxobutanoic acid (INT-5)
Figure imgf000121_0001
Step a. Succinic anhydride (0.0879 g, 0.869 mmol) was added to INT-3 (0.4417 g, 0.435 mmol) in DCM/Py (20 mL). The reaction mixture was stirred at room temperature overnight. LC/MS 8min Positive/negative showed the desired peak mass at 4.3 min on negative ionization. The solvent was removed and the residue was loaded onto an Isco Gold 24g column and eluted with 4- 6%MeOH/DCM to give 0.27 g of the desired product. 13C NMR (75 MHz, Chloroform-d) δ 172.68, 170.94, 170.88, 170.65, 170.23, 169.62, 169.44, 169.35, 169.1 6, 168.99, 1 68.64, 85.52, 85.30, 84.08, 78.1 0, 77.57, 75.52, 73.60, 71 .75, 71 .32, 69.95, 68.03, 66.60, 66.41 , 62.56, 61 .86, 52.16, 51 .87, 50.68, 39.40, 30.89, 30.22, 29.68, 20.98, 20.86, 20.78, 20.66, 20.63, 20.58, 20.43. Step b. NaOMe in MeOH (25%, 1 .42 mL, 25 equiv.) was added into a 50-mL RB Flask which contained the product of Step a (0.270 g, 0.242 mmol) in 5 mL of MeOH. The mixture was stirred at room temperature for 60 hours. It was then acidified with 1 N aq. HCI and purified with reversed phase C18 column (0-3% CAN/water) to give 0.168 g (99.8%) of the title compound (INT-5). LC/MS 8 min pos/neg method showed negative mass at the very beginning (M-H, 694.2). 13C NMR (75 MHz, water-d): δ 181 .01 (e), 175.85 (e), 86.73 (o), 85.96 (o), 84.51 (o), 81 .72 (o), 81 .58 (o), 79.67 (o), 77.08 (o), 72.57 (o), 72.24 (o), 71 .81 (o), 69.27 (o), 66.88 (o, 2C), 61 .02 (e), 60.92 (e), 60.59 (e), 56.01 (o), 55.76 (o), 39.36 (e), 32.92 (e), 32.25 (e), 29.10 (e). Example 6: Synthesis of INT-6
Figure imgf000122_0001
Step a. Synthesis of 1 ,2,3,4-tetra-0-acetyl-6-deoxy-6-iodo-beta-D-glucopyranose
Iodine (9.42 g, 37.1 mmol) was added at room temperature to a mixture of 1 ,2,3,4-tetra-O- acetyl-beta-D-glucose (9.93 g, 28.55 mmol) and chlorodiphenylphosphine (CIDPP, 6.82 mL, 37.1 mmol) and imidazole (4.28 g, 62.8 mmol) in toluene (-100 mL). After 5 minutes of stirring the reaction mixture started to produce heat. The temperature rose to about 50 °C. After 30 minutes the reaction mixture was heated at 50 °C for 6 hours when TLC indicated that the reaction was complete. Workup: The reaction mixture was cooled to room temperature and poured into an equal volume of saturated Na2C03 in a separatory funnel. The funnel was shaken for 5 minutes while iodine was added portion wise until the toluene phase remained iodine-colored. The aqueous layer was separated and the organic layer was washed with saturated aqueous Na2S203 to remove the excess iodine and then washed with water and brine. Dried and removed the solvent. Purified with 0-40% EA/Hex to give 8.02 g of iodide 2 as a white solid (61 %). 1 H NMR (300 MHz, Chloroform-d) δ 5.77 (d, J = 8.2 Hz, 1 H), 5.28 (dd, J = 9.4 Hz, 1 H), 5.15 (dd, J = 9.4, 8.2 Hz, 1 H), 5.01 (dd, J = 9.4 Hz, 1 H), 3.59 (ddd, J = 9.54 6.4, 3.0 Hz, 1 H), 3.35 (dd, J = 1 1 .3, 3.0 Hz, 1 H), 3.18 (dd, J = 1 1 .3, 6.4 Hz, 1 H), 2.15 (s, 3H), 2.08 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H).
Step b. Synthesis of (1->6)-Thiodisaccharide: 1 ,2,3,4-tetra-0-acetyl-6-S-(2,3,4,6-tetra-0- acetyl-beta-D-glucopyranosyl)-6-thio-beta-D-glucopyranose
Sodium hydride (0.576 g, 14.4 mmol) was added to a solution of 2,3,4,6-tetra-O-acetyl-l-thio- β-D-glucopyranose (5.01 g, 13.75 mmol) in dry THF (130 mL) at 0 °C. The suspension was stirred under nitrogen until hydrogen formation had ceased. The resulting solution was then concentrated under reduced pressure, and the residue was dissolved in 60 mL of DMF. To this solution, 1 ,2,3,4- tetra-0-acetyl-6-deoxy-6-iodo-beta-D-glucopyranose (1 eq in 30 mL of DMF) was added. The mixture was stirred for 3 hours at room temperature under nitrogen, then concentrated under reduced pressure. A solution of the residue in DCM (250 mL) was washed with water (50 mL x 2), dried (Na2S04), and concentrated. Crystallization of the crude product was accomplished from EtOH. After drying, 7.23 g of the title compound as a white powder was obtained (79%). 1 HNMR showed that there was no alpha isomer. Mother liquor was purified by silica column. After removal of solvents, the residue was subjected to EtOH precipitation and 0.37 g of a white crystalline solid was obtained (4.1 %). Both materials showed the correct 1 HNMR and 13CNMR, identical to the reference.
Step c. Synthesis of (1->6)-Thiodisaccharide Bromide: 2,3,4-tri-0-acetyl-6-S-(2,3,4,6- tetra-O-acetyl-beta-D-g lucopyranosyl)-6-th io-alpha-D-g lucopyranosyl brom ide
To a solution of 1 ,2,3,4-tetra-0-acetyl-6-S-(2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl)-6- thio-beta-D-glucopyranose (7.600 g, 10.94 mmol) in dry DCM (120 mL) at 0 °C was added dropwise commercial 33% HBr in AcOH (23.8 mL, 12 equiv.). After the mixture was stirred for 3 hours in an ice- bath, TLC (1 :1 EtOAc-hexane) showed complete conversion of the starting material into a single product. DCM was added (240 mL), and the solution was washed with cold water (2 x 100 mL). After removal of the solvents, the residue was subjected to EtOH precipitation and 6.87 g of the title compound (as a white crystalline solid) was obtained (87.8%). Both showed the correct 1 HNMR and 13CNMR, identical to the reference.
Step d. Synthesis of (1->6)-Thiodisaccharide Thiol: 2,3,4-tri-0-acetyl-6-S-(2,3,4,6-tetra- 0-acetyl-beta-D-glucopyranosyl)-1 ,6-dithio-beta-D-glucopyranose
A similar procedure was used as that in Example 3, Step e. Crystallization from EtOH gave 3.74 g of the title compound (white solid) from 4.27 g of 2,3,4-tri-0-acetyl-6-S-(2,3,4,6-tetra-0-acetyl- beta-D-glucopyranosyl)-6-thio-alpha-D-glucopyranosyl bromide (94% yield). 1 HNMR and 13CNMR were identical to the reference (Carbohydrate Research, 281 (1996) 99-1 18). Step e. Synthesis of (1->6)-Thiotrisaccharide: 2,3,4,6-tetra-O-acetyl-beta-D- glucopyranosyl-(1->6)-2,3,4-tri-0-acetyl-6-thio-beta-D-glucopyranosyl-(1->6)-1 ,2,3,4-tetra-0- acetyl-6-th io-beta-D-g lucopyranose
Reaction and workup procedure are analogous to those described above in Step b.
Purification: normal phase silica gel column 0-90% purify the crude residue. The collection was clean by TLC but contained NMP. After removing EA/Hex, added water and lyophilized twice to remove NMP. 1 HNMR is identical to the reference (Carbohydrate Research, 281 (1996) 99-1 18). 4.62 g of the title compound was obtained (73% based on bromide). Step f. Synthesis of (1->6)-Thiotrisaccharide Bromide: 2,3,4,6-tetra-O-acetyl-beta-D- glucopyranosyl-(1->6)-2,3,4-tri-0-acetyl-6-thio-beta-D-glucopyranosyl-(1->6)-2,3,4-tri-0-acetyl- 6-thio-alpha-D-glucopyranosyl bromide
An analogous procedure to that used in Step c of this Example was used. 4.26 g of the title compound was obtained as a white solid (82%). 13C NMR (75 MHz, CDC ): δ 170.69 (e), 170.12 (e, 2C), 169.83 (e), 169.76 (e), 169.70 (e), 169.64 (e), 169.49 (e), 169.44 (e), 169.37 (e), 86.17 (o), 83.48 (o), 83.1 8 (o), 78.26 (o), 76.00 (o), 74.33 (o), 73.72 (o), 73.56 (o), 71 .52 (o), 70.67 (o), 70.43 (o), 70.09 (o), 70.00 (o), 69.87 (o), 68.20 (o), 62.07 (e), 31 .07 (e), 30.17 (e), 20.84 (o, CH3), 20.76 (o, 3 CH3), 20.70 (o, CH3), 20.66 (o, CH3), 20.65 (o, CH3), 20.61 (o, 3 CH3). Step g. Synthesis of (1->6)-Thiotrisaccharide Thiol: 2,3,4,6-tetra-O-acetyl-beta-D- glucopyranosyl-(1->6)-2,3,4-tri-0-acetyl-6-thio-beta-D-glucopyranosyl-(1->6)-2,3,4-tri-0-acetyl- 1 ,6-dithio-beta-D-glucopyranose
An analogous procedure as that used in Example 3, Step e was used. 3.20 g of the title compound was obtained as a white solid (75%). 1 H NMR (300 MHz, Chloroform-d): δ 5.10 -5.29 (m, 3H), 4.91 - 5.07 (m, 5H), 4.74 (d, J = 10.1 , 1 H), 4.68 (d, J = 1 0.4, 1 H), 4.62 (dd, J = 9.8 Hz, 1 H), 4.30 (dd, J = 4.9, 12.4, 1 H), 4.18 (dd, J = 1 .6, 1 1 .0, 1 H), 3.74 - 3.84 (m, 2H), 3.65 - 3.73 (m, 2H), 2.79 - 2.90 (m, 2H), 2.42 (d, J = 9.8 Hz, 1 H), 2.15 (s, 3H), 2.1 1 (s, 3H), 2.10 (s, 3H), 2.09 (s, 6H), 2.08 (s, 3H), 2.05 (s, 3H), 2.03 (s, 6H), 2.02 (s, 3H). 13C NMR (75 MHz, CDCI3) δ 1 70.69 (e), 170.17 (e), 170.13 (e), 170.1 1 (e), 169.65 (e), 169.62 (e, 2C), 1 69.42 (e), 1 69.40 (e), 169.36 (e), 83.44 (o), 83.12 (o), 78.92 (o), 78.54 (o), 77.93 (o), 76.1 0 (o), 73.73 (o), 73.65 (o, 2C), 73.40 (o), 71 .52 (o), 71 .40 (o), 70.44 (o), 69.74 (o), 68.17 (o), 62.04 (e), 31 .23 (e), 31 .05 (e), 20.85 (o), 20.79 (o, 2C), 20.76 (o, 2C), 20.71 (o), 20.63 (o, 4C).
Step h. Synthesis of Peracetylated (1->6)-Trisaccharide ethyleneamine: 2-aminoethyl 2,3,4,6-tetra-O-acetyl-beta-D-g lucopyranosyl-(1 ->6)-2,3,4-tri-0-acetyl-6-th io-beta-D- glucopyranosyl-(1->6)-2,3,4-tri-0-acetyl-1 ,6-dithio-beta-D-glucopyranoside
Part 1 (Mitsunobu Reaction). The reaction was carried out in a similar manner as Example 3, Step j, Part 1 except the purification method was different. Reversed phase C18 column (10-80% ACN/water with 0.1 %TFA) was used. 1 .02 g of the desired (1 ->6) product was obtained (87%) from 2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl-(1 ->6)-2,3,4-tri-0-acetyl-6-thio-beta-D-glucopyranosyl- (1 ->6)-2,3,4-tri-0-acetyl-1 ,6-dithio-beta-D-glucopyranose (1 .00 g 1 .03 mmol). 13C NMR (75 MHz, CDCb) δ 170.66 (e), 1 70.1 8 (e), 170.13(e), 170.06 (e), 169.67(e), 169.61 (e), 169.44 (e, 2C), 1 69.40 (e), 169.34 (e), 156.33 (e), 136.57 (e), 136.40 (e), 128.51 (o), 128.10 (o, 2C), 83.76 (o, 2C), 83.53 (o), 77.57 (o), 76.20 (o), 73.65 (o), 73.49 (o, 2C), 73.45 (o), 71 .49 (o), 71 .45 (o), 70.16 (o), 70.13 (o), 69.61 (o), 68.15 (o), 66.81 (e), 66.62 (e), 62.17 (e), 62.10 (e), 43.47 (e), 41 .05 (e), 20.83 (o, CH3), 20.78 (o, CH3), 20.73 (o, CH3), 20.69 (o, 2 CH3), 20.60 (o, 5 CH3).
Part 2 (Hydrogenolysis). The reaction was carried out in a similar manner as Example 3, Step j, Part 2 to obtain INT-6. Ion found by LCMS (M+H+: 101 6.1 ).
Example 7: Synthesis of INT-7
Figure imgf000125_0001
In a manner similar to that described for the synthesis of INT-4 but using INT-6 as the starting material, INT-7 is obtained having an exact mass of 595.14.
Example 8: Synthesis of (1->6)-Thiotrisaccharide ethyleneamine: 4-[(2-{[beta-D- glucopyranosyl-(1->6)-6-thio-beta-D-glucopyranosyl-(1->6)-6-thio-beta-D- glucopyranosyl]thio}ethyl)amino]-4-oxobutanoic acid (INT-8)
Figure imgf000125_0002
Step a. An analogous procedure was used as that for the preparation of the compound from Example 5, Step a. The desired compound (0.480 g) was obtained in 99% yield. 13C NMR (75 MHz, CDCb): δ 172.65 (e), 170.75 (e), 170.22 (e), 1 70.1 7 (e), 170.09 (e), 169.78 (e), 169.75 (e, 3C), 169.57 (e), 169.49 (e), 169.46 (e), 83.85 (o), 83.63 (o), 83.55 (o), 77.49 (o), 77.43 (o), 76.24 (o), 73.65 (o), 73.43 (o), 73.38 (o), 71 .58 (o), 71 .50 (o), 70.25 (o, 2C), 69.59 (o), 68.16 (o), 62.14 (e),
39.69 (e), 32.29 (e), 31 .29 (e), 30.78 (e), 30.38 (e, 2C), 20.86 (o,CH3), 20.79 (o,CH3), 20.75 (o, CH3), 20.72 (o, 3 CH3), 20.62 (o, 4 CH3).
Step b. An analogous procedure was used as that for the preparation of the compound from Example 5, Step b. INT-8 (0.275 g, 99% yield) was obtained. Negative ion was found (M-H-: 694.0). 13C NMR (75 MHz, D20): δ 180.94 (e), 175.76 (e), 87.07 (0), 86.04 (0), 85.34 (0), 79.74 (0), 79.23 (0), 79.20 (0), 77.14 (0), 76.87 (0, 2C), 72.70 (0), 72.46 (0), 72.41 (0, 2C), 72.33 (0), 69.37 (0), 60.77 (e), 39.43 (e), 33.07 (e), 32.94 (e), 32.30 (e), 32.01 (e), 29.51 (e). Example 9: Synthesis of INT-9
Figure imgf000126_0001
Step a. Synthesis of benzyl [2-(2-hydroxyethoxy)ethyl]carbamate
Triethylamine (1 .31 mL, 9.32 mmol) was added to a cold (0°C) solution of 2-(2- aminoethoxy)ethan-1 -ol (CAS# 929-06-6, 1 .00 g, 9.32 mmol) in anhydrous THF (100 mL). To the mixture was then added slowly Cbz chloride (1 .50 mL, 10.3 mmol). After stirring at room temperature for 1 hour, the reaction was diluted with ethyl acetate (250 mL) and the organic layer was washed with a mixture of saturated sodium bicarbonate and brine (50 mL + 50 mL), dried (Na2S04) and concentrated under reduced pressure to provide the crude product. The crude residue was purified by normal phase silica flash column (0-1 0% EA/Hex) to give the desired product (14.15 g, 89%) as a colorless oil. 1 HNMR (300MHz, Chloroform-d): δ 7.45 - 7.29 (m, 5H), 5.18 (bs, 1 H, NH), 5.13 (m, 2H), 3.75 (td, J = 5.6, 3.9 Hz, 2H), 3.59 (m, 4H), 3.43 (td, J = 5.6, 3.9 Hz, 2H), 2.06 (t, J = 6.0 Hz, 1 H, OH).
Step b. Synthesis of Per-acetyl Rhamnose Bromide: 2,3,4-tri-0-acetyl-6-deoxy-beta-L- mannopyranosyl bromide
To a solution of L-rhamnose (69.0 g, 0.3799 mol, 1 .0 eq) and DMAP (1 .40 g, 0.02x) in pyridine (280mL, 4V/M) was added acetic anhydride (232.0 g, 2.273 mol, 6.0 equiv) dropwise with cooling by an ice-water bath (control the temperature below 20°C). The mixture was stirred at ambient temperature (12 hrs), and volatiles were removed under reduced pressure (toluene azeotrope). The crude product was dissolved in EtOAc (800 mL), washed with hydrochloric acid (1 N, 800 mL*2), sat. NaHCO3 (800 mL), brine (800 mL), and dried with sodium sulfate (100g). Volatiles were removed under reduced pressure, and crude acetate (131 .0g, yield: 100%) was used directly for the next step.
To a solution of the crude peracetylated rhamnose (6.34 g, 15.3 mmol) in dry DCM (150 mL) at 0 °C was added dropwise commercial 33% HBr in AcOH (33.2 mL, 12 equiv.). After the mixture was stirred for 3 hours at ice-bath, TLC (1 :1 EtOAc-hexane) showed complete conversion of the mixed SM into a single product. DCM was added (240mL), and the solution was washed with cold water (2 x 100 mL) and dried with Na2S04. DCM was removed by reduced pressure. The residue was purified using silica column (0-50% EA/Hex) to give a white solid (Rf = 0.5 at 30%EA/Hex) in 84% yield.
Step c. Synthesis of Peracetylated Rhamnosyl Thiol: 2,3,4-tri-0-acetyl-6-deoxy-1-thio- alpha-L-mannopyranose
Thiourea (2.82 g, 37.0 mmol, 5 equiv.) was added into a solution of the above 2,3,4-tri-O- acetyl-6-deoxy-beta-L-mannopyranosyl bromide in dry acetone (40ml_). The reaction mixture was refluxed with TLC monitoring. After 1 0 minutes, the reaction mixture became a clear solution. After 2 hrs, another 5 equiv. of thiourea was added and the mixture was refluxed for another 2 hours. After completion of conversion of starting material (checked by TLC), the reaction mixture was cooled to room temperature. Acetone was removed under reduced pressure. To the solid residue was added chloroform and water (1 :1 , 300 mL) and stirred at 85 °C for 1 hour with condenser. The mixture was cooled to room temperature and extracted with DCM (3 x 200 mL), the DCM layer dried, filtered and the solvent removed. The residue was purified by silica gel chromatography (0-50% EA/Hex) to give a white solid (Rf = 0.5 at 30%EA/Hex) in over 80% yield. 1 H NMR (300 MHz, Chloroform-d): δ 5.49 (dd, J = 6.9, 1 .3 Hz, 1 H), 5.33 (s, 1 H), 5.38 - 5.26 (m, 1 H), 5.10 (t, J = 9.4 Hz, 1 H), 4.30 - 4.06 (m, 1 H), 2.26 (d, J = 7.0 Hz, 1 H), 2.17 (s, 3H), 2.08 (s, 3H), 2.01 (s, 3H), 1 .52 (d, J = 6.2 Hz, 3H). 13C NMR (75 MHz, Chloroform-d): 170.0 (CO), 170.0 (CO), 169.3 (CO), 84.1 (CH), 76.7 (CH), 72.3 (CH), 71 .0 (CH), 69.5 (CH), 67.6 (CH), 20.9 (CH3), 20.8 (CH3), 20.7 (CH3), 17.3 (CH3).
Step d. Synthesis of Rhamnose-PEG1-NHCbz: benzyl (2-{2-[(2,3,4-tri-0-acetyl-6-deoxy- alpha-L-mannopyranosyl)thio]ethoxy}ethyl)carbamate
Trimethylphosphine (TMP, 1 .0M in THF, 1 .3 mL, 1 .3 mmol) was added to a solution of 1 ,1 '- (azodicarbonyl)dipiperidine (ADDP, 0.329 g, 1 .3 mmol) in 2 mL of THF at 0 °C and stirred for 30 min. The Cbz-2-(2-hydroxyethoxy)ethyl alcohol (0.164 g, 0.686 mmol) from Step a and the 2,3,4-tri-O- acetyl-6-deoxy-1 -thio-alpha-L-mannopyranose from Step b (in 2 mL of THF) were added sequentially to the solution, with further stirring at room temperature for 2 hours. Any precipitate was then filtered off and the solution evaporated to dryness. Normal phase silica gel column purification (0-70% EtOAc/Hex) gave the desired product as a white foam (0.946 g, 80%). 1 H NMR (300 MHz,
Chloroform-d): δ 7.42 - 7.28 (m, 5H), 5.40 - 5.25 (m, 2H, NH, CH), 5.28 (d, J = 1 .5 Hz, 1 H), 5.22 (dd, J = 10.0, 3.3 Hz, 1 H), 5.17 - 5.05 (m, 3H), 4.20 (m, 1 H), 3.64 (m, 2H), 3.53 (m, 2H), 3.38 (m, 2H), 2.84 (m, 1 H), 2.72 (m, 1 H), 2.13 (s, 3H), 2.05 (s, 3H), 1 .99 (s, 3H), 1 .23 (d, J = 6.2 Hz, 3H). 13C NMR (75 MHz, CDCI3) δ 170.19 (e), 169.99 (e), 169.88 (e), 156.47 (e), 136.57 (e), 128.50 (o, 2C), 128.07 (o, 3C), 82.64 (o), 77.52 (CDCI3), 77.09 (CDCI3), 76.67 (CDCI3), 71 .52 (o), 71 .15 (o), 70.55 (e), 69.94 (e), 69.24 (o), 67.19 (o), 66.64 (e), 40.87 (e), 30.72 (e), 20.95 (o), 20.82 (o), 20.70 (o), 17.37 (o). Step e. Synthesis of Rhamnose-PEG1-NH Succinic Anhydride Adduct: 4-oxo-4-[(2-{2- [(2,3,4-tri-0-acetyl-6-deoxy-alpha-L-mannopyranosyl)thio]ethoxy}ethyl)amino]butanoic acid
Part 1 (Hydrogenolysis): Benzyl (2-{2-[(2,3,4-tri-0-acetyl-6-deoxy-alpha-L- mannopyranosyl)thio]ethoxy}ethyl)carbamate (0.200 g, 0.379 mmol) and 30% Pd/C (0.134 g, 0.379 mmol) were loaded in the flask with 8 mL of EtOAc and 2 ml_ of CHCI3. Under H2, the reaction mixture was stirred overnight. Check TLC and mass spectrum. The material was filtered through celite and washed with EtOH to give the title compound 0.14 g. Mass spectrum showed a strong detectable positive charge signal (5-95%) (found M+H+: 394.2 and M-Boc+H+: 293.2). Part 2 (Succinic anhydride adduct): To the material from Part 1 in DCM/Py (10 mL) was added succinic anhydride (0.540 g, 0.534 mmol, 1 .5 equiv.). The reaction mixture was stirred at room temperature overnight. LC/MS 8min Positive/negative showed the desired peak mass at 3.72 min on both positive (M+H+: 494.2) and negative ionization (492.2). The solvent was removed and the residue was loaded onto a silica gel column and eluted with 4-6% MeOH/DCM to give the title compound. 13C NMR (75 MHz, CDCI3) δ 175.94 (CO), 172.53 (CO), 1 70.42 (CO), 170.02 (2CO),
82.53 (CH), 71 .63 (CH), 71 .08 (CH), 70.51 (CH2), 69.60 (CH2), 69.25 (CH), 67.20 (CH), 39.38 (CH2), 30.82 (CH2), 30.71 (CH2), 28.9 (CH2), 21 .00 (CH3), 20.80 (CH3), 20.70 (CH3), 17.36 (CH3).
Step f. Synthesis of Rhamnosyl-PEG1-Succinic acid linker: 4-[(2-{2-[(6-deoxy-alpha-L- mannopyranosyl)thio]ethoxy}ethyl)amino]-4-oxobutanoic acid (INT-9)
NaOMe in MeOH (0.33 mL, 1 .42 mmol) was added into the 20-mL vial which contained the product of Step e (0.140 g, 0.284 mmol) in 3 mL of MeOH. Stirred at room temperature for overnight. LC/MS 5 min pos/neg method showed desired mass at 2.01 7 min (M+H+: 368.2 and M-H-: 366.2). Acidified to pH~3 with AcOH and the solvent was evaporated under reduced pressure. The residue as purified by C1 8 reverse phase chromatography to give the title compound INT-9.
Example 10: Synthesis of INT-10
Figure imgf000129_0001
Step a. Nitration of CD101 Acetate
To a stirring solution of CD101 acetate (100 mg, 0.078 mmol) in glacial acetic acid (1 .5 mL) was added sodium nitrite (1 1 mg, 0.159 mmol) and the reaction was stirred at ambient temperature for 20 hours. The mixture was applied directly to reversed phase HPLC (Isco CombiFlash Rf; 50g RediSep C18 column, 5 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 15 minute gradient). The pure fractions were pooled and lyophilized to yield 85 mg of nitro-CD101 as a light yellow solid, formate salt. 1 H-NMR (300 MHz, methanol-d4) δ 8.58 (d, 1 H, J = 1 1 .7Hz), 8.47 (t, 2H, J = 8.7Hz), 8.05 (d, 1 H, J = 2.1 Hz), 7.99 (d, 2H, J = 9.3 Hz), 7.82 (d, 2H, J = 8.7 Hz), 7.79-7.60 (m, 12H), 7.17 (d, 1 H, J = 8.7 Hz), 7.03 (d, 2H, J = 9 Hz), 5.48 (d, 1 H, J = 6 Hz), 5.08 (dd, 1 H, J = 1 .2, 5.7 Hz), 4.95-4.73 (m, 5H), 4.68-4.56 (m, 2H), 4.53 (d, 1 H, J = 5.7 Hz), 4.48-4.39 (m, 2H), 4.31 -3.79 (m, 6H), 4.04 (t, 2H, J = 5.7 Hz), 3.72-3.44 (m,3H), 3.18 (s, 9H), 2.60-1 .99 (m, 5H), 1 .83 (m, 2H, J = 8.7 Hz), 1 .56-1 .35 (m, 5H), 1 .28 (d, 6H, J = 4.2 Hz), 1 .09 (d, 3H, J = 10.2 Hz), 0.99 (t, 3H, J = 8.7 Hz); LC/MS, [M+H]/2+: 635.79, 635.80 calculated.
Step b. Reduction of Nitro-CD101 To Amino-CD101 (INT-10)
To a stirring solution of nitro-CD101 (100 mg, 0.075 mmol) in glacial acetic acid (1 .5 mL) was added zinc powder (50 mg, 0.77 mmol) and the reaction was stirred at ambient temperature for 1 hour. The mixture was filtered and applied directly to reversed phase HPLC (Isco CombiFlash Rf, 50g Redisep C18 column; 5 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 15 minute gradient). The pure fractions were pooled and lyophilized to yield 55 mg of the desired product (INT- 10) as a white solid, formate salt. 1 H-NMR (300 MHz, methanol-d4) δ 8.47 (bs, 1 H), 7.99 (d, 2H, J = 10.8Hz), 7.82 (d, 2H, J = 7.5 Hz), 7.80-7.67 (m, 6H), 7.62 (d, 2H, J = 8.7 Hz), 7.03 (d, 2H, J = 7.5 Hz), 6.77 (d, 1 H, J = 1 .9 Hz), 6.68 (d, 1 H, J = 8.2 Hz), 6.55 (dd, 2H, J = 8.2, 1 .9 Hz), 5.43 (d, 1 H, J = 2.5 Hz), 5.05 (d, 1 H, J = 3 Hz), 4.83-4.73 (m, 2H), 4.64- 4.56 (m, 2H), 4.43-4.34 (m, 2H), 4.31 -4.15 (m, 4H), 4.03-4.08 (m, 1 H), 4.1 1 -3.89 (m, 8H), 3.83 (d, 1 H, J = 10.8 Hz), 3.68-3.47 (m, 3H), 3.17 (s, 9H), 2.57-2.42 (m, 2H), 2.35-2.27 (m, 1 H), 2.14-1 .98 (m, 2H), 1 .83 (m, 2H, J = 6 Hz), 1 .56-1 .38 (m, 4H), 1 .28 (dd, 6H, J = 6.5, 2 Hz), 1 .09 (d, 3H, J = 7 Hz), 0.986 (t, 3H, J = 7 Hz); High Res LC/MS:
[M+H]+ 1241 .6163; 1241 .6136 calculated.
Exam -11
Figure imgf000130_0001
In a procedure analogous to that described in Example 10, anidulafungin is nitrated and the nitro group reduced to provide INT-1 1 with an exact mass of 1 154.52.
Example 12: Synthesis of INT-12
Figure imgf000131_0001
In a procedure analogous to that described in Example 10, pneumocandin Bo is nitrated and the nitro group reduced to provide INT-12 with an exact mass of 1079.57.
Example 13: Synthesis of INT-13 (Gala1-3Galp1-4GlcNAcp-OCH2CH2NH2)
Step a. Synthesis of protected thiagalactose
Figure imgf000131_0002
Figure imgf000132_0001
INT-13 (Gala1 -3Galp1 -4GlcNAcp-OCH2CH2NH2) was prepared in a manner similar to that described in WO 2014/151423 A1 (Example 1 , Scheme 5) with the modifications noted in the preceding scheme detailing the preparation. 1 H NMR (400 MHz, D20): δ 5.03 (d, 3.6 Hz, 1 H), 4.41 (d, 7.6 Hz, 2H), 4.10-4.04 (m, 2H), 4.06-3.49 (m, 15H). 2.73-2.71 (m, 2H), 1 .93 (s, 3H). LCMS: m/z calcd for C22H40N2O16: 588.24; found: 589.2 [M+H]+ Example 14: Synthesis of Compound 1
Figure imgf000133_0001
HATU (122 mg, 0.32 mmol, in 1 ml_ DMF) was added dropwise over 20 minutes, to a stirring mixture of INT-2 (1 18 mg, 0.34 mmol), triethylamine (46 mg, 0.46 mmoL) and INT-10 (190 mg, 0.15 mmol) in DMF (2 ml_). The reaction was stirred for an additional 20 minutes then applied directly to reversed phase HPLC (10 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 25 minute gradient). The pure fractions were pooled and lyophilized to afford the product as a white solid. The compound (a bis-rhamnose adduct) was dissolved in methanol (15 mL) and sodium carbonate (~5 mg) was added and the mixture stirred for 30 minutes at which point LC/MS analysis showed complete hydrolysis of the bis-rhamnose adduct and formation of the desired mon-rhamnose adduct. The mixture was filtered and neutralized with glacial acetic acid (~1 mL), then concentrated and applied directly to reversed phase HPLC (10 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 25 minute gradient). The pure fractions were pooled and lyophilized to afford the product
(Compound 1 formate) as a white solid. Yield: 54%. LC/MS [m+H]/2+ = 787.3.
Example 15: Synthesis of Compound 2
Figure imgf000133_0002
Using a procedure analogous to that described in Example 14, Compound 2 is synthesized from INT-1 1 and INT-2. Compound 2 has an exact mass of 1487.66. Example 16: Preparation of Compound 3
Figure imgf000134_0001
In a manner analogous to the preparation of Compound 1 , Compound 3 is prepared from INT- 12 and INT-2. Compound 3 has an exact mass of 1412.72.
Example 17: Preparation of Compounds 4a and 4b
Preparation of Compound 4a
Figure imgf000134_0002
Step a. Selective protection of caspofungin
Caspofungin acetate (0.62 g, 0.51 mmol) was dissolved in DMF (3 mL) and cooled to -40*C. Fmoc-OSu (0.22 g, 0.66 mmol, in 0.5 mL DMF) was added and the mixture was stirred for 45 minutes while allowing to gradually rise to ambient temp. The crude reaction mixture was applied directly to RP HPLC (10-95% acetonitrile in Dl water containing 0.1 % TFA: 20 minute gradient). The pure fractions were pooled and lyophilized to afford Fmoc-caspofungin as a white solid. Yield: 63%. LC/MS [m/2+H]+ = 658.8.
Step b. Acylation of Fmoc-caspofungin with INT-2
Fmoc-caspofungin (75 mg, 0.057 mmol) and 4-[(2-{2-[(6-deoxy-alpha-L- mannopyranosyl)oxy]ethoxy}ethyl)amino]-4-oxobutanoic acid (INT-2) (30 mg, 0.086 mmoL), HOBT (1 1 mg, 0.086 mmol) and EDC (16 mg, 0.086 mmol) were stirred together in DMF (1 mL) at room temperature for 2 hours. The reaction mixture was applied directly to reversed phase HPLC (20-95% acetonitrile in Dl water containing 0.1 % formic acid: 20 minute gradient). The pure fractions were pooled and lyophilized to afford the product as a white solid. Yield: 28%. LC/MS [M/2 + H] + = 824.8.
Step c. Removal of Fmoc group to provide Compound 4a
The product of Step b. (27 mg, 0.016 mmol) was stirred in a solution of 5% piperidine in DMF (1 mL) at ambient temperature for 30 minutes. The reaction mixture was applied directly to reversed phase HPLC (10-95% acetonitrile in Dl water containing 0.1 % formic acid: 20 minute gradient). The pure fractions were pooled and lyophilized to afford the product (Compound 4a) as a white solid. Yield: 40%. LC/MS [M/2 + H] + = 713.8.
Preparation of Compound 4b
Figure imgf000135_0001
In a procedure analogous to that described in the Preparation of Compound 4a above, Step b, Compound 4b with an exact mass of 1425.79 is prepared starting with caspofungin and INT-2.
Example 18: Preparation of Compounds 5a-5c
In a procedure analogous to that described in Example 14, the following compounds in Table 3 are prepared starting with INT-10 and the indicated carboxylic acid intermediate.
Table 3
Figure imgf000136_0001
Example 19: Synthesis of Compound 6
Figure imgf000137_0001
Step a. Synthesis of 3 -htyr-hemisuccinamido-CD101
3'-Amino-htyr-CD101 (INT-10) (1 .0 mmol, 1 .0 eq) and trimethylamine (1 .1 mmol, 1 .1 eq) is dissolved in DMF (1 0 mL) and succinic anhydride (1 .1 mmol, 1 .1 eq) is added followed by DMAP (0.05 eq). The mixture is stirred until the INT-10 is mostly consumed as determined by analytical HPLC. The fractions containing compound with an exact mass of 1340.63 are collected by preparative reversed phase HPLC and lyophilization of those fractions gives the desired product.
Step b. Coupling of INT-13
In a procedure analogous to that described in Example 14, the product from Step a. is coupled with INT-13 to give Compound 6 formate with an exact mass of 1910.86.
Example 20: Antifungal Activity of Compounds
Test Organisms
The test organisms consisted of strains from the Micromyx collection. Reference isolates were originally received from the American Type Culture Collection (ATCC; Manassas, VA).
Organisms received at Micromyx were initially streaked for isolation on Sabouraud dextrose or potato dextrose agar. Colonies were picked by swab from the medium and resuspended in the appropriate broth containing cryoprotectant. The suspensions were aliquoted into cryogenic vials and maintained at -80SC. Prior to testing, Candida isolates were streaked from the frozen vials on Sabouraud dextrose agar. The yeast isolates were incubated at overnight at 35SC before use. The fungal isolates were incubated at least 7 days on Sabouraud dextrose agar slants at 35SC before harvesting. Test Media
Isolates were tested in RPMI medium (Catalog No. SH3001 1 .04; Lot No. AWA92121 B;
HyClone Labs, Logan, UT) which was prepared according to CLSI guidelines. The pH of the medium was adjusted to 7.0 with 1 N NaOH. The medium was sterile filtered using a 0.2 μιτι PES filter and stored at 4°C until used.
Minimal Inhibitory Concentration (MIC) Assay Procedure
The MIC assay method employed automated liquid handlers to conduct serial dilutions and liquid transfers. Automated liquid handlers included the Multidrop 384 (Labsystems, Helsinki, Finland), Biomek 2000 and Biomek FX (Beckman Coulter, Fullerton CA). The wells in columns 2-12 in standard 96-well microdilution plates (Costar 3795) were filled with 150 μΙ of the correct diluent
(50% DMSO for investigational compounds, 1 00% DMSO for comparator compounds). These would become the 'mother plates' from which 'daughter' or test plates would be prepared. Stocks were diluted to 40X the desired top concentration in the test plates in the indicated solvent, and 300 μί of the 40X stock was dispensed into the appropriate well in Column 1 of the mother plates. The Biomek 2000 was used to make serial serial 2-fold dilutions through Column 1 1 in the "mother plate". The wells of Column 12 contained no drug and served as the organism growth control wells.
The daughter plates were loaded with 185 μί per well of RPMI described above using the Multidrop 384. The daughter plates were prepared using the Biomek FX which transferred 5 μί of drug solution from each well of a mother plate to the corresponding well of the daughter plate in a single step.
A standardized inoculum of each organism was prepared. For Candida, colonies were picked from the streak plate and a suspension was prepared in RPMI medium equal to a 0.5 McFarland standard, then diluted 1 :100 in RPMI and transferred to compartments of sterile reservoirs divided by length (Beckman Coulter). For the Aspergillus isolates, previously prepared and quantitated suspensions were used to make dilutions in RPMI to reach 20X the final concentration. These dilutions were also transferred to compartments of sterile reservoirs divided by length (Beckman Coulter). The final concentration of the Aspergillus isolates was approximately 0.2-2.5 x 104 CFU/mL.
The Biomek 2000 was used to inoculate the plates. Daughter plates were placed on the Biomek 2000 work surface reversed so that inoculation took place from low to high drug
concentration. The Biomek 2000 delivered 10 μί of standardized inoculum into each well. Thus, the wells of the daughter plates ultimately contained 1 85 μί of RPMI, 5 μί of drug solution, and 10 μί of inoculum. The final concentration of DMSO in the test well was 2.5% for the evaluated comparators and 1 .25% for the investigational agents. Plates were stacked 3 high, covered with a lid on the top plate, placed into plastic bags, and incubated at 35SC for approximately 24-48 hr prior to reading. Plates were read when inoculum was confluent in growth wells. Plates were viewed from the bottom using a plate viewer. An un-inoculated solubility control plate was observed for evidence of drug precipitation. MICs were read where visible growth of the organism was inhibited. MECs were read where the growth shifted to a small, rounded, compact hyphal form as compared to the hyphal growth seen in the growth control well. MIC and MEC values are shown in Table 4 below.
Table 4. Antifungal Activity for Select Compounds
Figure imgf000139_0001
Example 21 : Compound 1 mediates binding of rabbit anti-Rha antibody to Aspergillus fumigatus
7x103 A. fumigatus (AF293) cells were plated on 8-well glass chamber slides in XTT media [RMPI (FisheM 1835055) + 10% HI FCS)] and grown overnight at 37 °C. Cells were washed with PBS and 100 μΙ_ of pre-warmed XTT media was added to each well. 50 μΙ of a pre-warmed solution of either CD1 01 acetate (the structure of CD101 acetate is shown in Example 10) or Compound 1 (starting 0.12 μg/ml with 2-fold dilutions) in XTT media was added. Slides were incubated for 3 hours at 37 °C. Purified rabbit anti-Rha antibody (1 :1000) was added (final 3 μg/mL). Slides were then incubated for 1 hour at 37 °C. The chamber was washed twice with PBS and fixed in 2% PFA (in PBS) for 10 minutes at RT. The fixed samples were washed twice with PBS and blocked with 100 μΙ_ of 3% BSA in PBS. The samples were stained with a secondary antibody (anti-rabbit IgG at 1 :1000 (Fisher A1 0040) in blocking medium). The chambers were washed twice with PBS and mounted slides with Prolong anti-fade mountant (Fisher P36941 ). The samples were cured for 24 hours per manufacturer's instructions and visualized on a Zeiss fluorescent microscope where images were collected at 43X and 63X magnification.
FIGS. 1 A and 1 B show binding of the secondary anti-rabbit lgG1 (red fluorescence) to rabbit anti-Rha antibodies which in turn are bound to A. fumigatus hyphae. These data demonstrate that Compound 1 coordinates the deposition of anti-Rha antibodies (visualized with fluorescent anti-rabbit lgG1 ) to A. fumigatus hyphae. In contrast, in FIG. 1 B, CD101 acetate (which lacks the rhamnose of Compound 1 ; the structure of CD101 acetate is shown in Example 10) does not coordinate binding of rabbit anti-Rha antibodies to A. fumigatus hyphae since little fluorescence is seen upon addition of fluorescent anti-rabbit lgG1 . These data demonstrate that Compound 1 is capable of coordinating the binding of anti-Rha antibodies to A. fumigatus hyphae. This is considered the first step in an immune response against the fungal pathogen.
Example 22: Inoculation of rabbits with OVA-Rha-linked vaccine, isolation of serum and purification of anti-Rha antibodies
Part 1. Preparation of OVA-Rha-linked vaccine (OVA-Rha)
Step a. Synthesis of N-(2-{2-[(6-deoxy-alpha-L-mannopyranosyl)oxy]ethoxy}ethyl)-4- [(2,5-dioxopyrrolidin-1-yl)oxy]-4-oxobutanamide
(0-(N-Succinimidyl)-1 ,1 ,3,3-tetramethyl uronium tetrafluoroborate-' STU") (206 mg, 0.68 mmol) was added to a stirring mixture of 4-[(2-{2-[(6-deoxy-alpha-L- mannopyranosyl)oxy]ethoxy}ethyl)amino]-4-oxobutanoic acid (INT-2) (200 mg, 0.57 mmol) and triethylamine (690 mg, 0.68 mmol) in DMF (4 ml_) and the reaction was stirred for 4 hours at room temperature. The solvent was removed on a rotary evaporator then dried under high vacuum for 12 hours. The crude product mixture was used for protein conjugation without further treatment. (~2 mg of the crude product was treated with excess benzylamine and analyzed by LC/MS to confirm formation of the activated ester).
Step b. Conjugation to ovalbumin
A solution of N-(2-{2-[(6-deoxy-alpha-L-mannopyranosyl)oxy]ethoxy}ethyl)-4-[(2,5- dioxopyrrolidin-1 -yl)oxy]-4-oxobutanamide (30 mg/mL in 2x PBS pH 7.4) was added to the same volume of ovalbumin (10 mg/mL in 2x PBS pH 7.4) and was gently stirred at 25 °C for 1 h, followed by 5 h incubation at 4°C. The solution was concentrated and buffer exchanged into 1 x PBS pH 7.4 using Amicon Centrifugal Filter Devices (10,000 MWCO). Extensive buffer washes removed unconjugated linker from the protein solution. Solution purity and a molecular weight shift were confirmed by SDS- PAGE and size exclusion chromatography (Superdex 75). The solution was determined to be endotoxin free using the Endosafe Assay (Charles River). The glycoprotein solution was quantitated using a NanoDrop 2000 Spectrophotometer and stored at 4°C for immunizations. Part 2. Vaccination of rabbits
Sixty day old New Zealand rabbits were vaccinated subcutaneously with OVA-Rha ±
Complete Freund's Adjuvant (CFA, Sigma F5881 ) or Incomplete Freund's Adjuvant (IFA Sigma F5506). Rabbits were held at indicated time points and serum was prepared using a standard procedure.
Week 0: 1 st immunization with 0.25 mg of OVA-Rha in Complete Freund's Adjuvant
Week 2: 2nd immunization with 0.2 mg of OVA-Rha in Incomplete Freund's Adjuvant (IFA)
Week 4: 3rd immunization with 0.2 mg of OVA-Rha in IFA
Week 5: 1 st production bleed - -20-25 mL of serum
Week 6: 4th immunization with 0.2 mg of OVA-Rha in IFA
Week 7: 2nd Production bleed - -20-25 mL of serum
Week 8: 3rd Production bleed - -20-25 mL of serum
Part 3. Purification of Rha-specific antibodies from serum
Step a. Preparation of the anti-rhamnose antibody affinity column
6-Aminohexyl-Agarose (5 mL, 4% crosslinked beaded agarose, -5 μιηοΙ per mL) suspended in saline was centrifuged (3500 rpm for 5 min), then decanted to remove water. The resulting solid was suspended in DMF (4 x 15 mL), centrifuged (3500 rpm for 5 min) and decanted. The agarose was resuspended in DMF (1 mL), and treated with INT-2 (0.140 g, 0.40 mmol), followed by DIEA (0.21 mL, 1 .20 mmol), and HATU (0.152 g, 0.40 mmol). The mixture was rotated for 3 hr at room temperature, then transferred to a plastic column and washed with phosphate buffered saline (5 x 1 5 mL, pH 7.4). The solid supported a-L-rhamnose was stored in phosphate buffered saline (pH 7.4) with 20% ethanol, at room temperature. Step b. Purification of anti-rhamnose antibody from rabbit serum
Serum from immunized rabbits was diluted 2-fold in 2X PBS pH 7.4. The solution was passaged over the solid supported a-L-rhamnose column (from Step a) by gravity flow followed by a wash step using 10 CV of 1 X PBS pH 7.4. Protein was eluted using 20 mM Glycine Buffer pH 2.0 and immediately adjusted to a neutral pH by the addition of 1 M Tris pH 9.0. The eluate was buffer exchanged with 1 X PBS pH 7.4 and concentrated in Amicon centrifugal concentrators (10K MWCO). The presence of IgG was determined by reducing and non-reducing SDS-PAGE and quantitated using a NanoDrop 2000 Spectrophotometer. The resultant purified antibodies can be used in place of serum adjusting for relative antibody titers. Example 23: Efficacy of Compound 1 in a Mouse Candidiasis Model
Test articles. Compound 1 , caspofungin acetate and purified rabbit anti-rhamnose antibodies (rAbs) were stored at 4 °C. Compound 1 was dissolved in 10% DMSO/1 % Tween 20 in water for injection (WFI) to generate five doses of 0.03, 0.1 , 0.3, 1 and 3 mg/kg and caspofungin at 0.1 mg/kg was dissolved in WFI before using. A pre-formulated solution of purified rabbit anti-Rha antibodies was injected 0.1 mL/mouse by intravenous (IV) injection. The dosing volume was 10 mL/kg by intraperitoneal (IP) administration for Compound 1 and caspofungin acetate in the study.
Challenge inoculum. Candida albicans (ATCC R303) was cryopreserved as single-use working stock cultures which stored at -80 SC. A 0.1 mL aliquot stock was transferred to a sabouraud agar (SA) plate and incubated at 35-37 SC overnight. The culture was re-suspended with 1 mL cold PBS (>3.0 x 109 CFU/mL, OD62o 3.0-3.2) and diluted with PBS to 1 x 104 CFU/mL. The actual colony counts were determined by plating dilutions to sabouraud agar plates followed by 20 - 24 hr incubation. The actual inoculum count was 2.93 x 104 CFU/mL.
Animals. Male ICR mice weighing 22 ± 2 g were acclimated for 3 days prior to use. All animals were maintained in a hygienic environment with controlled temperature (20 - 24SC), humidity (30% - 70%) and 12 hours light/dark cycles. Free access to sterilized standard lab diet [MFG (Oriental Yeast Co., Ltd., Japan)] and autoclaved tap water were granted.
Experimental design. Groups of male ICR mice (n=10) weighing 22 ± 2 g were used.
Immune suppression was induced by two intraperitoneal injections of cyclophosphamide at 150 mg/kg 4 days (Day -4) and at 100 mg/kg 1 day before inoculation (Day -1 ). On Day 0, animals were inoculated intravenously (0.1 mL/mouse) with C. albicans (R303), 2.93 x 103 CFU per mouse.
Purified rabbit anti-Rha antibodies in PBS (pH 7.4) were injected once at 100 μί/ιτιουεβ by intravenous administration 1 day prior to C. albicans challenge. On day 0, Compound 1 was intraperitoneally administered at 0.03, 0.1 , 0.3, 1 and 3 mg/kg 2 hours post-inoculation to the rAbs untreated/treated animals. Caspogungin acetate at 0.1 mg/kg was administered IP 2 hours after inoculation. The dosing volume was 10 mL/kg for all groups, (see figure above)
The animals were euthanized by CO2 asphyxiation 2 or 72 hr post-inoculation. Paired kidneys were harvested and weighed. The harvested kidneys were homogenized in 1 mL of PBS, pH 7.4, with a Polytron homogenizer. A 0.1 mL aliquot of each homogenate was used for serial 10-fold dilutions and plated onto SA plates for fungal enumeration. The fungal counts (CFU/g) in kidneys were calculated and the percentage decrease in counts compared to the corresponding vehicle control was calculated with the following formula:
Decrease (%) = [(CFU/g of vehicle -CFU/g of treatment)/ (CFU/g of vehicle)] x 100%
At least a two-log reduction in counts (≥99% reduction) indicates significant activity according to our in-house significance criterion. Statistical significance (p < 0.05) was also assessed with oneway ANOVA followed by Dunnett's method using the Prism Graphpad software version 5.0.
Results. The results in the Table 5 demonstrate that Compound 1 significantly reduces the fungal burden in kidney tissue (CFU/g kidney) at doses of at least 3 mg/kg in the presence or absence of rAb and is substantially more efficacious than caspofungin, a drug used clinically for Candida infections, at a dose of 0.1 mg/kg.
Table 5
Figure imgf000143_0001
Example 24: Efficacy of Compound 1 in a Mouse Aspergillosis Model
Test articles. For this study, amphotericin B was dissolved in 0.9% saline and Compound 1 in 1 0% DMSO/1 % Tween 20/0.9% NaCI. Rabbit anti-Rha antibody, affinity purified from immunized rabbits as described in Example 22, was administered 24 hours prior to fungal challenge to achieve an in vivo titer of 4000.
Animals. Female ICR mice weighing 22 ± 2 g were maintained in a well-controlled temperature (20 - 24 °C) and humidity (30% - 70%) environment with 12 hours light/dark cycles. Free access to standard lab diet [MFG (Oriental Yeast Co., Ltd., Japan)] and autoclaved tap water were granted. Animals were immunosuppressed by three intraperitoneal injections of cyclophosphamide (the first injection was at 6 mg/mouse 3 days before inoculation, the second and third injections were at 2 mg/mouse 1 and 4 days after inoculation. On Day 0, animals were inoculated (0.1 mL/mouse IV) with A. fumigatus (ATCC 13073), 3.65 x 104 CFU per mouse.
Challenge inoculum. Aspergillus fumigatus (ATCC 13073) growth was taken from 96 hr Potato dextrose agar (PDA) and re-suspended in 0.1 % Tween 20. The culture was resuspended in 1 mL cold PBS (>1 .0 χ 1 08 CFU/mL, OD62o 2.3-2.8). The culture was then diluted in PBS to final cellular densities of 3.0 χ 105 CFU/mL. The actual colony counts were determined by plating dilutions on PDA plates to confirm inoculation concentration.
Experimental design. Table 6 below provides the details of the experiment (dosing times, concentrations, etc.). In general, a dose titration was run with Compound 1 to establish intrinsic activity in this model, and a second arm included the same dose titration plus rAb to elucidate the contribution of the immune system. The design and results of the study are presented in the Table 6.
Study 1.
Table 6
Figure imgf000145_0001
The percent survival was higher in Group 8 where mice received 0.3 mg/kg of Compound 1 plus rAb compared to those that received 0.3 mg/kg of Compound 1 alone (Group 4). These results demonstrate that Compound 1 is effective as an antifungal agent and that immune engagement when mediated by Compound 1 further enhances survival in a lethal mouse aspergillosis model.
Study 2.
Using a similar protocol as that used in Study 1 but with the following differences (increasing the number of mice to 10, including serum collection to quantitate rAb levels, increasing the dosage of Compound 1 and reducing the dosage of amphotericin B, and the challenge inoculum of A. fumigatus 13073 was 2.35E4), the following results were obtained as shown in the Table 7. Table 7
Figure imgf000146_0001
In mice receiving Compound 1 at doses of 3, 1 and 0.3 mg/kg and also receiving rAb (Groups 8, 9 and 10 resp.), survival was higher than the corresponding groups receiving Compound 1 alone (Groups 4, 5 and 6). These results demonstrate that Compound 1 is effective as an antifungal agent and that efficacy is enhanced by the immune system in mice in a neutropenic model of disseminated aspergillosis.
Example 25: Efficacy of Compound 1 in a Murine Model of Invasive Candidiasis
The objective of this study was to evaluate the in vivo efficacy of Compound 1 as therapy against invasive pulmonary candidiasis in a murine model.
Summary of Approach. Outbred ICR mice were inoculated intravenously (IV) through the lateral tail vein with a susceptible Candida albicans isolate. A single dose of the polyclonal antibody (AB) that is absent in mice was administered on Day -1 relative to infection. Treatment with each antifungal began one day post-challenge and continued through Day 7. Survival and fungal burden arms were included. A placebo (vehicle) control was included in each arm.
Isolate. A Candida albicans isolate, ATCC 90028, was utilized that is susceptible to antifungal agents. Isolates were sub-cultured at 37°C for 48 hours on Sabouraud dextrose agar twice. Prior to inoculation, isolates taken from the second subculture were placed into brain heart infusion broth and grown overnight at 37°C with shaking at 200 rpm. Cells were then collected by centrifugation and washed three times in sterile saline. Animal Model. Outbred ICR mice (Envigo) were housed 5 per cage and had access to food and water ad libitum. On Day 0, mice were infected intravenously with 0.2 ml_ of C. albicans with the number of Candida cells per animal adjusted to body weight (e.g., 50,000 C. albicans cells/g of weight = 1 .0 x 106 cells per animal for a 25 g mouse). The starting inoculum was determined by counting Candida cells using a hemocytometer and adjusting to the target number of cells for each isolate. Following the preparation of the inoculum, serial dilutions were prepared in saline and plated onto Sabouraud dextrose agar plates and incubated at 37°C in order to verify the number of viable Candida cells.
Antifungal Therapy. Antifungal treatment experiments were used to evaluate the in vivo efficacy of Compound 1 against invasive candidiasis. Mice were administered the polyclonal antibody on Day -1 relative to inoculation. Treatment with antifungals began 24 hours following inoculation and were continued through Day 7 post-inoculation. Compound 1 was administered by intraperitoneal (IP) injection at doses of 3 mg/kg, 10 mg/kg, and 30 mg/kg once daily (QD). Survival and fungal burden arms were included in the study. Treatment groups and the number of animals in each group and each arm are shown in the Table 8.
Table 8. Treatment groups and number of mice per group in both the survival and fungal burden
Figure imgf000147_0001
Survival and Fungal Burden. Survival and fungal burden arms were included in this experiment. In the survival arm, antifungal therapy was continued through Day 7 post-inoculation. Mice were then monitored off therapy at least twice daily to prevent and minimize unnecessary pain or distress until Day 21 post-inoculation. Moribund animals were identified by the following criteria: (1 ) ruffled/matted fur, (2) hypothermia, (3) weight loss (e.g., > 20%), (4) inability to eat or drink, and (5) hunched posture. Any animal demonstrating > 1 of these criteria was humanely euthanized by isoflurane anesthesia followed by exsanguination via cardiac puncture and cervical dislocation.
In the fungal burden arm, mice were humanely euthanized on Day 8 post-inoculation.
Kidneys were harvested, weighed, and homogenized in sterile saline supplemented with antibiotics. Serial dilutions of the tissue homogenates were prepared and plated in duplicate onto Sabouraud dextrose agar. After 24 hours of incubation at 37°C, the colonies were counted and the numbers of colony forming units (CFU) per gram of tissue calculated. Fungal burden was also measured in mice as they succumb to infection in the survival arm and in those that survive to the study endpoint (Day 21 ). Blood was also collected by cardiac puncture on Day 8 in the fungal burden arm of mice administered Compound 1 . Plasma was separated and immediately frozen. Compound 1 concentrations were measured in plasma and kidney tissue samples.
Data Analysis - Survival. Survival was plotted by Kaplan-Meier analysis, and differences in median survival time and the percent survival among groups were analyzed by the log-rank test and Fischer's exact test, respectively. The results of this analysis are shown in Table 9.
Table 9. Survival Analysis
Figure imgf000148_0001
Data Analysis - Fungal Burden. Differences in kidney fungal burden (CFU/g) among the groups were assessed for significance by ANOVA with Tukey's post-test for multiple comparisons. A p-value of < 0.05 was considered statistically significant for all comparisons. Kidney fungal burden in the fungal arm is shown in Table 10. Kidney fungal burden in the survival arm is shown in Table 1 1 . Table 10. Kidney Fungal Burden - Fungal Burden Arm
Figure imgf000149_0001
Table 11. Kidney Fungal Burden - Survival Arm
Figure imgf000149_0002
Example 26: Efficacy of Compound 1 in a Murine Model of Invasive Pulmonary Aspergillosis
The objective of this study was to evaluate the in vivo efficacy of Compound 1 as therapy against invasive pulmonary aspergillosis in a murine model of invasive pulmonary aspergillosis.
Strategy. First, a preliminary pharmacokinetic / dose tolerability study was performed to evaluate Compound 1 in immunosuppressed mice. In this study, a single dose of a polyclonal antibody that is absent in mice was administered on Day -1 . Compound 1 was administered by two routes of administration, including intravenous (IV) and intraperitoneal (IP) injection, to
immunosuppressed mice for seven days at two different doses (beginning two days after the administration of the polyclonal antibody). Plasma and lung samples were collected at various time points after the last dose and concentrations of Compound 1 were measured. The tolerability of Compound 1 was also evaluated.
Next, Compound 1 was administered as treatment against established pulmonary infection. A single dose of the polyclonal antibody (AB) that is absent in mice was administered on Day -1 relative to infection. Compound 1 was administered at different doses beginning one day after pulmonary inoculation with A. fumigatus. A placebo (vehicle) control group was also included. Endpoints included survival and changes in pulmonary fungal burden. Preliminary Pharmacokinetic / Dose Tolerability Study. A preliminary pharmacokinetic / dose tolerability study was conducted with Compound 1 . Uninfected male ICR mice were immunosuppressed, as described below for the infection model. Mice were administered a single dose of the polyclonal antibody by intravenous injection. Beginning two days after administration of the antibody, mice were administered Compound 1 at the highest and lowest anticipated doses IV and IP doses for seven days. After the morning dose on Day 7, blood was collected by cardiac puncture from three mice per time point in each group, and the plasma was separated and frozen. Lung samples were also collected from the mice at these time points and stored frozen. Compound 1 concentrations were measured in the frozen plasma and lung samples. Mice were also monitored multiple times per day, including close observation following IV and IP administration. These observations, along with daily weights, were used to evaluate the tolerability of Compound 1 in immunosuppressed mice. The number of mice per time point for each dose of Compound 1 is shown in Table 12.
Compound 1 concentrations were measured in the frozen plasma and lung samples.
Compound 1 concentrations as measured in frozen plasma are shown in FIGs. 2A and 4A
(Compound 1 IV) and FIGs. 2B and 4B (Compound 1 IP). Compound 1 concentrations as measured in lung homogenate are shown in FIGs.3A and 4A (Compound 1 IV) and FIGs.3B and 4B (Compound 1 IP). The mean ratio of Compound 1 concentration in lung/plasma are shown in FIGs. 4A and 4B. Compound 1 showed a sustained lung tissue/plasma ratio of 1 .
Table 12. Number of mice per time point per Compound 1 dose for the preliminary
pharmacokinetic/dose tolerability experiment.
Figure imgf000150_0001
Figure imgf000151_0001
84 mice that receive Compound 1 plus 6 controls that receive vehicle alone were included in the preliminary PK/dose tolerability experiment (N = 90 total mice).
The pharmacokinetic data from this preliminary study were evaluated prior to the initiation of the invasive pulmonary aspergillosis (IPA) model. The pharmacokinetic and tolerability results in the immune suppressed mice were also used to help determine which doses would be used for the efficacy experiment.
Infection Model
Isolate. Aspergillus fumigatus clinical isolate 293 (Af293) was used as the infecting organism. This isolate, recovered from lung tissue at autopsy from a patient with fatal invasive pulmonary aspergillosis, was also the isolate used in the A. fumigatus genome sequencing project.
Prior to in vivo experiments, an aliquot of the Af293 stock was plated onto potato dextrose agar (PDA). The PDA plates inoculated with conidia were placed in a humidified incubator at 37°C and allowed to germinate for 10 days prior to harvesting and preparation of conidia suspension for inoculation via the aerosol chamber. On the day of infection, PDA surfaces were flooded with sterile physiologic phosphate buffered saline containing 0.1 % of the surfactant polysorbate 80 (Tween 80). The agar surfaces were then gently scraped with a disposable plastic loop. The conidial suspension was then collected in two centrifuge tubes, and concentrated by high speed centrifugation. The conidial suspension was then diluted (1 :1000 to 1 :1 0,000) and the number of conidia measured by hemocytometer. The number of conidia per milliliter was then adjusted for a target starting inoculum for the murine model.
The viability of the conidia within the starting inoculum was verified by plating onto PDA and counting the number of colony-forming units. Three serial 1 :100 dilutions prepared from the starting inoculum were plated (0.05 mL each) onto PDA in triplicate. The plates were incubated at 37°C overnight and the colonies enumerated the next day. The starting inoculum consisted of at least 13 mL of conidial suspension at the desired concentration. This volume was required for a single 1 hour run of the aerosol chamber, which requires 12 mL. Immunosuppression. Standard neutropenic immunosuppression regimen was used for this model of invasive pulmonary aspergillosis. This regimen utilized cyclophosphamide and cortisone acetate to render animals immunosuppressed prior to aerosolized inoculation.
• Cyclophosphamide (25 mg/mL) was dissolved by the addition of sterile water to the vial. This was administered as a dose of 250 mg/kg two days prior to inoculation. A second dose of cyclophosphamide was administered at a dose of 200 mg/kg three days following inoculation (cyclophosphamide concentration 20 mg/mL).
• Cortisone acetate powder was weighed out and a suspension (25 mg/mL) prepared using sterile physiologic phosphate buffered saline and 0.1 % polysorbate 80. The cortisone acetate suspension was prepared immediately prior to administration to the animals and was administered subcutaneously at a dose of 250 mg/kg two days prior to pulmonary inoculation and again three days following inoculation.
Antibacterial Prophylaxis. To prevent bacterial superinfection and deaths in the
immunosuppressed mice, animals received antibacterial prophylaxis. This consisted of enrofloxacin, which were made available at 50 ppm in the animals' drinking water.
Aerosol Inoculation. Male ICR mice weighing -25 grams were placed inside an acrylic inhalation chamber that was kept within a Class II A2 biosafety cabinet. Six milliliters of the conidial suspension were added to the Micro Mist® nebulizer and connected to the inhalation chamber and a tank of compressed air. Air was run through the nebulizer at 100 kPa, in turn driving aerosolizing conidia into the inhalation chamber, for 15 minutes. After the first 15 minutes, the remaining 6 mL of the conidial suspension was added to the nebulizer and aerosolized using 100 kPa of compressed air over 30 minutes. Once all of the conidial suspension was aerosolized, the compressed air was discontinued, and the animals were allowed to remain in the acrylic chamber for a total exposure time of one hour.
One hour after completing the aerosolized inoculation, five mice were randomly selected in order to confirm conidial delivery to the lungs. Animals were sacrificed and the lungs aseptically removed and weighed. Lungs were then placed into saline, homogenized, and serial dilutions of 1 :10 and 1 :100 prepared. One hundred microliters of each dilution were then plated onto PDA plates in duplicate and allowed to incubate at 37°C for 24 hours. Colonies were then counted and the number of colony-forming units per gram of lung tissue calculated to verify delivery of conidia to the lungs.
Antifungal Therapy. Antifungal treatment experiments were used to evaluate the in vivo efficacy of Compound 1 against IPA. As in the preliminary PK/dose tolerability experiment, mice were administered the polyclonal antibody on Day -1 relative to inoculation. Treatment with antifungals began 24 hours following inoculation and continued through Day 7 post-inoculation. Compound 1 was administered by IP injection at doses based on the results of the initial PK/dose tolerability experiment. These doses were 3, 10, and 30 mg/kg QD. Survival and fungal burden arms were included. Treatment groups and the number of animals in each group and each arm are shown in Table 13. Table 13. Dosing groups for in vivo efficacy experiment.
Figure imgf000153_0001
Survival. In the survival arm, antifungal therapy was continued through Day 7 post- inoculation and mice were followed off therapy until Day 12. Each group consisted of 10 mice per group. Mice were monitored at least twice daily to prevent and minimize unnecessary pain or distress. Any animal that appeared moribund prior to the scheduled endpoint were euthanized. Moribund animals were identified by the following criteria: (1 ) ruffled/matted fur, (2) hunched posture, (3) weight loss (e.g., >20%), (4) hypothermia (cool to touch), (5) hyper-/hypoventilation, and (6) inability to eat or drink. Any animal demonstrating > 1 of these criteria was humanely euthanized by isoflurane anesthesia followed by exsanguination and cervical dislocation.
Differences in median survival time and the percent survival among groups were analyzed by the log-rank test and Fisher's exact test, respectively (Tables. 14 and 15).
Table 14. Survival through end of study in survival arm
Figure imgf000153_0002
Table 15. Survival on treatment in survival arm
Figure imgf000154_0001
*p-value vs. Vehicle Control
Fungal Burden / Pharmacokinetic Analysis. In the fungal burden arm of each experiment, antifungal therapy was continued through Day 7 post-inoculation. For fungal burden analysis, all mice were humanely euthanized as described above on Day 8 and the lungs from each animal were collected. Colony-forming units were used to measure tissue fungal burden. In addition, lungs were also collected for moribund animals in the survival arm as they succumb to infection and at the pre- specified endpoint (Day 12 post-inoculation). Tissue collected from each animal was weighed and placed into sterile saline containing gentamicin (25 g/mL) and chloramphenicol (400 g/mL) and homogenized. Serial 1 0-fold dilutions of the homogenates were prepared and plated onto potato dextrose agar. Following 48 hours of incubation, colonies were counted and the number of colony- forming units per gram of lung tissue were calculated for each animal. The fungal burden in lung tissue collected from the survival arm is shown in Table 16. Fungal burden in lung tissue collected from the fungal burden arm is shown in Tables 17 and 18.
Table 16. Fungal burden in survival arm
Figure imgf000154_0002
Table 17. Fungal burden in fungal burden arm
Figure imgf000154_0003
Table 18. Fungal burden in fungal burden arm (Treatment Groups -
Figure imgf000155_0001
In addition, real-time PCR was also used to measure pulmonary fungal burden. The amount of DNA per sample was measured by qPCR with the use of an ABI PRISM 7300 sequence detection system (Applied Biosystems) with primers and a dual-labeled fluorescent hybridization probe specific for the A. fumigatus (1→3)- -D-glucan synthase gene (AFKS; GeneBank accession number U79728). The pulmonary lung burden in the survival arm, as assessed by qPCR, is shown in Table 1 9. The pulmonary lung burden in the fungal burden arm, as assessed by qPCR, is shown in Table 20. Table 19. Lung burden assessed by qPCR in survival arm
Figure imgf000155_0002
Differences in pulmonary fungal burden (CFU/g) were assessed for significance by analysis of variance with Tukey's post-test for multiple comparisons. A p-value of < 0.05 was considered statistically significant for all comparisons. Descriptive statistics and non-linear regression were used to assess the relationship between Compound 1 plasma concentrations and pulmonary fungal burden.
Other Embodiments
While the disclosure has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the disclosure following, in general, the principles of the disclosure and including such departures from the present disclosure come within known or customary practice within the art to which the disclosure pertains and may be applied to the essential features hereinbefore set forth.
All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
What is claimed is:

Claims

1 . A compound comprising a conjugate A-L-(E)d, wherein A is a β-1 ,3-glucan synthase inhibitor that is conjugated to at least one monosaccharide or oligosaccharide moiety, E, by way of a linker, L, wherein the compound is described by formula (I):
Figure imgf000157_0001
wherein R1 is a lipophilic moiety;
R2 is hydrogen or methyl;
each of R3 and R4 is, independently, hydrogen or hydroxyl;
R5 is hydrogen, methyl, or optionally substituted C1 -C5 alkamino;
R6 is hydrogen, hydroxyl, methyl, or amino;
R7 is hydrogen or hydroxyl;
R8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(0(CH2)a)bR',
-(NH(CH2)a)bR', -(S(CH2)a)bR', -(0(CH2)a)bN(R')2, -(NH(CH2)a)bN(R')2, -(S(CH2)a)bN(R')2,
-(0(CH2)a)bN+(R')3, -(NH(CH2)a)bN+(R')3, -(S(CH2)a)bN+(R')3, -(0(CH2)a)bOR', -(NH(CH2)a)bOR', -(S(CH2)a)bOR', -(OCH2CH2)a(NHCH2CH2)bN(R')2, -(OCH2CH2)a(NHCH2CH2)bN+(R')3,
-(OCH2CH2)a(NHCH2CH2)bOR', -(NHCH2CH2)a(OCH2CH2)bN(R')2, -(NHCH2CH2)a(OCH2CH2)bN+(R')3, or -(NHCH2CH2)a(OCH2CH2)bOR';
R9 is hydrogen, hydroxyl, or amino;
n is 0 or 1 ;
d is 1 , 2, 3, 4, 5, or 6;
each of a and b is, independently, an integer from 1 to 5;
each R' is, independently, hydrogen, optionally substituted C1 -C1 0 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyi, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1 -C10 heteroaryl;
L is a linker; and
each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein the compound is described by formula (1-1 ):
Figure imgf000158_0001
wherein R1 , R2, R3, R4, R5, R6, R7, R8, R9, n, d, L, and E are as defined above, or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 or 2, wherein the compound is described by formula (I-2):
Figure imgf000158_0002
wherein R1 is a lipophilic moiety;
R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2;
R6 is hydrogen or methyl;
R8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(0(CH2)a)bR', -(NH(CH2)a)bR', -(S(CH2)a)bR', -(0(CH2)a)bN(R')2, -(NH(CH2)a)bN(R')2, -(S(CH2)a)bN(R')2, -(0(CH2)a)bN+(R')3, -(NH(CH2)a)bN+(R')3, -(S(CH2)a)bN+(R')3, -(0(CH2)a)bOR', -(NH(CH2)a)bOR', -(S(CH2)a)bOR", -(OCH2CH2)a(NHCH2CH2)bN(R')2, -(OCH2CH2)a(NHCH2CH2)bN+(R')3, -(OCH2CH2)a(NHCH2CH2)bOR', -(NHCH2CH2)a(OCH2CH2)bN(R')2, -(NHCH2CH2)a(OCH2CH2)bN+(R')3, or -(NHCH2CH2)a(OCH2CH2)bOR';
each of a and b is, independently, an integer from 1 to 5;
d is 1 , 2, 3, 4, 5, or 6;
each R' is, independently, hydrogen, optionally substituted C1 -C1 0 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyi, optionally substituted C3-C10 heterocycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1 -C10 heteroaryl;
L is a linker; and
each E is, independently, a monosaccharide or oligosaccharide moiety,
or a pharmaceutically acceptable salt thereof.
4. A compound comprising a β-1 ,3-glucan synthase inhibitor conjugated to at least one
monosaccharide or oligosaccharide moiety by way of a linker, wherein the compound is described by formula (II):
Figure imgf000159_0001
wherein R1 is a lipophilic moiety;
R2 is hydrogen or methyl;
each of R3 and R4 is, independently, hydrogen or hydroxyl;
R6 is hydrogen, hydroxyl, methyl, or amino;
R7 is hydrogen or hydroxyl;
R8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(0(CH2)a)bR',
-(NH(CH2)a)bR', -(S(CH2)a)bR', -(0(CH2)a)bN(R')2, -(NH(CH2)a)bN(R")2, -(S(CH2)a)bN(R')2,
-(0(CH2)a)bN+(R')3, -(NH(CH2)a)bN+(R')3, -(S(CH2)a)bN+(R')3, -(0(CH2)a)bOR', -(NH(CH2)a)bOR', -(S(CH2)a)bOR\ -(OCH2CH2)a(NHCH2CH2)bN(R')2, -(OCH2CH2)a(NHCH2CH2)bN+(R')3,
-(OCH2CH2)a(NHCH2CH2)bOR', -(NHCH2CH2)a(OCH2CH2)bN(R')2, -(NHCH2CH2)a(OCH2CH2)bN+(R')3, or -(NHCH2CH2)a(OCH2CH2)bOR'; R9 is hydrogen, hydroxyl, or amino;
n is 0 or 1 ;
each of a and b is, independently, an integer from 1 to 5;
d is 1 , 2, 3, 4, 5, or 6;
each R' is, independently, hydrogen, optionally substituted C1 -C1 0 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyi, optionally substituted C3-C10 heterocycloalkyi, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1 -C10 heteroaryl; each R" is, independently, hydrogen or C1 -C10 alkyl;
L is a linker; and
each E is, independently, a monosaccharide or oligosaccharide moiety,
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 4, wherein the compound is described by formula (11-1 ):
Figure imgf000160_0001
wherein R1 , R2, R3, R4, R6, R7, R8, R9, n, d, L, and E are as defined above,
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 4 or 5, wherein the compound is described by formula (11-2):
Figure imgf000161_0001
wherein R1 is a lipophilic moiety;
R6 is hydrogen or methyl;
R8 is hydrogen, hydroxyl, amino, optionally substituted alkamino, -(0(CH2)a)bR',
-(NH(CH2)a)bR', -(S(CH2)a)bR', -(0(CH2)a)bN(R')2, -(NH(CH2)a)bN(R")2, -(S(CH2)a)bN(R')2,
-(0(CH2)a)bN+(R')3, -(NH(CH2)a)bN+(R')3, -(S(CH2)a)bN+(R')3, -(0(CH2)a)bOR', -(NH(CH2)a)bOR', -(S(CH2)a)bOR', -(OCH2CH2)a(NHCH2CH2)bN(R')2, -(OCH2CH2)a(NHCH2CH2)bN+(R')3,
-(OCH2CH2)a(NHCH2CH2)bOR', -(NHCH2CH2)a(OCH2CH2)bN(R')2, -(NHCH2CH2)a(OCH2CH2)bN+(R')3, or -(NHCH2CH2)a(OCH2CH2)bOR';
each of a and b is, independently, an integer from 1 to 5;
d is 1 , 2, 3, 4, 5, or 6;
each R' is, independently, hydrogen, optionally substituted C1 -C1 0 alkyl, optionally substituted C1 -10 heteroalkyi, optionally substituted C3-C10 cycloalkyi, optionally substituted C3-C10 heterocycloalkyi, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 heterocycloalkenyl, optionally substituted C5-C10 aryl, or optionally substituted C1 -C10 heteroaryl; each of R" is, independently, hydrogen or C1 -C10 alkyl;
L is a linker; and
each E is, independently, a monosaccharide or oligosaccharide moiety,
or a pharmaceutically acceptable salt thereof.
7. A compound comprising a β-1 ,3-glucan synthase inhibitor conjugated to at least one monosaccharide or oligosaccharide moiety by way of a linker, wherein the compound is described by formula (III):
Figure imgf000162_0001
wherein R1 is a lipophilic moiety;
R2 is hydrogen or methyl;
each of R3 and R4 is, independently, hydrogen or hydroxyl;
R5 is hydrogen, methyl, -CH2CH2NH2, or -CH2(CO)NH2;
R6 is hydrogen, hydroxyl, methyl, or amino;
R7 is hydrogen or hydroxyl;
R9 is hydrogen, hydroxyl, or amino;
X is O or NH;
n is 0 or 1 ;
d is 1 , 2, 3, 4, 5, or 6;
L is a linker; and
each E is, independently, a monosaccharide or oligosaccharide
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 7, wherein the compound is described by formula (111-1 ):
Figure imgf000163_0001
wherein R1 , R2, R3, R4, R5, R6, R7, R9, X, n, d, L, and E are as defined above, or a pharmaceutically acceptable salt thereof.
9. The compound of claim 7 or 8, wherein the compound is described by formula (III-2):
Figure imgf000163_0002
wherein R1 is a lipophilic moiety;
R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2;
R6 is hydrogen or methyl;
X is O or NH;
d is 1 , 2, 3, 4, 5, or 6;
L is a linker; and
each E is, independently, a monosaccharide or oligosaccharide moiety, or a pharmaceutically acceptable salt thereof.
10. The compound of any one of claims 1 -3, wherein R8 is -(0(CH2)a)bR', -(NH(CH2)a)bR',
-(S(CH2)a)bR', -(0(CH2)a)bN(R')2, -(NH(CH2)a)bN(R')2, -(S(CH2)a)bN(R')2, -(0(CH2)a)bOR',
-(NH(CH2)a)bOR', -(S(CH2)a)bOR", -(OCH2CH2)a(NHCH2CH2)bN(R')2, -(OCH2CH2)a(NHCH2CH2)bOR', -(NHCH2CH2)a(OCH2CH2)bN(R')2, or -(NHCH2CH2)a(OCH2CH2)bOR';
each of a and b is, independently, an integer from 1 to 5; and
each R' is, independently, hydrogen or optionally substituted C1 -C5 alkyl,
or a pharmaceutically acceptable salt thereof.
1 1 . The compound of claim 10, wherein R8 is -OCH2CH2N(R')2, -NHCH2CH2N(R')2,
-(NHCH2CH2)2N(R')2, -NHCH2CH2OR', -(NHCH2CH2)2OR\ -OCH2CH2NHCH2CH2N(R')2,
-NHCH2CH2OCH2CH2N(R')2, -NHCH2CH2(OCH2CH2)2N(R')2, -NHCH2CH2(OCH2CH2)3N(R')2, -OCH2CH2NHCH2CH2OR', -NHCH2CH2OCH2CH2OR', or -NHCH2CH2(OCH2CH2)30R';
each R' is, independently, hydrogen or methyl;
or a pharmaceutically acceptable salt thereof.
12. The compound of any one of claims 4-6, wherein R8 is -(0(CH2)a)bR', -(NH(CH2)a)bR',
-(S(CH2)a)bR', -(0(CH2)a)bN(R')2, -(NH(CH2)a)bN(R")2, -(S(CH2)a)bN(R')2, -(0(CH2)a)bOR',
-(NH(CH2)a)bOR', -(S(CH2)a)bOR", -(OCH2CH2)a(NHCH2CH2)bN(R')2, -(OCH2CH2)a(NHCH2CH2)bOR', -(NHCH2CH2)a(OCH2CH2)bN(R')2, or -(NHCH2CH2)a(OCH2CH2)bOR';
each of a and b is, independently, an integer from 1 to 5; and
each R' is, independently, hydrogen or optionally substituted C1 -C5 alkyl; and
each R" is, independently, hydrogen, or C1 -C10 alkyl,
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 12, wherein R8 is -OCH2CH2N(R')2, -NHCH2CH2N(R")2,
-(NHCH2CH2)2N(R")2, -NHCH2CH2OR', -(NHCH2CH2)20R', -OCH2CH2NHCH2CH2N(R')2,
-NHCH2CH2OCH2CH2N(R')2, -NHCH2CH2(OCH2CH2)2N(R')2, -NHCH2CH2(OCH2CH2)3N(R')2, -OCH2CH2NHCH2CH2OR', -NHCH2CH2OCH2CH2OR', or -NHCH2CH2(OCH2CH2)30R';
each R' is, independently, hydrogen or methyl;
each R" is, independently, hydrogen or methyl;
or a pharmaceutically acceptable salt thereof.
14. The compound of any one of claims 1-6, wherein R8 is
Figure imgf000165_0001
15. The compound of any one of claims 1-6, wherein R8 is -(O(CH2)a)bN+(R’)3, -(NH(CH2)a)bN+(R’)3, -(S(CH2)a)bN+(R’)3, -(OCH2CH2)a(NHCH2CH2)bN+(R’)3, or -(NHCH2CH2)a(OCH2CH2)bN+(R’)3;
each of a and b is, independently, an integer from 1 to 5; and
each R’ is, independently, hydrogen or optionally substituted C1-C5 alkyl,
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 15, wherein R8 is -OCH2CH2N+(R’)3, -(OCH2CH2)2N+(R’)3,
-NHCH2CH2N+(R’)3, or–(NHCH2CH2)2N+(R’)3;
each R’ is, independently, hydrogen or methyl,
or a pharmaceutically acceptable salt thereof.
17. The com ound of claim 15 or 16, wherein R8 is
Figure imgf000166_0001
18. The compound of any one of claims 1 -6, wherein R' is
Figure imgf000166_0002
wherein each RA is, independently, hydrogen or optionally substituted C1 -C1 0 alkyl.
19. The compound of any one of claims 1 -3, wherein the compound is described by formula (I-3):
Figure imgf000167_0001
wherein R1 is a lipophilic moiety;
R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2;
R6 is hydrogen or methyl;
d is 1 , 2, 3, or 4;
each E is, independently, a monosaccharide or oligosaccharide moiety,
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 19, wherein the compound is described by formula (I-4) or (I-5):
Figure imgf000167_0002
wherein R1 is a lipophilic moiety;
or a pharmaceutically acceptable salt thereof.
21 . The compound of any one of claims 1 -3, wherein the compound is described by formula (I-6):
Figure imgf000168_0001
wherein R1 is a lipophilic moiety;
R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2;
R6 is hydrogen or methyl;
d is 1 , 2, 3, or 4;
each E is, independently, a monosaccharide or oligosaccharide
or a pharmaceutically acceptable salt thereof.
22. The compound of claim 21 , wherein the compound is described by formula (I-7):
Figure imgf000168_0002
wherein R1 is a lipophilic moiety;
or a pharmaceutically acceptable salt thereof.
23. The compound of any one of claims 1 -3, wherein the compound is described by formula (I-8):
Figure imgf000169_0001
wherein R1 is a lipophilic moiety;
R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2;
R6 is hydrogen or methyl;
d is 1 , 2, 3, or 4;
each E is, independently, a monosaccharide or oligosaccharide moiety,
or a pharmaceutically acceptable salt thereof.
24. The compound of claim 23, wherein the compound is described by formula (I-9) or (1-10):
Figure imgf000169_0002
wherein R1 is a lipophilic moiety;
or a pharmaceutically acceptable salt thereof.
25. The compound of any one of claims 4-6, wherein the compound is described by formula (11-3):
Figure imgf000170_0001
wherein R1 is a lipophilic moiety;
R6 is hydrogen or methyl;
d is 1 , 2, 3, or 4;
each E is, independently, a monosaccharide or oligosaccharide moiety,
or a pharmaceutically acceptable salt thereof.
26. The compound of claim 25, wherein the compound is described by formula (M-4):
Figure imgf000170_0002
wherein R1 is a lipophilic moiety;
or a pharmaceutically acceptable salt thereof.
27. The compound of any one of claims 4-6, wherein the compound is described by formula (11-5):
Figure imgf000171_0001
wherein R1 is a lipophilic moiety;
R6 is hydrogen or methyl;
d is 1 , 2, 3, or 4;
each E is, independently, a monosaccharide or oligosaccharide moiety,
or a pharmaceutically acceptable salt thereof.
28. The compound of claim 27, wherein the compound is described by formula (II-6):
Figure imgf000171_0002
wherein R1 is a lipophilic moiety;
or a pharmaceutically acceptable salt thereof.
29. The compound of any one of claims 4-6, wherein the compound is described by formula (11-7):
Figure imgf000172_0001
wherein R1 is a lipophilic moiety;
R6 is hydrogen or methyl;
d is 1 , 2, 3, or 4;
each E is, independently, a monosaccharide or oligosaccharide moiety,
or a pharmaceutically acceptable salt thereof.
30. The compound of claim 29, wherein the compound is described by formula (II-8):
Figure imgf000172_0002
wherein R1 is a lipophilic moiety;
or a pharmaceutically acceptable salt thereof.
31 . The compound of any one of claims 7-9, wherein the compound is described by formula (III-3):
Figure imgf000173_0001
wherein R1 is a lipophilic moiety;
R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2;
R6 is hydrogen or methyl;
d is 1 , 2, 3, or 4;
each E is, independently, a monosaccharide or oligosaccharide moiety,
or a pharmaceutically acceptable salt thereof.
32. The compound of claim 31 , wherein the compound is described by formula (MI-4):
Figure imgf000173_0002
wherein R1 is a lipophilic moiety;
or a pharmaceutically acceptable salt thereof.
33. The compound of any one of claims 1 -32, wherein:
Figure imgf000174_0001
each of X and Y is, independently, optionally substituted alkyl, optionally substituted heteroalkyi, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, or optionally substituted heteroarylene, or is absent;
Z is optionally substituted alkyl, optionally substituted heteroalkyi, optionally substituted alkenyl, optionally substituted heteroalkenyl, optionally substituted alkynyl, optionally substituted heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, or is absent;
at least one of X, Y, and Z is present; and
wherein X and Y, when present, are joined by a direct bond, -0-, or -CH2=CH2- and Y and Z, when present, are joined by a direct bond, -0-, or -CH2=CH2- or a pharmaceutically acceptable salt thereof.
34. The compound of claim 33, wherein X, Y, and Z, together, form
Figure imgf000174_0002
wherein R' is an optionally substituted C1 -C10 alkyl, or a pharmaceutically acceptable salt thereof.
35. The compound of claim 33, wherein X, Y, and Z, together, form
Figure imgf000174_0003
wherein RB is optionally substituted C1 -C10 alkyl, or a pharmaceutically acceptable salt thereof.
36. The compound of claim 33, wherein X, Y, and Z, together, form
Figure imgf000174_0004
wherein RB is optionally substituted C1 -C8 alkyl, or a pharmaceutically acceptable salt thereof.
37. The compound of claim 33, wherein X, Y, and Z, together, form
Figure imgf000175_0001
wherein RB is optionally substituted C1 -C6 alkyl, or a pharmaceutically acceptable salt thereof.
38. The compound of any one of claims 1 -37, wherein R1 is
Figure imgf000175_0002
39. The compound of any one of claims 1 -3, wherein the compound is described by formula (1-1 1 ) or (1-12):
Figure imgf000176_0001
wherein R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2;
R6 is hydrogen or methyl;
RB is optionally substituted C1 -C6 alkyl;
d is 1 , 2, 3, or 4;
each E is, independently, a monosaccharide or oligosaccharide moiety,
or a pharmaceutically acceptable salt thereof.
40. The compound of claim 39, wherein the compound is described by formula (1-13) or (1-14):
Figure imgf000176_0002
wherein RB is optionally substituted C1 -C6 alkyl,
or a pharmaceutically acceptable salt thereof.
41 . The compound of any one of claims 1 -3, wherein the compound is described by formula (1-15):
Figure imgf000177_0001
wherein R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2;
R6 is hydrogen or methyl;
d is 1 , 2, 3, or 4;
each E is, independently, a monosaccharide or oligosaccharide moiety,
or a pharmaceutically acceptable salt thereof.
42. The compound of claim 41 , wherein the compound is described by formula (1-16):
Figure imgf000177_0002
or a pharmaceutically acceptable salt thereof.
43. The compound of any one of claims 1 -3, wherein the compound is described by formula (1-17) or (1-18):
Figure imgf000178_0001
wherein R5 is methyl, -CH2CH2NH2, or -CH2(CO)NH2;
R6 is hydrogen or methyl;
RB is optionally substituted C1 -C6 alkyl;
d is 1 , 2, 3, or 4;
each E is, independently, a monosaccharide or oligosaccharide moiety,
or a pharmaceutically acceptable salt thereof.
44. The compound of claim 43, wherein the compound is described by formula (1-19) or (I-20):
Figure imgf000178_0002
wherein RB is optionally substituted C1 -C6 alkyl,
or a pharmaceutically acceptable salt thereof.
45. The compound of any one of claims 4-6, wherein the compound is described by formula (II-9) or (II-10):
Figure imgf000179_0001
wherein R6 is hydrogen or methyl;
RB is optionally substituted C1-C6 alkyl;
d is 1, 2, 3, or 4;
each E is, independently, a monosaccharide or oligosaccharide moiety,
or a pharmaceutically acceptable salt thereof.
46. The compound of claim 45, wherein the compound is described by formula (II-11) or (II-12):
Figure imgf000179_0002
wherein RB is optionally substituted C1-C6 alkyl,
or a pharmaceutically acceptable salt thereof.
47. The compound of any one of claims 4-6, wherein the compound is described by formula (11-13) or ( -14):
Figure imgf000180_0001
wherein R6 is hydrogen or methyl;
RB is optionally substituted C1 -C6 alkyl;
d is 1 , 2, 3, or 4;
each E is, independently, a monosaccharide or oligosaccharide moiety,
or a pharmaceutically acceptable salt thereof.
48. The compound of claim 47, wherein the compound is described by formula (11-15) or (11-16):
Figure imgf000180_0002
wherein RB is optionally substituted C1 -C6 alkyl,
or a pharmaceutically acceptable salt thereof.
49. The compound of any one of claims 4-6, wherein the compound is described by formula (11-17) or -18):
Figure imgf000181_0001
wherein R6 is hydrogen or methyl;
RB is optionally substituted C1 -C6 alkyl;
d is 1 , 2, 3, or 4;
each E is, independently, a monosaccharide or oligosaccharide moiety,
or a pharmaceutically acceptable salt thereof.
50. The compound of claim 49, wherein the compound is described by formula (11-19) or (M-20):
Figure imgf000181_0002
wherein RB is optionally substituted C1 -C6 alkyl,
or a pharmaceutically acceptable salt thereof.
51 . The compound of any one of claims 7-9, wherein the compound is described by formula (III-5) or (III-
Figure imgf000182_0001
wherein d is 1 , 2, 3, or 4;
RB is optionally substituted C1 -C6 alkyl,
each E is, independently, a monosaccharide or oligosaccharide moiety,
or a pharmaceutically acceptable salt thereof.
52. The compound of any one of claims 1 -51 , wherein L is a bond.
53. The compound of any one of claims 1 -51 , wherein L is described by formula (L-l):
Figure imgf000182_0002
wherein I1 is a bond attached to the β-1 ,3-glucan synthase inhibitor;
I2 is a bond attached to E;
each of U1 , U2, U3, and U4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C1 -C15 heteroarylene;
each of V1 , V2, V3, V4, and V5 is, independently, O, S, NR', P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino;
wherein R' is H, optionally substituted C1 -C20 alkyl, optionally substituted C1 -C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C5-C15 heteroaryl ; and
each of f, g, h, i, j, k, I, m, and n is, independently, 0 or 1 .
54. The compound of claim 53, wherein each of U1 , U2, U3, and U4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C1 5 arylene, or optionally substituted C1 -C15 heteroarylene;
each of V1 , V2, V3, V4, and V5 is, independently, O, S, NR', P, carbonyl ;
R' is H or optionally substituted C1 -C20 alkyl; and
each of f, g, h, i, j, k, I, m, and n is, independently, 0 or 1 .
55. The compound of claim 53 or 54, wherein L is described by formula (L-11 ):
Figure imgf000183_0001
wherein I1 is a bond attached to the β-1 ,3-glucan synthase inhibitor;
I2 is a bond attached to E;
each of U1 , U2, U3, and U4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C1 5 arylene, or optionally substituted C1 -C15 heteroarylene;
each of V2, V3, V4, and V5 is, independently, O, S, NR', P, carbonyl;
R' is H or optionally substituted C1 -C20 alkyl; and
each of h, i, j, k, I, m, and n is, independently, 0 or 1 .
56. The compound of claim 55, wherein L is described by formula (L-I2):
Figure imgf000183_0002
wherein I1 is a bond attached to the β-1 ,3-glucan synthase inhibitor;
I2 is a bond attached to E; each of U1 , U2, U3, and U4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C1 5 arylene, or optionally substituted C1 -C15 heteroarylene;
each of V2, V3, and V4 is, independently, O, S, NR', P, carbonyl;
R' is H or optionally substituted C1 -C20 alkyl; and
each of h, i, j, k, I, and m is, independently, 0 or 1 .
57. The compound of claim 55, wherein L is described by formula (L-I3):
Figure imgf000184_0001
wherein I1 is a bond attached to the β-1 ,3-glucan synthase inhibitor;
I2 is a bond attached to E;
each of U1 , U2, U3, and U4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C1 5 arylene, or optionally substituted C1 -C15 heteroarylene;
each of V2, V3, and V4 is, independently, O, S, NR', P, carbonyl;
R' is H or optionally substituted C1 -C20 alkyl; and
each of h, i, j, k, I, and m is, independently, 0 or 1 .
58. The compound of claim 55, wherein L is described by formula (L-I4):
Figure imgf000184_0002
wherein I1 is a bond attached to the β-1 ,3-glucan synthase inhibitor;
I2 is a bond attached to E;
each of U1 , U2, U3, and U4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C1 5 arylene, or optionally substituted C1 -C15 heteroarylene; each of V2, V3, and V4 is, independently, O, S, NR', P, carbonyl; R' is H or optionally substituted C1 -C20 alkyl; and
each of h, i, j, k, I, and m is, independently, 0 or 1 .
59. The compound of any one of claims 53-55, wherein L is
Figure imgf000185_0001
wherein each of p, q, r, and s is, independently, an integer from 1 to 10.
60. The compound of any one of claims 1-51, wherein L is described by formula (L-II):
Figure imgf000186_0001
wherein:
LA is described by formula GA1-(ZA1)g1-(YA1)h1-(ZA2)i1-(YA2)j1-(ZA3)k1-(YA3)l1-(ZA4)m1-(YA4)n1- (ZA5)o1-GA2;
LB is described by formula GB1-(ZB1)g2-(YB1)h2-(ZB2)i2-(YB2)j2-(ZB3)k2-(YB3)l2-(ZB4)m2-(YB4)n2-(ZB5)o2- GB2;
LC is described by formula GC1-(ZC1)g3-(YC1)h3-(ZC2)i3-(YC2)j3-(ZC3)k3-(YC3)l3-(ZC4)m3-(YC4)n3- (ZC5)o3-GC2;
GA1 is a bond attached to N in formula (L-II);
GA2 is a bond attached to the β-1,3-glucan synthase inhibitor;
GB1 is a bond attached to N in formula (L-II);
GB2 is a bond attached to a first monosaccharide or oligosaccharide moiety, E1;
GC1 is a bond attached to N in formula (L-II);
GC2 is a bond attached to a second monosaccharide or oligosaccharide moiety, E2;
each of YA1, YA2, YA3, YA4, YB1, YB2, YB3, YB4, YC1, YC2, YC3, and YC4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C1-C15 heteroarylene;
each of ZA1, ZA2, ZA3, ZA4, ZA5, ZB1, ZB2, ZB3, ZB4, ZB5, ZC1, ZC2, ZC3, ZC4, and ZC5 is, independently, O, S, NRi, P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino;
wherein Ri is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C5-C15 heteroaryl; and
each of g1, h1, i1, j1, k1, l1, m1, n1, o1, g2, h2, i2, j2, k2, l2, m2, n2, o2, g3, h3, i3, j3, k3, l3, m3, n3, and o3 is, independently, 0 or 1.
61 . The compound of claim 60, wherein each of YA1 , YA2, YA3, YA4, YB1 , YB2, YB3, YB4, YC1 , YC2, YC3, and YC4 is, independently, optionally substituted C1 -C20 alkylene, optionally substituted C1 -C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20
heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5-C15 arylene, or optionally substituted C1 -C15 heteroarylene;
each of ZA1 , ZA2, ZA3, ZA4, ZA5, ZB1 , ZB2, ZB3, ZB4, ZB5, ZC1 , ZC2, ZC3, ZC4, and ZC5 is, independently, O, S, NR', P, carbonyl;
R' is H or optionally substituted C1 -C20 alkyl; and
each of g1 , hi , i1 , j1 , k1 , 11 , ml , n1 , o1 , g2, h2, i2, j2, k2, I2, m2, n2, o2, g3, h3, i3, j3, k3, I3, m3, n3, and o3 is, independently, 0 or 1 .
62. The compound of claim 60 or 61 , wherein L is
Figure imgf000187_0001
wherein each of p, q, r, s, and t is, independently, an integer from 1 to 10.
63. The compound of claim 62, wherein L is
Figure imgf000187_0002
64. The compound of claim 60 or 61 , wherein L is
Figure imgf000188_0001
wherein each of p, q, r, s, t, and u is, independently, an integer from 1 to 10.
65. The compound of any one of claims 1-51, wherein L is described by formula (L-III):
Figure imgf000189_0001
wherein:
LA is described by formula GA1-(ZA1)g1-(YA1)h1-(ZA2)i1-(YA2)j1-(ZA3)k1-(YA3)l1-(ZA4)m1-(YA4)n1- (ZA5)o1-GA2;
LB is described by formula GB1-(ZB1)g2-(YB1)h2-(ZB2)i2-(YB2)j2-(ZB3)k2-(YB3)l2-(ZB4)m2-(YB4)n2-(ZB5)o2- GB2;
LC is described by formula GC1-(ZC1)g3-(YC1)h3-(ZC2)i3-(YC2)j3-(ZC3)k3-(YC3)l3-(ZC4)m3-(YC4)n3- (ZC5)o3-GC2;
LD is described by formula GD1-(ZD1)g4-(YD1)h4-(ZD2)i4-(YD2)j4-(ZD3)k4-(YD3)l4-(ZD4)m4-(YD4)n4- (ZD5)o4-GD2;
LE is described by formula GE1-(ZE1)g5-(YE1)h5-(ZE2)i5-(YE2)j5-(ZE3)k5-(YE3)l5-(ZE4)m5-(YE4)n5- (ZE5)o5-GE2, or is hydrogen;
LF is described by formula GF1-(ZF1)g6-(YF1)h6-(ZF2)i6-(YF2)j6-(ZF3)k6-(YF3)l6-(ZF4)m6-(YF4)n6-(ZF5)o6- GF2;
LG is described by formula GG1-(ZG1)g7-(YG1)h7-(ZG2)i7-(YG2)j7-(ZG3)k7-(YG3)l7-(ZG4)m7-(YG4)n7- (ZG5)o7-GG2, or is hydrogen;
GA1 is a bond attached to NA in formula (L-III);
GA2 is a bond attached to the β-1,3-glucan synthase inhibitor;
GB1 is a bond attached to NA in formula (L-III);
GB2 is a bond attached to NB in formula (L-III);
GC1 is a bond attached to NA in formula (L-III);
GC2 is a bond attached to NC in formula (L-III);
GD1 is a bond attached to NB in formula (L-III);
GD2 is a bond attached to a first monosaccharide or oligosaccharide moiety, E1;
GE1 is a bond attached to NB in formula (L-III);
GE2 is a bond attached to a second monosaccharide or oligosaccharide moiety, E2;
GF1 is a bond attached to NC in formula (L-III);
GF2 is a bond attached to a third monosaccharide or oligosaccharide moiety, E3;
GG1 is a bond attached to NC in formula (L-III);
GG2 is a bond attached to a fourth monosaccharide or oligosaccharide moiety, E4; each of YA1, YA2, YA3, YA4, YB1, YB2, YB3, YB4, YC1, YC2, YC3, YC4, YD1, YD2, YD3, YD4, YE1, YE2, YE3, YE4, YF1, YF2, YF3, YF4, YG1, YG2, YG3, and YG4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C1-C15 heteroarylene;
each of ZA1, ZA2, ZA3, ZA4, ZA5, ZB1, ZB2, ZB3, ZB4, ZB5, ZC1, ZC2, ZC3, ZC4, ZC5, ZD1, ZD2, ZD3, ZD4, ZD5, ZE1, ZE2, ZE3, ZE4, ZE5, ZF1, ZF2, ZF3, ZF4, ZF5, ZG1, ZG2, ZG3, ZG4, and ZG5 is, independently, O, S, NRi, P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino;
wherein Ri is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C5-C15 heteroaryl;
each of g1, h1, i1, j1, k1, l1, m1, n1, o1, g2, h2, i2, j2, k2, l2, m2, n2, o2, g3, h3, i3, j3, k3, l3, m3, n3, o3, g4, h4, i4, j4, k4, l4, m4, n4, o4, g5, h5, i5, j5, k5, l5, m5, n5, o5, g6, h6, i6, j6, k6, l6, m6, n6, o6, g7, h7, i7, j7, k7, l7, m7, n7, and o7 is, independently, 0 or 1; and
each of NA, NB, and NC is a nitrogen.
66. The compound of claim 65, wherein each of YA1, YA2, YA3, YA4, YB1, YB2, YB3, YB4, YC1, YC2, YC3, YC4, YD1, YD2, YD3, YD4, YE1, YE2, YE3, YE4, YF1, YF2, YF3, YF4, YG1, YG2, YG3, and YG4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4- C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C5- C15 arylene, or optionally substituted C1-C15 heteroarylene;
each of ZA1, ZA2, ZA3, ZA4, ZA5, ZB1, ZB2, ZB3, ZB4, ZB5, ZC1, ZC2, ZC3, ZC4, ZC5, ZD1, ZD2, ZD3, ZD4, ZD5, ZE1, ZE2, ZE3, ZE4, ZE5, ZF1, ZF2, ZF3, ZF4, ZF5, ZG1, ZG2, ZG3, ZG4, and ZG5 is, independently, O, S, NRi, P, carbonyl;
Ri is H or optionally substituted C1-C20 alkyl; and
each of g1, h1, i1, j1, k1, l1, m1, n1, o1, g2, h2, i2, j2, k2, l2, m2, n2, o2, g3, h3, i3, j3, k3, l3, m3, n3, o3, g4, h4, i4, j4, k4, l4, m4, n4, o4, g5, h5, i5, j5, k5, l5, m5, n5, o5, g6, h6, i6, j6, k6, l6, m6, n6, o6, g7, h7, i7, j7, k7, l7, m7, n7, and o7 is, independently, 0 or 1.
67. The compound of claim 65 or 66, wherein L is
Figure imgf000191_0001
wherein each of p, q, r, s, t, u, v, w, x, y, and z is, independently, an integer from 1 to 10.
68. The compound of claim 67, wherein L is
Figure imgf000191_0002
69. The compound of claim 65 or 66, wherein L is
Figure imgf000191_0003
wherein each of p, q, r, s, and t is, independently, an integer from 1 to 10.
70. The compound of any one of claims 1-51, wherein L is described by formula (L-IV):
Figure imgf000191_0004
wherein:
LA is described by formula GA1-(ZA1)g1-(YA1)h1-(ZA2)i1-(YA2)j1-(ZA3)k1-(YA3)l1-(ZA4)m1-(YA4)n1- (ZA5)o1-GA2; LB is described by formula GB1-(ZB1)g2-(YB1)h2-(ZB2)i2-(YB2)j2-(ZB3)k2-(YB3)l2-(ZB4)m2-(YB4)n2-(ZB5)o2- GB2;
LC is described by formula GC1-(ZC1)g3-(YC1)h3-(ZC2)i3-(YC2)j3-(ZC3)k3-(YC3)l3-(ZC4)m3-(YC4)n3- (ZC5)o3-GC2;
LD is described by formula GD1-(ZD1)g4-(YD1)h4-(ZD2)i4-(YD2)j4-(ZD3)k4-(YD3)l4-(ZD4)m4-(YD4)n4- (ZD5)o4-GD2, or is hydrogen;
GA1 is a bond attached to N in formula (L-IV);
GA2 is a bond attached to the β-1,3-glucan synthase inhibitor;
GB1 is a bond attached to C in formula (L-IV);
GB2 is a bond attached to a first monosaccharide or oligosaccharide moiety, E1;
GC1 is a bond attached to C in formula (L-IV);
GC2 is a bond attached to a second monosaccharide or oligosaccharide moiety, E2;
GD1 is a bond attached to C in formula (L-IV);
GD2 is a bond attached to a third monosaccharide or oligosaccharide moiety, E3;
each of YA1, YA2, YA3, YA4, YB1, YB2, YB3, YB4, YC1, YC2, YC3, YC4, YD1, YD2, YD3, and YD4 is, independently, optionally substituted C1-C20 alkylene, optionally substituted C1-C20 heteroalkylene, optionally substituted C2-C20 alkenylene, optionally substituted C2-C20 heteroalkenylene, optionally substituted C2-C20 alkynylene, optionally substituted C2-C20 heteroalkynylene, optionally substituted C3-C20 cycloalkylene, optionally substituted C3-C20 heterocycloalkylene, optionally substituted C4-C20 cycloalkenylene, optionally substituted C4-C20 heterocycloalkenylene, optionally substituted C8-C20 cycloalkynylene, optionally substituted C8-C20 heterocycloalkynylene, optionally substituted C5-C15 arylene, or optionally substituted C2-C15 heteroarylene;
each of ZA1, ZA2, ZA3, ZA4, ZA5, ZB1, ZB2, ZB3, ZB4, ZB5, ZC1, ZC2, ZC3, ZC4, ZC5, ZD1, ZD2, ZD3, ZD4, and ZD5 is, independently, O, S, NRi, P, carbonyl, thiocarbonyl, sulfonyl, phosphate, phosphoryl, or imino;
Ri is H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 heteroalkyl, optionally substituted C2-C20 alkenyl, optionally substituted C2-C20 heteroalkenyl, optionally substituted C2-C20 alkynyl, optionally substituted C2-C20 heteroalkynyl, optionally substituted C3-C20 cycloalkyl, optionally substituted C3-C20 heterocycloalkyl, optionally substituted C4-C20 cycloalkenyl, optionally substituted C4-C20 heterocycloalkenyl, optionally substituted C8-C20 cycloalkynyl, optionally substituted C8-C20 heterocycloalkynyl, optionally substituted C5-C15 aryl, or optionally substituted C2-C15 heteroaryl; and
each of g1, h1, i1, j1, k1, l1, m1, n1, o1, g2, h2, i2, j2, k2, l2, m2, n2, o2, g3, h3, i3, j3, k3, l3, m3, n3, o3, g4, h4, i4, j4, k4, l4, m4, n4, and o4 is, independently, 0 or 1;
or a pharmaceutically acceptable salt thereof.
71 . The compound of claim 70, wherein L is
Figure imgf000193_0001
wherein each of p, q, r, s, and t is, independently, an integer from 1 to 10.
72. The compound of any one of claims 1 -71 , wherein E is
Figure imgf000193_0002
73. The compound of claim 72, wherein E is
Figure imgf000193_0003
74. The compound of any one of claims 1 -73, wherein the monosaccharide moiety comprises an optionally substituted C6-C9 monosaccharide residue.
75. The compound of any one of claims 1 -73, wherein the oligosaccharide moiety comprises 2-18 optionally substituted C6-C9 monosaccharide residues.
76. The compound of claim 74 or 75, wherein each of the optionally substituted C6-C9
monosaccharide residues is, independently, glucose (Glc), galactose (Gal), mannose (Man), allose (All), altrose (Alt), gulose (Gul), idose (Ido), talose (Tal), fucose (Fuc), rhamnose (Rha or L-Rha), thia-rhamnose (thia-Rha or thia-L-Rha), quinovose (Qui), 2-deoxyglucose (2-dGlc), glucosamine (GlcN), galactosamine (GaIN), mannosamine (ManN), fucosamine (FucN), quinovosamine (QuiN), N-Acetyl-glucosamine (GlcNAc), N-Acetyl-galactosamine (GalNAc), N-Acetyl-mannosamine
(ManNAc), N-acetyl-fucosamine (FucNAc), N-acetyl-quinovosamine (QuiNAc), glucuronic acid (GIcA), galacturonic acid (GalA), mannuronic acid (ManA), iduronic acid (IdoA), sialic acid (Sia), neuraminic acid (Neu), N-Acetyl-neuraminic acid (Neu5Ac), N-Glycolyl-neuraminic acid (Neu5Gc), glucitol (Glc-ol), galactitol (Gal-ol), mannitol (Man-ol), fructose (Fru), sorbose (Sor), tagatose (Tag), thevetose (The), acofriose (Aco), digitoxose (Dig), cymarose (Cym), abequose (Abe), colitose (Col), tyvelose (Tyv), ascarylose (Asc), paratose (Par), or N-acetyl-muramic acid (MurNAc).
77. The compound of any one of claims 74-76, wherein each of the optionally substituted C6-C9 monosaccharide residues is, independently, an optionally substituted C6 monosaccharide residue.
78. The compound of claim 77, wherein the optionally substituted C6 monosaccharide residue is
Figure imgf000194_0001
79. The compound of claim 78, wherein the optionally substituted C6 monosaccharide residue is
Figure imgf000194_0002
80. The compound of claim 79, wherein the optionally substituted C6 monosaccharide residue is
Figure imgf000195_0001
81 . The compound of any one of claims 1 -71 , wherein E is any one of the moieties in Tables 2A and 2B.
82. The compound of any one of claims 1 -81 , wherein E directly or indirectly activates an immune cell.
83. The compound of any one of claims 1 -82, wherein E is a ligand to an innate immune receptor.
84. The compound of claim 83, wherein the innate immune receptor is AICL, BDCA2, CLEC2, Complement receptor 3, Complement receptor 4, DCIR, dectin-1 , dectin-2, DC-SIGN, a C-Type lectin receptor, MMR, langerin, TLR2, Mincle, MBL, or KCR.
85. The compound of claims 1 -84, wherein E binds to an antibody.
86. The compound of claim 85, wherein the antibody is a natural antibody.
87. The compound of claim 86, wherein the natural antibody is an antibody of the immunoglobulin M (IgM) isotype.
88. The compound of any one of claims 85-87, wherein E is any one of the moieties in Tables 2A and 2B.
89. The compound of any one of claims 85-88, wherein the antibody is anti-aGal antibody or anti- aRha antibody.
90. A compound selected from
Figure imgf000196_0001
Figure imgf000197_0001
or pharmaceutically acceptable salts thereof.
91. The compound of claim 90, wherein the pharmaceutically acceptable salt of the compound is an formate salt.
92. The compound of claim 90, wherein the compound is Compound 1
Figure imgf000197_0002
or a pharmaceutically acceptable salt thereof.
93. The compound of claim 92, wherein the pharmaceutically acceptable salt of Compound 1 is an formate salt.
94. The compound of claim 90, wherein the compound is Compound 4a
Figure imgf000198_0001
or a pharmaceutically acceptable salt thereof.
95. The compound of claim 94, wherein the pharmaceutically acceptable salt of Compound 4a is an formate salt.
96. A pharmaceutical composition comprising a compound of any one of claims 1 -95, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
97. A method of treating a fungal infection in a subject, the method comprising administering to the subject a pharmaceutical composition of claim 96 in an amount sufficient to treat the infection.
98. A method of stabilizing or inhibiting a fungal infection in a subject, the method comprising administering to the subject a pharmaceutical composition of claim 97 in an amount sufficient to stabilize or inhibit the infection.
99. The method of claim 98, wherein the subject is immunocompromised.
100. The method of any one of claims 97-99, wherein the pharmaceutical composition is administered intravenously.
101 . The method of any one of claims 97-99, wherein the pharmaceutical composition is administered subcutaneously.
102. The method of any one of claims 97-99, wherein the pharmaceutical composition is administered topically.
103. The method of any one of claims 97-99, wherein the pharmaceutical composition is administered orally.
104. The method of any one of claims 97-103, wherein the pharmaceutical composition is administered to treat a blood stream infection or tissue infection in the subject.
105. The method of claim 97-104, wherein the infection is selected from candidemia, invasive candidiasis, tinea capitis, tinea corporis, tinea pedis, onychomycosis, perionychomycosis, pityriasis versicolor, oral thrush, vaginal candidiasis, respiratory tract candidiasis, biliary candidiasis, eosophageal candidiasis, urinary tract candidiasis, systemic candidiasis, mucocutaneous candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, sporotrichosis, fungal sinusitis, or chronic sinusitis.
106. The method of claim 105, wherein the infection is candidemia or invasive candidiasis.
107. The method of claim 97-106, wherein the fungal infection is an infection of Candida albicans, C. glabrata, C. dubliniensis, C. krusei, C. parapsilosis, C. tropicalis, C. orthopsilosis, C. guilliermondii, C. rugosa, C. auris, or C. lusitaniae, Aspergillus fumigatus, A. flavus, A. terreus, A. niger, A. candidus, A. clavatus, or A. ochraceus.
108. The method of any one of claims 97-107, wherein the fungal infection is an infection of Fusarium solani, Fusarium oxysporum, Fusarium verticillioides, Fusarium moniliforme, Scedosporium apiospermum, Scedosporium prolificans, Mucor circinelloides, Mucor azygosporus, Mucor circinelloides, Rhizopus oryzae, Rizomucor pusillus, Cunninghamella bertholletiae, Apophysomyces elegans, Absidia corymbifera, Saksenaea vasiformis, Acremonium strictum, Paecilomyces lilacinus, Paecilomyces variotii, Trichoderma longibrachiatum, Trichoderma harzianum, Trichoderma koningii, Trichoderma pseudokoningii, Trichoderma citrinovirde, Trichoderma viride, Stachybotrys chartarum, Trichophyton rubrum, Trichophyton mentagrophytes, Trichophyton tonsurans, Trichophyton violaceum, Microsporum gypseum, Epidermophyton floccosum, Sporothrix schenckii, Histoplasma capsulatum, Coccidioides immitis, Coccidioides posadasii, Blastomyces dermatitidis,
Paracoccidioides brasiliensis, Cladosporium trichoides, Exophiala jeanselmei, Exserohilum rostratum, Exserohilum longirostratum, or Exserohilum mcginnisii.
109. The method of any one of claims 97-107, wherein the fungal infection is a dermatophyte infection.
1 10. The method of any one of claims 97-109, wherein the pharmaceutical composition comprises any one of Compounds 1 -6, or a pharmaceutically acceptable salt thereof.
1 1 1 . A method of stabilizing or inhibiting the growth of fungi, or killing fungi, the method comprising contacting the fungi or a site susceptible to fungal growth with a compound of any of claims 1 -95, or a pharmaceutically acceptable salt thereof.
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