TW201625311A - Compositions and methods for the treatment of fungal infections - Google Patents

Abstract

Compositions and methods for the treatment of fungal infections including compounds containing a chemotaxis receptor ligand moiety and a polyene antifungal agent moiety are disclosed. In particular, compounds containing a polyene antifungal agent and a formyl peptide receptor ligand can be used in the treatment of fungal infections caused by a fungus of the genus Aspergillus or Candida.

Description

Methods and compositions for the treatment of fungal infections

The need for new antifungal treatments is important and particularly critical in the medical field. Immunocompromised patients may be the biggest challenge for modern health care services. The most common pathogens associated with invasive fungal infections are the opportunistic yeast Candida albicans and the filamentous fungus Aspergillus fumigatus .

The development of antifungal therapy has been a constant challenge. The US Food and Drug Administration (FDA) has approved several different classes of antifungal agents, such as polyenes, pyrimidines, azoles, and echinocandins. Among them, the polyene antifungal agent exhibits an effective antifungal activity by breaking into the fungal film to destroy the film integrity. These polyene antifungal agents form complexes with ergosterol and structurally related sterols in the lipid bilayer, thereby altering the membrane structure and promoting leakage of cellular components. Polyene antifungal agents generally comprise a large lactone ring with from 3 to 8 conjugated carbon-carbon double bonds, and may also include a monosaccharide structure and an aromatic structure.

Even if many effective polyene macrolide antifungal has been isolated Agents, but the use of antibiotics in this category is limited by lack of absorption, high toxicity and low tolerance. Amphotericin B is still an ideal polyene antifungal agent for the treatment of life-threatening fungal infections.

Because of the lack of existing antifungal treatment, there is a change in the technical field. Good antifungal therapy for better efficiency, bioavailability, and reduced toxicity.

The present disclosure relates to methods, compositions, and methods of treating fungal infections that inhibit fungal growth. In particular, such compositions include bifunctional molecules comprising: a polyene antifungal structure, ergosterol and structurally related sterols that bind to the fungal membrane; and a chemotactic receptor Moiety, which interacts with chemotactic receptors. Such a composition is effective in a method of inhibiting fungal growth and a method of treating fungal infection, for example, an infection caused by a fungus of the genus Fusarium or Candida.

Thus, the disclosure discloses a compound (eg, a synthetic bifunctional non-antibody compound) or a pharmaceutically acceptable salt thereof, comprising, consisting essentially of, or consisting of a chemotactic receptor ligand structure E The composition is covalently bonded to the polyene antifungal structure via linker L. In some embodiments, the linker is a polypeptide. In some embodiments, the chemotactic receptor ligand structure E is attached to the linker L via a guanamine bond and/or the polyene antifungal structure is attached to the linker L via a guanamine bond. In some embodiments, the linker is attached to the carbonyl group of the chemotactic acceptor ligand structure E. In some embodiments, the compound is formed from a diamine linker. In some embodiments, the diamine linker is bonded to a carbonyl group of a polyene antifungal structure to form a guanamine bond. In some embodiments, the diamine linker is attached to the carbonyl group of the chemotactic acceptor ligand structure E to form a guanamine bond.

In some embodiments, the polyene antifungal agent is 67-121-A, 67-121-C, amphotericin B, arenomvcin B, aurenin, aureofungin A, aureotuscin, candidin, chinin, demethoxyrapamycin, dermostatin A, dermatocin B, DJ-400-B ₁ , DJ-400-B ₂ , elizabethin, eurocidin A, eurocilin B, filipin I, filipin II, filipin III, filipin IV , fungichromin, gannibamycin, hamycin, levorin A ₂ , lienomycin, lusensomycin, heptamycin ( Mycoheptin), mycoticin A, mycoticin B, natamycin, nystatin A, nystatin A ₃ , rosary beads Partricin A, partricin B, perimycin A, pimaricin, polifungin B, rapamycin, Rectilavendomvcin, rimoidin, tetramycin A, tetramycin B, tetrin A or tetrin B. In some embodiments, the polyene antifungal agent is selected from the group consisting of amphotericin B, natamycin, and nystatin. In some embodiments, the polyene antifungal agent is amphotericin B. In some embodiments, the polyene antifungal agent is natamycin.

In some embodiments, the chemotactic receptor ligand is a ligand of the forminyl peptide receptor family. In some embodiments, the chemotactic receptor ligand is a mercaptopeptide receptor 1 (FPR1), a mercaptopeptide receptor 2 (FPR2), a mercaptopeptide receptor 3 (FPR3), a ligand of the methionyl peptide receptor 1 (FPRL1) and/or the methionyl peptide receptor 2 (FPRL2). In some embodiments, the chemotactic receptor ligand is a ligand for neuropilin 1 , chemokine receptor 1 (CXCR1), and/or chemokine receptor 2 (CXCR2).

In some embodiments, the chemotactic receptor ligand is selected from the group consisting of chemotaxis Peptide, phagocytosis peptide (tuftsin peptide) and ethionyl-proline-glycine-proline (PGP) peptide.

In some embodiments, the chemotactic receptor ligand structure E is a chemotactic peptide comprising an amino acid of the formula: R ¹⁴ -X1-X2-X3-X4-X5-X6-X7 -X8-X9-式V

Wherein X1 is any amino acid residue; X2-X9 is any amino acid residue or is absent; R ¹⁴ is hydrogen or Wherein X ₁₀ is a bond, NH or O; R ¹⁵ is hydrogen, a C1-C6 alkyl group which is optionally substituted, a C1-C6 heteroalkyl group which is optionally substituted, and a C2-C6 alkene which is optionally substituted a selectively substituted C2-C6 heteroalkenyl group, a selectively substituted C2-C6 alkynyl group, a selectively substituted C2-C6 heteroalkynyl group, a selectively substituted C3-C10 cycloalkyl group, a choice Substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 cycloalkynyl, optionally substituted oxime, optionally substituted hydrazone, optionally substituted C6- C12 aryl or alternatively substituted C2-C6 heterocycle. In some embodiments, if R ¹⁴ is hydrogen then X 2 will not be absent.

In some embodiments, the chemotactic peptide comprises an amino acid of the formula: R ¹⁴ -X1-X2-X9-Formula VI

Wherein X1 is an arbitrary amino acid residue; X2 is an leucine residue, an isoleucine residue or absent; and X9 is an arbitrary amino acid residue.

In some embodiments, the chemotactic peptide comprises an amino acid of the formula: R ¹⁴ -X1-X2-X9-Form VI

Wherein X1 and X9 are each independently a hydrophobic amino acid residue, and X2 is a hydrophobic amino acid residue or is absent. In some embodiments, X1 is a methionine residue, an oxymethionine residue, or a norleucine residue. In some embodiments, X2 is an leucine residue, an isoleucine residue, or is absent. In some embodiments, X9 is a phenylalanine residue, a 1-amino-2-phenylcyclopropane-1-carboxylic acid residue, a methionine residue, (O-benzyl)serine ( O-benzyl)serine) residue, 2-pyridylylalanine residue or 4-pyridylalanine residue.

In some embodiments, R ¹⁴ is —C(O)H. In some embodiments, R ¹⁴ is —C(O)CH ₃ . In some embodiments, R ¹⁴ is —C(O)OCH ₂ CH(CH ₃ ) ₂ . In some embodiments, R ¹⁴ is —C(O)NH—(4-chlorophenyl).

In some embodiments, the chemotactic receptor ligand structure E is selected from the group consisting of

Wherein R ²⁴ is H or a C1-C3 alkyl group; wherein q ¹ is 1 or 2; and wherein -NH-A ⁴ -C(O)- and -NH-A ⁵ -C(O)- are each independently a base Amino acid residue;

Wherein R ²⁵ is H, C1-C6 alkyl or phenyl; wherein t ¹ is 1 or 2; wherein u ¹ is 1, 2, 3, 4, 5 or 6; and wherein v ¹ is 1 or 2;

Wherein -NH-A ¹ -C(O)- and -NH-A ² -C(O)- are each independently a hydrophobic amino acid residue; wherein -NH-A ³ -C(O)- is hydrophobic Amino acid residue or absent; wherein R ²⁶ is H, C1-C6 alkyl, OR ²⁸ or NR ²⁹ ; wherein R ²⁷ is heterocyclyl, heteroaryl or heteroalkenyl; wherein R ²⁸ and R ²⁹ are each independently a C1-C10 alkyl or phenyl, optionally substituted with C1-C3 alkyl or halogen; and wherein w ¹ is 0, 1 or 3.

In some embodiments, the chemotactic receptor ligand structure E is selected from the group consisting of:

Wherein R ²⁴ is H or C1-C3 alkyl; wherein q ¹ is 1 or 2; wherein -NH-A ⁴ -C(O)- and -NH-A ⁵ -C(O)- are each independently basic Amino acid residue;

Wherein R ²⁵ is H, C 1 -C 6 alkyl or phenyl; wherein t ¹ is 1 or 2; wherein u ¹ is 1, 2, 3, 4, 5 or 6; wherein v ¹ is 1 or 2;

Wherein -NH-A ¹ -C(O)- and -NH-A ² -C(O)- are each independently a hydrophobic amino acid residue; wherein -NH-A ³ -C(O)- is hydrophobic Amino acid residue or absent; wherein R ²⁶ is H, C1-C6 alkyl, OR ²⁸ or NR ²⁹ ; wherein R ²⁷ is heterocyclyl, heteroaryl or heteroalkenyl; wherein R ²⁸ and R ²⁹ are each independently a C1-C10 alkyl or phenyl, optionally substituted with C1-C3 alkyl or halogen; wherein w ¹ is 0, 1, 2 or 3.

In some embodiments, the chemotactic receptor ligand structure E is

Wherein R ²⁴ is H or methyl; wherein r ¹ and s ^{1 are} each ¹ , 2, 3 or 4; wherein q ¹ is 1 or 2; wherein the basic amino acid residue is selected from the group consisting of lysine A group consisting of a residue, an aminic acid residue, a arginine residue, a diaminobutyric acid residue, and a diaminopropionic acid residue. In some embodiments, R ²⁴ is methyl; and the basic amino acid residue is an lysine or arginine residue.

In some embodiments, the chemotactic receptor ligand structure E is

Wherein R ²⁷ is a C3-C10 heteroalkyl, heteroaryl or heteroalkenyl group having from 1 to 5 O, S or N heteroatoms.

In some embodiments, R ²⁷ is piperidinyl, tetrahydrofuranyl, pyridyl, piperidine Pyrimidine

Base, thienyl or furanyl. In some embodiments, R ²⁷ is 2-pyridyl, 4-pyridyl or -NHC(NH)NH ₂ ; w ¹ is 3; -NH-A ¹ -C(O)- is a methionine residue; -NH-A ² -C(O)- is an leucine residue.

In some embodiments, the chemotactic receptor ligand structure E is

In some embodiments, the chemotactic receptor ligand structure E is .

In some embodiments, the chemotactic receptor ligand structure E has a structure selected from the group consisting of

In some embodiments, the chemotactic receptor ligand structure E has a structure selected from the group consisting of

In some embodiments, the chemotactic receptor ligand structure E has a structure selected from the group consisting of

In some embodiments, the linker in the compound or a pharmaceutically acceptable salt thereof comprises a non-reactive link structure having a length of from 1 to 100 atoms.

In some embodiments, the linker has the structure: G ¹ -(Z ¹ ) _b -(Y ¹ ) _c -(Z ² ) _d -(R ¹⁶ )-(Z ³ ) _e -(Y ² ) _f - (Z ⁴ ) _g -G ² Formula VII

Wherein G ¹ is a bond between the linker and the polyene antifungal structure; G ² is a bond between the chemotactic acceptor ligand structure E and the linker; Z ¹ , Z ² , Z ³ and Z ^{4 are} each Independently selected from: optionally substituted C1-C4 alkylene, optionally substituted C1-C3 heteroalkyl, optionally substituted C3-C9 cycloalkyl, optionally substituted C6- C12 arylene group, optionally substituted C2-C6 stretch of heterocyclyl, O, S, and NR ^17; each R ¹⁷ is independently hydrogen, optionally substituted alkyl of C1-C4, optionally substituted by the C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C6 heterocyclyl, optionally substituted C6-C12 aryl or alternatively substituted C1-C7 heteroalkane a group; Y ¹ and Y ^{2 are} each independently a carbonyl group, a thiocarbonyl group, a sulfonyl group or a phosphate group; b, c, d, e, f and g are independently 0 or 1; R ¹⁶ is a C1 which is optionally substituted -C10 alkylene, optionally substituted C2-C10 alkenyl group, optionally substituted C2-C10 alkynyl group, optionally substituted C3-C9 cycloalkylene group, optionally substituted C2- C6 extended heterocyclic group, selectively substituted C6-C12 extended aryl group, selectively taken Instead of C2-C100 polyethylene glycolene or a selectively substituted C1-C10 heteroalkyl or chemical bond, when b, c, d, e, f and g are 0, then R ¹⁶ is not a chemical bond. Or G1-(Z ¹ ) _b -(Y ¹ ) _c -(Z ² ) _d -(R ¹⁶ )-(Z ³ ) _e -(Y ² ) _f -(Z ⁴ ) _g -G ² The linkage of the olefinic antifungal structure to the chemotactic receptor ligand structure.

In some embodiments, the linker is selected from the group consisting of:

Wherein i, k, l and m are independently from 0 to 12; h is from 1 to 6; j is from 1 to 7; t is from 1 to 5; u is from 0 to 4; v is from 1 to 4; and w is from 0 to 3. A is a selectively substituted C3-C8 cycloalkyl, a selectively substituted C2-C6 extended heterocyclic group or a selectively substituted C6-C12 extended aryl group; R ¹⁸ and R ^{19 are} independently hydrogen. Amino, fluoro, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 a heteroalkenyl group, a selectively substituted C2-C6 alkynyl group, a selectively substituted C2-C6 heteroalkynyl group, a selectively substituted C3-C10 cycloalkyl group, a selectively substituted C4-C10 cycloalkenyl group a selectively substituted C4-C10 cycloalkynyl group, a selectively substituted C6-C12 aryl group, a selectively substituted C2-C6 heterocyclic group, a selectively substituted C3-C10 cycloalkoxy group, and a choice a substituted C4-C10 cycloalkenyloxy group, a selectively substituted C4-C10 cycloalkynyloxy group, a selectively substituted C6-C12 aryloxy group or a selectively substituted C2-C6 heterocyclooxy group, or R ¹⁸ and R ¹⁹ and the carbon atom to which they are bonded form a combined sum optionally substituted C3-C10 cycloalkyl a optionally substituted C4-C10 cycloalkenyl group, a selectively substituted C4-C10 cycloalkynyl group, a selectively substituted C6-C12 aryl group or a selectively substituted C2-C6 heterocyclic group; Z ¹ and Z ^{4 are} each independently selected from a C1-C4 alkyl group which is optionally substituted, a C1-C3 heteroalkyl group which is optionally substituted, a C3-C9 cycloalkyl group which is optionally substituted, and a choice a substituted C6-C12 extended aryl group, a selectively substituted C2-C6 extended heterocyclic group, O, S and NR ¹⁷ ; each of R ^{17 is} independently hydrogen, a C1-C4 alkyl group which is optionally substituted, Optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C6 heterocyclyl, optionally substituted C6-C12 aryl or alternatively substituted C1-C7 heteroalkyl.

In some embodiments, Z ¹ and Z ⁴ are each independently a carbonyl group or NH.

In some embodiments, the link is

Wherein m is 0, and wherein Z ¹ and Z ^{4 are} each independently NH.

In some embodiments, the linker is selected from the group consisting of:

Wherein n ¹ , o and p ¹ are 1 to 4; and R ¹⁸ and R ^{19 are} independently hydrogen, amine, fluorine, hydroxyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 a heteroalkyl group, a selectively substituted C2-C6 alkenyl group, a selectively substituted C2-C6 heteroalkenyl group, a selectively substituted C2-C6 alkynyl group, a selectively substituted C2-C6 heteroalkynyl group, Optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 cycloalkynyl, optionally substituted C6-C12 aryl, optionally substituted Substituted C2-C6 heterocyclyl, optionally substituted C3-C10 cycloalkoxy, optionally substituted C4-C10 cycloalkenyloxy, optionally substituted C4-C10 cycloalkynyloxy, optionally by C6-C12 aryloxy group substituted with the combined or the optionally substituted C2-C6 heterocyclic group, or R ¹⁸ and R ¹⁹ bonded thereto to carbon atom to form optionally substituted C3-C10 cycloalkyl group of Optionally, a substituted C4-C10 cycloalkenyl group, a optionally substituted C4-C10 cycloalkynyl group, a selectively substituted C6-C12 aryl group or a selectively substituted C2-C6 heterocyclic group.

In some embodiments, the link is:

Wherein x is an integer between 0 and 12; wherein Z ¹ is a C1-C2 alkylene group which is optionally substituted, a C1-C3 heteroalkyl group which is optionally substituted, and a C3-C9 ring extension which is optionally substituted An alkyl group, a selectively substituted C6-C12 extended aryl group, a selectively substituted C2-C6 extended heterocyclic group, O, S or NR ¹⁷ ; and R ^{17 are} each independently hydrogen, optionally substituted C1 a C4 alkyl group, a selectively substituted C2-C4 alkenyl group, a selectively substituted C2-C4 alkynyl group, a selectively substituted C2-C6 heterocyclic group, a selectively substituted C6-C12 aryl group or A substituted C1-C7 heteroalkyl group is optionally selected. In some embodiments, Z ¹ is NH and x is 0.

In another aspect, a compound is selected from the group consisting of:

Or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure:

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} each independently hydrogen, hydroxy, -SH, amine, nitro, cyano, halo, optionally substituted C1 a C6 alkyl group, a selectively substituted C6-C10 aryl C1-C6 alkyl group, a selectively substituted C1-C6 alkoxy group, a selectively substituted C1-C6 alkyl fluorenyl group, a decylamine group, a carboxyl group, And an ester comprising -LE; wherein at least one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ includes -LE; R ⁸ is hydrogen or a C2-C6 heterocyclic ring which is optionally substituted m; m is an integer between 5 and 13; n is an integer between 3 and 8; p is 0, 1 or 2; A' is or ; B' and C' are each independently hydrogen, hydroxyl, C1-C6

An alkyl group, an oxo group, or a combination of B' and C' to form -O-; wherein the dashed bond is a single bond or a double bond, if the compound of formula I includes at least 2 double bonds; Or a pharmaceutically acceptable salt thereof. In some embodiments, R ⁷ is -LE.

In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure:

Wherein R ¹ , R ² , and R ^{3 are} each independently hydrogen, hydroxy, optionally substituted C1-C6 alkyl or alternatively substituted C6-C10 aryl C1-C6 alkyl; R ⁴ independently Is hydrogen, hydroxy, optionally substituted C1-C6 alkyl or pendant oxy; R ⁵ and R ^{6 are} each independently hydrogen, hydroxy or C1-C6 alkoxy; R ⁹ is -LE; R ¹⁰ is hydrogen Or a hydroxyl group; R ¹¹ is a hydroxyl group or an amine; R ¹² is hydrogen or m is an integer between 5 and 13; n is an integer between 3 and 8; p is 0, 1 or 2; q is 1, 2 or 3; A' is or B' and C' are each independently hydrogen, hydroxy, C1-C6 alkyl, pendant oxy, or B' and C' combine to form -O-; wherein the dash bond is a single bond or a double bond, if The compound of II includes at least 2 double bonds. In some embodiments, R ⁹ is -NR ¹³ (CH ₂ ) _a NR ¹³ E or -NR ¹³ (CH ₂ ) _a O(CH ₂ ) _a NR ¹³ E; each R ^{13 is} independently hydrogen or C1-C3 alkane Base; and a are each independently 2, 3 or 4.

In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure: , where R is -LE. In some embodiments, R is -NR'(CH ₂ ) _a NR'E or -NR'(CH ₂ ) _a O(CH ₂ ) _a NR'E; each R' is independently hydrogen or C1-C3 alkyl And a are independently 2, 3 or 4.

In some embodiments, the compound or a pharmaceutically acceptable salt thereof has the structure: Wherein R "is -LE. In some embodiments, R" is a -NHCH ₂ CH ₂ NHE or _{-NHCH 2 CH 2 OCH 2 CH 2} NHE.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure: , where R is -LE. In some embodiments, R is -NR '(CH _{2) a} NR'E or _{-NR' (CH 2) a O} (CH 2) a NR'E; R ' are each independently hydrogen or C1-C3 alkyl And a are independently 2, 3 or 4.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure: Wherein R "is -LE. In some embodiments, R" is a -NHCH ₂ CH ₂ NHE or _{-NHCH 2 CH 2 OCH 2 CH 2} NHE.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure: , where R is -LE. In some embodiments, R is -NR'(CH ₂ ) _a NR'E or -NR'(CH ₂ ) _a O(CH ₂ ) _a NR'E;R' is each independently hydrogen or C1-C3 alkyl And a are independently 2, 3 or 4.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure: Wherein R "is -LE. In some embodiments, R" is a -NHCH ₂ CH ₂ NHE or _{-NHCH 2 CH 2 OCH 2 CH 2} NHE.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure: , where L is a linker. In some embodiments, L is a linkage that covalently links the polyene antifungal structure to the chemotactic acceptor ligand structure E.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure:

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} each independently hydrogen, hydroxy, -SH, amine, nitro, cyano, halo, optionally substituted C1 a C6 alkyl group, a selectively substituted C6-C10 aryl C1-C6 alkyl group, a selectively substituted C1-C6 alkoxy group, a selectively substituted C1-C6 alkyl fluorenyl group, a decylamine group, a carboxyl group, Ester or -LE; R ⁹ and R ^{10 are} each independently hydrogen, hydroxy, -SH, amine, nitro, cyano, halo, optionally substituted C1-C6 alkyl, optionally substituted C6 -C10 aryl-C1-C6 alkyl, optionally substituted alkoxy of C1-C6, optionally substituted alkyl of C1-C6 acyl, acyl amine, carboxyl, ester, -LE, R ⁹ and R ^10, or Forming -O- together; wherein at least one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ and R ¹⁰ is -LE; R ⁸ is hydrogen or alternatively Substituted C2-C6 heterocyclic group; m is an integer between 3 and 13; n is an integer between 3 and 8; p is 0, 1 or 2; A' is or B' and C' are each independently hydrogen, hydroxy, C1-C6 alkyl, pendant oxy or B' combined with C' to form -O-; or a pharmaceutically acceptable salt thereof. In some embodiments, R ⁷ includes -LE.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure:

Wherein R ¹ , R ² and R ^{3 are} each independently hydrogen, hydroxy, optionally substituted C1-C6 alkyl, or alternatively substituted C9-C10 aryl C1-C6 alkyl; R ⁴ independently Is hydrogen, hydroxy, optionally substituted C1-C6 alkyl or pendant oxy; R ⁵ and R ^{6 are} each independently hydrogen, hydroxy or C1-C6 alkoxy; R ⁹ and R ^{10 are} each independently hydrogen a hydroxy group, a optionally substituted C1-C6 alkyl group, a pendant oxy group, or a combination of R ⁹ and R ¹⁰ to form -O-; R ¹¹ is -LE; R ¹² is hydrogen or a hydroxyl group; R ¹³ is a hydroxyl group or an amine; R ¹⁴ is hydrogen or m is an integer between 3 and 13; n is an integer between 3 and 8; p is 0, 1 or 2; A' is or And B' and C' are each independently hydrogen, hydroxy, C1-C6 alkyl, pendant oxy or B' combined with C' to form -O-. In some embodiments, R ¹¹ is -NR ¹⁵ (CH ₂ ) _a NR ¹⁵ E or -NR ¹⁵ (CH ₂ ) _a O(CH ₂ ) _a NR ¹⁵ E; each R ^{15 is} independently hydrogen or C1-C3 alkane And a are each independently an integer between 2 and 4.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure: , where R is -LE. In some embodiments, R is -NR'(CH ₂ ) _a NR'E or -NR'(CH ₂ ) _a O(CH ₂ ) _a NR'E;R' is each independently hydrogen or C1-C3 alkyl And a are each independently an integer between 2 and 4.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure: Wherein R "is -LE. In some embodiments, R" is a -NHCH ₂ CH ₂ NHE or _{-NHCH 2 CH 2 OCH 2 CH 2} NHE.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure: , where L is a linker. In some embodiments, L is a covalent attachment of a polyene antifungal structure to a bond of a chemotactic acceptor ligand structure E.

In some embodiments, the compound or a pharmaceutically acceptable salt thereof The concentration that induces maximum neutrophil shift is less than or equal to 10,000 nM. In some embodiments, the concentration of the compound or pharmaceutically acceptable salt that induces maximum neutrophil shift is less than or equal to 1,000 nM. In some embodiments, the concentration of the compound or pharmaceutically acceptable salt that induces maximum neutrophil shift is less than or equal to 100 nM.

In some embodiments, the compound or pharmaceutically acceptable salt inhibits fungal growth.

In some embodiments, acceptable salt of the compound or pharmaceutically IC ₅₀ of 1,000 nM or less. In some embodiments, acceptable salt of the compound or pharmaceutically IC ₅₀ of less than or equal to 100nM. In some embodiments, acceptable salt of the compound or pharmaceutically IC ₅₀ of less than or equal to 10nM.

In another aspect, the present disclosure includes a pharmaceutical composition comprising: any one or more of the compounds described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect, the present disclosure includes a method of treating an individual who has been infected with a fungal infection or a putative fungal infection. The method comprises administering to the individual an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure encompasses a method of prohylatic treatment of a fungal infection in an individual in need thereof. The method comprises administering to the individual an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

In some embodiments, the fungal infections are a genus aspergillus (Aspergillus) or a fungus Candida genus (Candida) caused. In some embodiments, the fungal infection is aspergillosis. In some embodiments, the mold is an invasive mold. In some embodiments, the castor disease is pulmonary mite. In some embodiments, the fungal infection is caused by Aspergillus fumigatus . In some embodiments, the fungal infection is candidiasis. In some embodiments, the candidiasis is an intra-abdominal abscess, peritonitis, pleural infection, esophagitis, candidemia, or invasive candidiasis. In some embodiments, the fungal infection is caused by Candida albicans .

In some embodiments, the individual's immunity is low. In some real For example, the individual is diagnosed with humoral immunodeficiency, T cell deficiency, neutropenia, asplenia, or complement deficiency. In some embodiments, the individual has been or will be treated with an immunosuppressive drug.

In some embodiments, the individual is diagnosed as having an immunosuppression The disease. In some embodiments, the disease is cancer or a post-immune syndrome. In some embodiments, the cancer is leukemia, lymphoma or multiple myeloma. In some embodiments, the individual has experienced or will undergo hematopoietic stem cell colonization. In some embodiments, the individual has experienced or will undergo organ transplanting.

In some embodiments, the administration includes intramuscular, intravenous, and intradermal Internal, intra-arterial, intraperitoneal, intralesional, intracranial, intra-articular, intraprostatic, intrathoracic, intratracheal, intranasal, intravitreal, intravaginal, intrarectal, local, intratumoral, peritoneal, subcutaneous, subconjunctival, Intravesical, mucosal, intrapericial, intraumbilitic, intraocular, oral, topical administration by inhalation, injection or infusion.

The terms "alkyl", "alkenyl" and "alkynyl" are used herein to include Linear, branched, and cyclic monovalent substituents (cyclic monovalent Substituted), as well as combinations of the foregoing, when unsubstituted, comprise only carbon and hydrogen. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl, 1,2-propenyl, 3-butynyl and the like. The term "cycloalkyl" as used herein, unless otherwise specified, represents a monovalent saturated or unsaturated non-aromatic cyclic alkyl group having from 3 to 9 carbons (eg, C3-C9 cycloalkyl), and, for example, a ring. Propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1.] heptyl and the like. When a cycloalkyl group includes at least one carbon-carbon double bond, the cycloalkyl group may be referred to as a "cycloalkenyl group." A cycloalkenyl group such as a cyclopentenyl group, a cyclohexenyl group or the like. When a cycloalkyl group includes at least one carbon-carbon reference bond, the cycloalkyl group may be referred to as a "cycloalkynyl group". For the purposes herein, cycloalkenyl groups exclude aryl groups. When it is listed as a general term, such as an alkyl group, an alkenyl group or an alkynyl group, and a cyclic form, such as a cycloalkyl group, a cycloalkenyl group, and a cycloalkynyl group, it should be understood that the general term refers only to Acyclic radicals.

In general, the alkyl, alkenyl, and alkynyl groups contain 1-12 carbons (eg, C1-C12 alkyl groups) or 2-12 carbons (eg, C2-C12 alkenyl or C2-C12 alkynyl). In some embodiments, the group is C1-C8, C1-C6, C1-C4, C1-C3 or C1-C2 alkyl; or C2-C8, C2-C6, C2-C4 or C2-C3 alkenyl or alkyne base. Further, any hydrogen atom of any of these groups may be substituted with the substituent described herein. For example, the term "alkyl group" herein refers to an alkyl group, comprising the amino optionally substituted (e.g., NH _2). Heteroalkyl, heteroalkenyl and heteroalkynyl are defined similarly and contain at least one carbon atom but also include one or more O, S or N heteroatoms or combinations thereof in the backbone residue, whereby a heteroalkyl group Each heteroatom in the heteroalkenyl or heteroalkynyl group replaces one carbon atom of the alkyl, alkenyl or alkynyl group corresponding to the heteroform. In some embodiments, the heteroalkyl, heteroalkenyl, and heteroalkynyl groups have carbon at each end where the group is attached to other groups and the heteroatoms are not at the terminal positions. As is known in the art, the above heterogeneous does not include more than 3 consecutive heteroatoms. In some embodiments, the heteroatom is O or N. The term "heterocyclyl" as used herein, denotes a cyclic heteroalkyl or heteroalkenyl group, and if not otherwise indicated, is, for example, a 3-, 4-, 5-, 6- or 7-membered ring containing 1, 2 , 3 or 4 heteroatoms independently selected from the group consisting of N, O and S. The 5-member ring has 0 to 2 double keys, and the 6- and 7-member rings have 0 to 3 double keys. The term "heterocyclyl" also denotes a bridged multicuclic heterocyclic compound in which one or more carbon and/or heteroatoms bridge two non-adjacent members of a single ring, such as a pyridine. Quinuclidinyl group. The term "heterocyclyl" includes bicyclic, tricyclic, and tetracyclic groups, wherein any of the above heterocyclic rings is fused to 1, 2, or 3 carbocyclic rings, such as aryl rings, cyclohexyl groups. An alkane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or other monocyclic heterocyclic ring, such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzo Benzofuryl, benzothienyl, and the like. When it is listed as a general term, such as a heteroalkyl group, a heteroalkenyl group or a heteroalkynyl group, and a cyclic form, for example, a heterocyclic group, it should be understood that the general term refers only to non-cyclic free radicals.

Heteroalkyl, heteroalkenyl or heteroalkynyl substituents may also include one or more carbonyl groups. Examples of heteroalkyl, heteroalkenyl and heteroalkynyl groups include CH ₂ OCH ₃ , CH ₂ N(CH ₃ ) ₂ , CH ₂ OH, (CH ₂ ) _n NR ₂ , OR, COOR, CONR ₂ , (CH _{2 n} OR, (CH ₂ ) _n COR, (CH ₂ ) _n COOR, (CH ₂ ) _n SR, (CH ₂ ) _n SOR, (CH ₂ ) _n SO ₂ R, (CH ₂ ) _n CONR ₂ , NRCOR , NRCOOR, OCONR ₂ , OCOR, etc., wherein the R group in the examples of heteroalkyl, heteroalkenyl and heteroalkynyl groups includes at least one carbon and the size of the substituents and as described herein, for example, alkyl, alkene The definitions of the radicals and alkynyl groups are identical (eg, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12).

As used herein, the terms "alkylene" and "alkenyl" "alkenylene", "alkynlene" and "alk" refer to a divalent or trivalent group of a particular size, usually a saturated group (eg, alkyl or alkyl). Is C1-C2, C1-C3, C1-C4, C1-C6 or C1-C8, and an unsaturated group (for example, an alkenyl group or an alkynyl group) is C2-C3, C2-C4, C2-C6 or C2-C8. They include linear, branched, cyclic, and combinations of the foregoing, and when unsubstituted, contain only carbon and hydrogen. Because they are divalent, they are capable of linking two parts of a molecule together. For example, methyl, ethyl, propyl, cyclopropane-1,1-diyl, ethylene, 2-butene-1,4-diyl, etc. These groups can be described as such It is generally suitable to be substituted as a substituent of an alkyl group, an alkenyl group and an alkynyl group. Thus, for example, C=O is a C1 alkylene group substituted by =0. For example, the term "alkaryl" refers to an aryl group as defined herein. Attached to a parent molecular group by an alkylene group as defined herein, and the term "alkheteroaryl" means a heteroaryl group as defined herein via an alkylene group as defined herein. Attached to a parent molecular group. Alkyl and aryl or heteroaryl group optionally substituted with each of said so.

Heteroalkyl, hetero-alkylene and hetero-alkynyl are similarly defined as having a divalent group of a particular size, usually a saturated group of C1-C3, C1-C4, C1-C6 or C1-C8, and The unsaturated group is C2-C3, C2-C4, C2-C6 or C2-C8. They include linear, branched and cyclic groups and combinations of the foregoing, and further include at least one carbon atom but also one or more O, S or N heteroatoms or combinations of the foregoing in the backbone residue, thereby a carbon in an alkyl, an alkenyl or an alkynyl group corresponding to each of the heteroatoms in a heteroalkyl, heteroalkylene or heteroalkylene group atom. As understood in the art, these hybrids do not include more than 3 consecutive heteroatoms.

The term "alkoxy" denotes a chemical substituent of the formula -OR, wherein Unless otherwise specified, R in -OR is a selectively substituted alkyl group (for example, a C1-C6 alkyl group). In some embodiments, an alkyl group can be substituted, for example, an alkoxy group can have 1, 2, 3, 4, 5 or 6 substituents as defined herein.

The term "alkoxyalkyl" denotes a heteroalkyl group as defined herein, An alkyl group substituted with an alkoxy group. Unsubstituted alkoxyalkyl groups, for example, include between 2 and 12 carbons. In some embodiments, the alkyl and alkoxy groups can each be further substituted with 1, 2, 3 or 4 substituents as defined herein for each group.

The term "amino" as used herein denotes -N(R ^N1 ) ₂ , wherein R ^{N1 are} each independently H, OH, NO ₂ , N(R ^N2 ) ₂ , SO ₂ OR ^N2 , SO ₂ R ^N2 , SOR ^N2 , N -protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkoxyalkyl, heterocyclic (eg, heteroaryl), alkane A group (for example, an alkaryl group), or two R ^N1 groups, to form a heterocyclic group or an N -protecting group, and wherein the R ^{N2 is} independently H, an alkyl group or an aryl group. In a preferred embodiment, the amine group is -NH ₂ or -NR ^N1 , and R ^{N1 is} independently OH, NO ₂ , NH ₂ , NR ^N2 ₂ , SO ₂ OR ^N2 , SO ₂ R ^N2 , SOR ^N2 , alkyl Or aryl, and each R ^N2 can be H, alkyl or aryl. The term "aminoalkyl" as used herein, denotes a heteroalkyl group, as defined herein, which is substituted, as described herein, with an alkyl group, as defined herein. Each of the alkyl group and the amine group may be further substituted with 1, 2, 3 or 4 substituents as described herein for each group. For example, the alkyl moiety can comprise a pendant oxy (=O) substituent.

"Aromatic" moiety or "aryl" moiety refers to any monocyclic or fused ring bicyclic system having an aromatic character in the electronic distribution of the overall ring system, and includes a monocyclic or fused bicyclic structure, for example, benzene Or a naphthyl group; "heteroaryl" or "heteroaryl" also refers to a monocyclic or fused bicyclic system containing one or more heteroatoms selected from O, S and N. The addition of heteroatoms allows the addition of a 5-membered ring to be considered aromatic, as is the 6-membered ring. Thus, typical aromatic/heteroaromatic systems include: pyridyl, pyrimidinyl, fluorenyl, benzimidazolyl, benzotriazolyl, isoquinolinyl, quinolinyl, benzothiazolyl, benzo Sulfhydryl, thienyl, fluorenyl, pyrrolyl, thiazolyl, Azolyl, different Azolyl, benzo Azolyl, benzopyrene Azolyl, imidazolyl and the like. Since tautomers are theoretically possible, phthalimido is also considered to be aromatic. In general, the ring system includes 5-12 ring atoms or 6-10 ring atoms. In some embodiments, the aromatic or heteroaromatic structure is a 6-membered aromatic ring system, optionally comprising 1-2 nitrogen atoms. More specifically, the structure is a selectively substituted phenyl, pyridyl, indenyl, pyrimidinyl, anthracene Base, benzothiazolyl, benzimidazolyl, pyrazolyl, imidazolyl, isomeric Azolyl, thiazolyl, benzothiazolyl, indenyl or imidazopyridyl. More specifically, such a structure is a phenyl group, a pyridyl group, a thiazolyl group, an imidazopyridyl group or a pyrimidinyl group, and more specifically, a phenyl group.

"O-aryl" or "O-heteroaryl" means via an oxygen atom and others An aromatic or heteroaromatic system in which a residue is coupled. A general example of an O-aryl group is a phenoxy group. Similarly, "arylalkyl" refers to an aromatic and heteroaromatic system coupled via a saturated or unsaturated carbon chain to other residues, typically C1-C8, C1-C6 or, more specifically, C1 when the carbon chain is saturated. -C4 or C1-C3, when unsaturated, is generally C2-C8, C2-C6, C2-C4 or C2-C3, also including its heteromorphism. More particularly, arylalkyl includes aryl or heteroaryl as defined above attached to an alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl or heteroalkyne structure as also defined above. Typical arylalkyl groups may be aryl (C6-C12) alkyl (C1-C8), aryl (C6-C12) alkenyl (C2-C8) or aryl (C6-C12) alkynyl (C2- C8), plus the hybrid. A typical example is phenylmethyl, commonly referred to as benzyl.

The term "hydrophobic amino acid residue" means an amine having a relatively low water solubility. Base acid residue. Hydrophobic amino acid residues include, but are not limited to, leucine, isoleucine, alanine, phenylalanine, valine, valine, tyrosine, cysteine, methionine, color Aminic acid, and non-natural amino acid residues with similar hydrophobicity.

The term "chemotactic receptor ligand" as used herein refers to a molecule, For example, peptides can be recognized and interacted with by chemotactic receptors. Chemotactic receptor ligands can be derived from prokaryotic or eukaryotic organisms, for example, fungi, bacteria or mammals. In some embodiments, the chemotactic receptor ligand or chemotactic recognition receptor ligand comprises a host immunostimulatory factor. For example, once a host organism's chemotactic receptor interacts with a chemotactic receptor ligand, the chemotactic receptor ligand can stimulate an immune response in the host organism.

The term "chemokine peptide" as used herein refers to a peptide which is associated with chemotaxis. Body interaction and induce chemotaxis.

The term "chemotactic receptor" as used herein refers to a receptor which is eukaryotic. Cells are used to sense the appearance of chemotactic stimuli, including formazin receptor (FRP), chemokine receptor (eg CCR, CXCR) and leukotriene receptor (BLT) For example, BLT1, BLT2). For example, the chemokine receptor family can include CCR1-CCR10, CXCR1-CXCR7, CX3CR1, and XCR1. Ligands for these receptors include naturally occurring, fragments derived from such ligands, and synthetically produced ligands.

The term "diamine linker" refers to a linker, for example, a polypeptide linker that includes an amine group (ie, -NH ₂ ) at each end. For example, an amine at one end of the diamine linker can conjugate to the carbonyl group of the chemotactic acceptor ligand structure E; the amine at the second end of the diamine linker can be attached to the polyene antifungal agent The carbonyl group of the structure.

The term "chemotaxis activity" as used herein refers to the induction of maximum neutrophil. The concentration of the compound of the maximal neutrophil migration is less than or equal to 10,000 nM, as measured in Example 20 herein according to the Transwell Migration Assay. In some aspects, according to the cross-well migration analysis, the concentration of the compound that induces the maximum neutrophil shift is less than or equal to 1000 nM or less than or equal to 100 nM, which is representative of the compound having chemotactic activity. The concentration of the compound is assumed to be the presence of the compound and, therefore, these amounts will be greater than 0 nM.

"Fungal infection" means a host organism (eg, a human individual) The growth of fungi in pathogens. For example, an infection can include excessive growth of a fungus that is normally present in the body or on the surface of the body, or growth of a fungus that is not normally present in or on the body. More generally, fungal infections can be arbitrarily responsible for host damage to the appearance of the fungal population. Thus, an individual is said to be "affected" by a fungal infection when an excessive amount of the fungal population is present in the body or on the surface of the body, or when the presence of the fungal population causes damage to the individual cells or other tissues.

The phrase "inhibiting fungal growth" means any slowing, stabilizing, disturbing, inhibiting, delaying, killing or inhibiting fungal growth. The compounds inhibiting fungal growth described herein exhibit a minimum inhibitory concentration (MIC), for example, less than 32 μg/mL (eg, less than 30 μg/mL, 20 μg/mL, 10 μg/mL, 5 μg/mL, 1 μg/mL) . Examples 18 and 19 describe the MIC of the compounds described herein. Inhibiting fungal growth includes, for example, inhibiting the growth of dormant fungal cells, which may include inhibiting spore germination, hyphal development, and/or forming a fruit body structure (e.g., sporangia/sporophores) on the fungus. Fungal growth can be produced by fungi of the genus Fusarium or Candida, for example, Aspergillus fumigatus or Candida albicans .

"Halo" or "halogen" may be any halogen atom, especially F, Cl, Br or I, and especially fluorine or chlorine.

The term "haloalkyl" as used herein, denotes an alkyl radical as defined herein, substituted by halo (i.e., F, Cl, Br or I). The haloalkyl group may be substituted by 1, 2 or 3 halogens, and when the alkyl group is 2 or more carbons, it may be substituted by 4 halogens. Haloalkyl groups include perfluoroalkyl groups. In some embodiments, haloalkyl groups can be further substituted with 1, 2, 3 or 4 substituents as described herein for alkyl groups.

The term "hadrazone" as used herein, refers to a group having the following structure: Wherein each R in the oxime is independently hydrogen, alkyl or aryl.

The term "hydroxy" as used herein denotes an -OH group.

The term "hydroxyalkyl" as used herein, denotes an alkyl group, as defined herein, substituted by 1 to 3 hydroxy groups, provided that the number of hydroxyl groups attached to a single carbon atom of the alkyl group is not more than one, examples being hydroxymethyl, Hydroxypropyl and the like.

As used herein, the term "immunocompromised" means that the immune response is attenuated by a symptom or immunosuppressive agent.

The term " N -protecting group" as used herein, refers to those groups used in the synthetic step to protect the amine group from unwanted reactions. Commonly used N - protecting groups disclosed in Greene, "Protective Groups in Organic Synthesis ," 3 rd Edition (John Wiley & Sons, New York, 1999), herein incorporated by reference. The N -protecting group includes a fluorenyl group, an aryl group or an amine carbyl group, for example, a methyl group, an ethyl group, a propyl group, a neopentyl group, a tert-butyl acetyl group, a 2-chloroethyl group. , 2-bromoethenyl, trifluoroethenyl, trichloroethenyl, benzyl, o-nitrophenoxyethyl, α-chlorobutylidene, benzamidine, 4-chlorobenzate Sulfhydryl, 4-bromobenzylidene, 4-nitrobenzhydryl, and chiral auxiliaries, for example, protected or unprotected D, L or D, L-amino acids Residues such as alanine, leucine, phenylalanine, etc.; sulfonyl group-containing groups, for example, benzenesulfonyl, p-toluenesulfonyl, etc.; forming a carbamate group, for example, benzyloxycarbonyl, p-Chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxy Carbocarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethyl Oxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenyl)-1-methyl Carbocarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, tert-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropyl Oxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl -9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, etc., alkaryl, for example, benzyl, triphenylmethyl, benzyloxy Bases and the like, and sulfhydryl groups, for example, trimethyl fluorenyl groups and the like. Preferred N -protecting groups are methyl fluorenyl, ethyl fluorenyl, benzamyl, neopentyl, tert-butylethyl, propylamino, phenylsulfonyl, benzyl, tert-butyl Oxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

"Sideoxy" is a substituent having a structure of =O, wherein a carbon atom There is a double bond between the oxygen atom and the oxygen atom.

The term "phosphate group" as used herein refers to a group having the following structure:

The term "polyene antifungal agent" as used herein, refers to a compound that binds to the ergosite in a fungal film at less than 5 [mu]M (eg, less than 4 [mu]M, 3 [mu]M, 2 [mu]M, 1 [mu]M, 500 nM, or 100 nM). Alcohol (ergosterol) and structurally related sterols, and destroy the integrity of the membrane structure, thus causing cellular components to leak from the fungus causing infection, or present less than 32μg / mL (for example, less than 30μg / mL, 20μg / mL, MIC of 10 μg/mL, 5 μg/mL, 1 μg/mL).

The term "sulfonyl" as used herein refers to a radical having the following structure:

General selective substituents on aromatic or heteroaromatic groups, including independently halo, for example: chloro, fluoro, CN, NO ₂ , CF ₃ , OCF ₃ , COOR', CONR' ₂ , OR' , SR', SOR', SO ₂ R', NR' ₂ , NR'(CO)R', NR'C(O)OR', NR'C(O)NR' ₂ , NR'SO ₂ NR' ₂ Or NR'SO ₂ R', wherein each R' is independently H or a selectively substituted group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hetero a cycloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and aryl group (all as defined above); or the substituent may be a selected substituent selected from the group consisting of alkyl, alkenyl , alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, O-aryl, O-heteroaryl and arylalkyl.

Selection on non-aromatic groups (eg, alkyl, alkenyl, and alkynyl) The optional substituents are generally selected from the substituents in the same tables as the aromatic or heteroaromatic groups, except as specifically indicated herein. The non-aromatic group also includes a selective substituent selected from =0 and =NOR', wherein R' is H or is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, hetero A selectively substituted group of a cycloalkyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and aryl group (all as defined above).

In general, a substituent (eg, an alkyl, alkenyl, alkynyl or aryl group, including all heterocycles as defined above) may itself be optionally substituted with additional substituents. The nature of these substituents is similar to the substituents described above for the basic structure. Thus, examples of substituents are alkyl groups which may be optionally substituted by other substituents which are listed as substituents, as long as they are chemically significant, and which do not destroy the size limitation of the alkyl group itself; for example, Substitution of an alkyl group with an alkyl or alkenyl group simply extends the upper limit of the carbon atom in these examples and is not included. However, substitution of an alkyl group with an aryl group, an amine group, a halogen (preferably chlorine or fluorine), and the like is included. For example, when a group is substituted, the group may be substituted with 1, 2, 3, 4, 5 or 6 substituents. Selective substituents include, but are not limited to, C1-C6 alkyl or heteroaryl, C2-C6 alkenyl or heteroalkenyl, C2-C6 alkynyl or heteroalkynyl, halogen; aryl, heteroaryl, azide (-N ₃ ), nitro (-NO ₂ ), cyano (-CN), decyloxy (-OC(=O)R'), fluorenyl (-C(=O)R'), alkane Oxy (-OR'), decylamino (-NR'C(=O)R" or -C(=O)NRR'), amine group (-NRR'), carboxylic acid (-CO ₂ H), Carboxylic ester (-CO ₂ R'), amine indenyl (-OC(=O)NR'R" or -NRC(=O)OR'), hydroxyl (-OH), isocyano (-NC) , sulfonate group (-S(=O) ₂ OR), sulfonamide (-S(=O) ₂ NRR' or -NRS(=O) ₂ R') or sulfonyl (-S(=O) ₂ R), wherein R or R' in the selective substituent are each independently selected from H, C1-C6 alkyl or heteroaryl, C2-C6 alkenyl or heteroalkenyl, C2-C6 alkynyl or hetero Alkynyl, aryl or heteroaryl. The substituent may have, for example, 1, 2, 3, 4, 5, 6, 7, 8, or 9 substituents. Unless otherwise specified, a cyclic alkyl group may be substituted without an aryl group or a heterocyclic ring.

In some embodiments, the chemotactic receptor ligand comprises an amino acid residue. The amino acid residue may be a naturally occurring amino acid residue (eg, Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, The Thr, Trp, Tyr or Val) or amino acid residue can be a non-naturally occurring amino acid residue. A "non-naturally occurring amino acid residue" is an amino acid residue that is not naturally produced or found in a mammal. For example, a non-naturally occurring amino acid residue includes: a D-amino acid residue; an amino acid residue having an ethylaminomethyl group attached to a sulfur atom of a cysteine; PEGylated ( Pegylated) an amino acid residue; an omega amino acid residue of the formula NH ₂ (CH ₂ ) _n COOH wherein n is 2-6; a neutral non-polar amino acid residue such as sarcosine ), tert-butylalanine, tert-butylglycine, N-methylisoleucine, and norleucine; oxymethionine; phenylglycine; citrulline; Amidoxime; oxidized cysteine; acineline; diaminobutyric acid; and hydroxyproline.

The "effective amount" of the terminology used herein is sufficient to produce beneficial Or the amount of desired result, for example: clinical outcome, and such as "effective amount" depends on the condition in which it is used. For example, where a pharmaceutical agent is administered to treat a fungal infection, the effective amount of the agent is, for example, an amount sufficient to slow or reverse the continued infection, as compared to a reaction in which the agent is not administered.

The term "pharmaceutical composition" is used herein to mean that it is included here. A composition of a compound formulated as a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is made or sold under the authority of a government regulatory agency, as Part of the therapy for treating diseases in mammals. The pharmaceutical composition can be formulated to be administered intramuscularly, intravenously (for example, as a sterile solution without granule emboli, and a solvent system suitable for intravenous use), intradermal, intraarterial, intraperitoneal, Intralesional, intracranial, intra-articular, intraprostatic, intrathoracic, intratracheal, intranasal, vitreous, intravaginal, rectal, local, intratumoral, peritoneal, subcutaneous, subconjunctival, vesicle, mucosa, pericardium (intrapericardially), intra-umbilical, intraocular, oral (eg, lozenges, capsules, caplets, gelcaps or syrups), topical (eg creams, gels, lotions or creams) The target cells, catheters, lavage, cream form or lipid composition are soaked by inhalation, injection or infusion, continuous infusion, local direct perfusion.

As used herein, "pharmaceutically acceptable excipient" means any non- The components of the compounds described herein (e.g., carriers capable of suspending or dissolving the active compound) are non-toxic and non-inflammatory in patients. Excipients may include, for example, anti-adhesives, antioxidants, binders, coatings, compression aids, disintegrants, dyes (pigments), emollients, emulsifiers, fillers (diluents), film formers Or coatings, flavorings, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners or hydrating agents. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, dibasic, calcium stearate, croscarmellose, crosslinked polyethylene. Pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol , mannitol, methionine, methyl cellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, Gelatinized starch, propyl paraben, vitamin A palmitate, shellac, ceria, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), hard Fatty acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

As used herein, the term "pharmaceutically acceptable salts", which refers to those salts of the compounds, is suitable for use in contact with human and animal tissues in a sound medical judgment without causing excessive toxicity, irritation, or allergies. Reactions, etc., and have a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al, J. Pharmaceutical Sciences 66: 1-19, 1977, and Pharmaceutical Salts: Properties, Selection, and Use , (Eds. PHStahl and CGWermuth), Wiley-VCH, 2008. Salts can be prepared in situ upon the final isolation and purification of the compounds described herein or when the free base of the compound is reacted separately with a suitable organic acid.

The compound may have a free group for preparation into a pharmaceutically acceptable Accept the salt. These salts may be acid addition salts involving inorganic or organic acids, or may be prepared from inorganic or organic bases when the salt is in the acidic form of the compound. The compounds are often prepared or used in the form of pharmaceutically acceptable salts which are prepared as addition products for pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, lactic acid, citric acid or tartaric acid for the formation of acid addition salts, and potassium hydroxide, hydrogen Sodium oxide, ammonium hydroxide, caffeine, various amines, and the like are used to form an alkali salt. Methods for preparing suitable salts have been well established in the art.

Representative acid addition salts include: acetate, adipate, algae Acid salt, ascorbate, aspartate, besylate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane Acid salt, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, hydrobromic acid, Hydrochloride, iodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate Acid salt, 2-naphthalene sulfonate, nicotinic acid salt, nitrate, oleate, oxalate, palmitate, pamoate, acid salt, persulphate, 3-phenylpropionate, Phosphate, picrate, trimethylacetate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate, valeric acid Salt and so on. Representative alkali or alkaline earth metal salts include: sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like, and non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium. , tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

The term "prophylactic treatment" as used herein refers to the initiation of treatment, For example, before the onset of a disease, disorder or symptom (pre-exposure prophylaxis) or post-exposure prophylaxis (eg, when an individual is or will be treated with an immunological drug, An individual has been diagnosed with a disease that causes immunosuppression (eg, cancer, such as blood cancer, lymphoma, multiple myeloma, or acquired immunodeficiency syndrome), an individual who has experienced or will undergo hematopoietic stem cell transplantation, or has experienced or will experience an organ Transplanted individuals). Prophylactic treatment comprising a compound described herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof can be acute, short-term or chronic. The dose administered can vary during the prophylactic treatment session.

The term "individual" used herein can be human or non-human primate. Classes or other mammals such as, but not limited to, dogs, cats, horses, cows, pigs, turkeys, goats, fish, monkeys, chickens, rats, mice, and sheep.

The term "treatment" as used herein and well known in the art "Treatment" of a plaque or fungal infection is a method of obtaining beneficial or desired results, such as clinical outcomes. Benefits or desired results can include, but are not limited to, alleviating or ameliorating one or more signs or symptoms; slowing the extent of a disease, disorder, or condition; stabilizing (ie, not worsening) the state of the disease, disorder, or condition; preventing the disease, disorder, or Symptoms spread; delay or slow the progression of a disease, condition or symptom; improve or alleviate a disease, condition or symptom; and relieve (partially or completely), whether detectable or undetectable. "Palliating" disease, condition or symptom means the degree or duration of a disease, condition or symptom, and/or undesired clinical manifestation and/or slowing down or extend.

The term "unit dosage form" means suitable for use as a human individual and other A physically discrete unit of unit dose of a milk animal, each unit containing a predetermined amount of an effective material calculated to produce the desired therapeutic effect and any suitable pharmaceutical excipient or agents. Non-limiting unit dosage forms include, for example, tablets (eg, chewable tablets), swallowable tablets, capsules (eg, hard or soft capsules), diamond shaped lozenges, films, strips, gel capsules. And syrup.

In some examples, the compound can include one or more optically active heart. The compounds include individual isolated stereoisomers, and mixtures of stereoisomers of varying degrees of optical purity, including racemic mixtures. Also included are various non-image isomers, mirror image isomers, and tautomers that may be formed.

Useful compounds can also be isotopically calibrated compounds. Useful isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine (eg, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S , ¹⁸ F, and ³⁶ Cl). Isotope-labeled compounds can be prepared by synthesizing compounds using readily available isotope-labeled reagents instead of reagents that are not isotopically labeled. In some embodiments, the compound or compound-containing composition, each element is abundantly present.

The compounds described herein are also useful for the treatment of fungal infections. Manufacturing.

Other features and advantages will be described in detail below and patent pending. Enclosed.

Synthetic difunctional compounds (e.g., non-antibody compounds) useful for treating fungal infections include chemotactic receptor ligand structure E and polyene antifungal structures. The inventors of the present invention have found that such compounds can have increased antifungal activity because they can bind to the fungal cell wall by forming a complex with ergosterol and structurally related sterols in the lipid bilayer. This drives a concentration gradient near the site of infection, and the chemotactic receptor ligand can thus act as a gradient against the neutrophil chemotaxis to this location. Compounds include, but are not limited to, compounds 1-16.

Polyene antifungal agent

Polyene antifungal agents are antifungal antibiotics comprising a macrocyclic ester ring and a series of 3 to 8 conjugated carbon-carbon double bonds, and may also include a sugar structure and an aromatic structure. The polyene antifungal agent can be inserted into the fungal cell membrane by binding to ergosterol or a structurally similar sterol in the fungal lipid bilayer, forming agglomerates and ergosterol-antibiotic complexes therein. . The antifungal action of such agents is generally due to the destruction of the fungal cell membrane, causing leakage of K ⁺ and Na ⁺ ions and other cellular components. There are many classes of polyene antifungal agents, including but not limited to 67-121-A, 67-121-C, amphotericin B, arenomvcin B, aurenin, aureofungin A, aureotuscin, candidin, chinin, de A Rapamycin, dermostatin A, dermostatin B, DJ-400-B ₁ , DJ-400-B ₂ , elizabethin, eurocilin A, eurocilin B, Filipin I, Filipin II, Filipino III, Filipino IV, fungichromin, gannibamycin, hamycin, levoin A ₂ , lennomycin, lusensomycin, mycoheptin, mycoticin A, mycoticin B, natamycin ( Natamycin), nystatin A, nystatin A ₃ , partricin A, partricin B, perimycin A, pimamycin (pimaricin), polifungin B, rapamycin, rectilavendomvcin, rimoidin, rhodamine (roflamycoi) n) An antifungal agent of tetramycin A, tetramycin B, tetrin A or tetrin B.

Polyene antifungal agents described herein include, but are not limited to, for example, compounds having the following structure:

Wherein each R ¹ , R ² and R ^{3 are} independently hydrogen, hydroxy, optionally substituted C1-C6 alkyl or alternatively substituted aryl (C6-C12)alkyl (C1-C8); R ^{4 is} independently hydrogen, hydroxy, optionally substituted C1-C6 alkyl or pendant oxy; each R ⁵ and R ^{6 are} independently hydrogen, hydroxy or C1-C6 alkoxy; R ⁹ is hydroxy, amine a group or a linker; R ¹⁰ is hydrogen or a hydroxyl group; R ¹¹ is a hydroxyl group or an amine; R ¹² is hydrogen or m is an integer between 5 and 13; n is an integer between 3 and 8; p is 0, 1 or 2; q is 1, 2 or 3; A' is or ; Each of B 'and C' are independently hydrogen, hydroxy, C1-C6 alkyl, oxo, or B 'and C' to form -O-; R ⁹ is _{^{-NR 13 (CH 2) a NR}} 13 or - NR ¹³ (CH ₂ ) _a O(CH ₂ ) _a NR ¹³ ; each R ^{13 is} independently hydrogen or a C1-C3 alkyl group; and each a is independently an integer between 2 and 4, wherein the dash bond is a single A bond or a double bond, provided that the compound of formula II comprises at least two double bonds.

Another example of the formula is:

Wherein each R ¹ , R ² and R ^{3 are} independently hydrogen, hydroxy, optionally substituted C1-C6 alkyl, or alternatively substituted C6-C12 aryl-C1-C6 alkyl; each R ^{4 is} independently The ground is hydrogen, a hydroxyl group, a C1-C6 alkyl group or a pendantoxy group which is optionally substituted; each of R ⁵ and R ^{6 is} independently hydrogen, a hydroxyl group or a C1-C6 alkoxy group; each of R ⁹ and R ^{10 is} independently Hydrogen, hydroxy, optionally substituted C1-C6 alkyl, pendant oxy or R ⁹ and R ^{10 are} bonded to -O-; R ¹¹ is hydroxy, amine or linker; R ¹² is hydrogen or hydroxy; R ¹³ Is a hydroxyl group or an amine; R ¹⁴ is hydrogen m is 3 to 13; n is an integer between 3 and 8; p is 0, 1 or 2; q is 1, 2 or 3; A' is or Each B' and C' is independently hydrogen, hydroxy, C1-C6 alkyl, pendant oxy or B' combined with C' to form -O-.

Specifically, R ¹¹ is -NR ¹⁵ (CH ₂ ) _a NR ¹⁵ or -NR ¹⁵ (CH ₂ ) _a O(CH ₂ ) _a NR ¹⁵ ; each R ^{15 is} independently hydrogen or C1-C3 alkyl; a is independently an integer between 2 and 4.

Other polyene antifungal agents are known in the art, such as amphotericin B, natamycin, and nystatin, having the structure shown below: Amphotericin B

Natamycin

Nystatin.

Other exemplary polyene antifungal agents include, but are not limited to: C2'-deoxy amphotericin B

Britanidin

Filipin

Candidin

In some embodiments, any of the foregoing compounds can be used as a polyene antifungal agent.

Chemotactic receptor

Chemotactic receptors are receptors of the innate immune system. The innate immune system represents the defensive machine that the host uses immediately or within hours when exposed to the antigen, which

This antigen is not specific. Unlike acquired immunity, previous immunization does not recognize every possible antigen. Instead, it is designed to identify some highly comserved structures that appear in many different pathogens. In some aspects, the identified structure is a pathogen-associated molecular pattern, including lipopolysaccharide (LPS), peptidoglycan, from Gram-negative bacterial cell wall, from Gram. Lipotechoic acid in the cell wall of positive bacteria, mannose, trehalose, N-ethyl glucosamine, bacterial DNA, N-methyl methionine, and double-stranded virus from viruses found in bacterial proteins RNA, and dextran from the fungal cell wall.

Chemotaxis includes migration of immune cells and activation of immune cells. In general, activation of immune cells includes, for example, directing their migration to the site of inflammation and/or infection; stimulating phagocytic cells and releasing toxic mediators both internally and externally, which destroy infectious agents and/or infected cells; A series of interleukins and vasoactive mediators; presenting antigens to promote humoral responses (antibodies from B cells) and cellular responses (T lymphocytes), and adhering platelets to the affected surface, releasing immunologically active mediators Substance to promote coagulation.

Most body defense cells have a pattern recognition receptor for the molecular pattern associated with these common pathogens. Therefore, the original response to the invading pathogenicity. Molecular patterns associated with pathogens can also be identified by a series of soluble pattern recognition receptors (PRRs) in the blood that act like opsonin and initiate the complement pathway. The innate immune system is considered to identify a total of about 10 ³ molecules mode.

As used herein, "PRR" refers to a surface PRR or a soluble PRR. Cell surface PRR can be subdivided into two functionally distinct categories: endocytic recognition receptors and signal pattern recognition receptors. The endocytic pattern recognition system is found on the surface of immune cells, which promotes the adsorption of pathogens to phagocytic cells and their subsequent engulfment and destruction.

Exemplary PRRs include mannose receptors (mannose) Receptor, MR), foryl-peptide receptor (FPR), toll-like receptor (TLRs), CD14, and nucleotide binding oligomerization protein (nucleotide binding oligomerization protein, NOD). Ligand binding to these receptors also promotes the synthesis and secretion of intracellular regulatory molecules (immune regulatory signals), for example, interleukins that are important for initiating innate and acquired immunity.

Compounds described herein can be used in any of the PRRs known in the art or described herein.

Methotrexate receptor

The family of methotrexate receptors belongs to the class of chemotactic receptors. FPR is a G protein-coupled receptor, which is mainly expressed in neutrophils and some macrophages or phagocytic lineages. The most thoroughly characterized ligand for these receptors is a peptide or protein fragment containing an N-methylmercaptomethionine residue that is a marker for a protein of prokaryotic origin. Thus, these peptides serve as effective immune homing signals for bacterial infection sites; signals for neutrophil response and activation at many stages, including chemical attraction; stimulation of immune signaling molecules (eg, interleukin, The production and release of interleukins, as well as degranulation, which include the chemical (eg, hydrogen peroxide and other reactive oxygen species) and enzyme properties of the production and release of exogenous agents or pathogens. Agents (eg, elastase and other digestions) Cellular steps of sex enzymes).

Yu Ren, has identified five related FPR family members: Hyperthyroidism Peptide receptor 1 (FPR1), FPR2, FPR3, methionyl peptide receptor-1 (FPRL1), and FPRL2. One of the naturally occurring ligands for FPR is formazan-methionine-leucine-phenylalanine (fMLF), while one of the non-natural ligands for FPR is formazan-methionine-alkamine Acid-(2-pyridyl)alanine.

Cellular responses to the thiol peptide receptor mediator include cell polarization and Transmigration, production of superoxide O2 radicals via respiratory burst oxidase, degranulation and release of various metamorphic enzymes, and phagocytosis. In some embodiments, the compound interacts with the FPR and induces at least one cellular response.

Formyl peptide receptor ligand

Formyl peptide receptor ligands are known in the art. Some are known as agonists, for example, the naturally occurring ligand for FPR as described above is formazan-methionine-leucine-phenylalanine (fMLF). Some are known as antagonists, for example, non-naturally occurring isobutoxycarbonyl-methionine-leucine-phenylalanine (ibMLF), which binds to FPR and interferes with agonist activity. Many synthetic mimics of fMLF have been shown to elicit an immune response. Such mercaptopeptides and antagonists can be used as chemotactic receptor ligands in the compounds described herein, for example, compounds of Formulas I-IV.

Chemotactic receptor ligand structure, including but not limited to peptides comprising the formula: R ¹⁴ -X1-X2-X3-X4-X5-X6-X7-X8-X9-

Wherein X1 is any amino acid residue; X2-X9 are each an amino acid residue or are absent; R ¹⁴ is hydrogen or Wherein X ₁₀ is a bond, NH or O; R ¹⁵ is hydrogen, a C1-C6 alkyl group which is optionally substituted, a C1-C6 heteroalkyl group which is optionally substituted, and a C2-C6 alkenyl group which is optionally substituted a selectively substituted C2-C6 heteroalkenyl group, a selectively substituted C2-C6 alkynyl group, a selectively substituted C2-C6 heteroalkynyl group, a selectively substituted C3-C10 cycloalkyl group, optionally Substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 cycloalkynyl, optionally substituted fluorene, optionally substituted fluorene, optionally substituted C6-C12 aryl or alternatively Substituted C2-C6 heterocycle.

In some aspects, the chemotactic receptor ligand comprises two amino acid residues, three amino acid residues, four amino acid residues or five amino acid residues, in particular, formazan. Methyl-methionine-leucine (fML), fMLF, fML (2-pyridyl-alanine), fML (4-pyridyl-alanine), ibMLF, fMLF-beta-deampamic acid, N- Ethyl-MLF-beta-alanine, ibMLF-beta-alanine, fMIFL, fMIVIL, N-(p-chlorophenyl-aminocarbonyl)-MLF, fMLF(N-epsilon-胍)K, fMLF(N -alpha-胍) K, fMLM, fML (O-benzyl) serine, N-ethinyl-PGP, and TKPR.

In a particular embodiment, the chemotactic receptor ligand structure is a chemotactic peptide, which may comprise, consist essentially of, or consist of an amino acid having the formula: R ¹⁴ -X1-X2-X9-Formula VI

X1 is any amino acid residue; X2 is leucine or isoleucine or is absent; X9 is any amino acid residue; R ¹⁴ is hydrogen or X ₁₀ is a bond, NH or O; and R ¹⁵ is hydrogen, a C1-C6 alkyl group which is optionally substituted, a C1-C6 heteroalkyl group which is optionally substituted, and a C2-C6 alkenyl group which is optionally substituted a selectively substituted C2-C6 heteroalkenyl group, a selectively substituted C2-C6 alkynyl group, a selectively substituted C2-C6 heteroalkynyl group, a selectively substituted C3-C10 cycloalkyl group, optionally Substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 cycloalkynyl, optionally substituted fluorene, optionally substituted fluorene, selectively substituted aryl or alternatively substituted ring.

In certain embodiments, the chemotactic peptide may comprise, consist essentially of, or consist of an amino acid residue having the formula: R14-X1-X2-X9-Formula VI

Wherein X1 and X9 are hydrophobic amino acid residues, and X2 is a hydrophobic amino acid residue or is absent.

Amino acid residues which may be included in the chemotactic peptide may be selected from naturally occurring amino acid residues (eg, Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys). , Met, Phe, Pro, Ser, Thr, Trp, Tyr or Val) or a non-naturally occurring amino acid residue. A "non-naturally occurring amino acid residue" is an amino acid residue that is not naturally produced or found in a mammal. a non-naturally occurring amino acid residue, for example, comprising a D-amino acid residue; an amino acid residue having an ethyl sulfhydryl methyl group attached to a sulfur atom of cysteine; a PEGylated amino acid Residue; an omega amino acid residue of the formula NH ₂ (CH ₂ ) _n COOH wherein n is 2-6; a neutral non-polar amino acid residue such as sarcosine, tert-butylalanine , tert-butylglycine, N-methylisoleucine, and norleucine; oxymethionine; phenylglycine; citrulline; imipenate; oxidized half Cysteine; acineline; diaminobutyric acid; diaminopropionic acid; and hydroxyproline. Other amino acid residues are α-aminobutyric acid, α-amino-α-methylbutyrate, aminocyclopropane-carboxylate, aminoisobutyric acid, amine-mercapto-carboxylic acid (aminonorbornyl-carboxylate), L-cyclohexylalanine, cyclopentylalanine, LN-methyl leucine, LN-methylmethionine, LN-methylnorsine, LN-methyl Phenylalanine, LN-methylproline, LN-methylserine, LN-methyltryptophan, D-ornithine, LN-methylethylglycine, L-positemin, --methyl-aminoisobutyrate, α-methylcyclohexylalanine, D-α-methylalanine, D-α-methyl arginine, D-α-methyl aspartate Acid, D-α-methyl aspartic acid, D-α-methylcysteine, D-α-methyl glutamic acid, D-α-methyl histidine, D-α-methyl Isoleucine, D-α-methyl leucine, D-α-methyl lysine, D-α-methylmethionine, D-α-methylornithine, D-α- Methamphetamine, D-α-methylproline, D-α-methylserine, DN-methylserine, D-α-methylthreonine, D-α-methyl Amine acid, D-α-methyl tyrosine, D-α-methylproline, DN-methyl alanine, DN-A Base arginine, DN-methyl aspartate, DN-methyl aspartic acid, DN-methylcysteine, DN-methyl glutamic acid, DN-methyl glutamic acid, DN-methylhistamine, DN-methylisoleucine, DN-methyl lysine, DN-methyl lysine, N-methylcyclohexylalanine, DN-methylornithine, N-methylglycine, N-methylaminoisobutyrate, N-(1-methylpropyl)glycine, N-(2-methylpropyl)glycine, DN-A Primate, DN-methyltyrosine, DN-methylproline, γ-aminobutyric acid, L-t-butylglycine, L-ethylglycine, L-high amphetamine Acid, L-α-methyl arginine, L-α-methyl aspartic acid, L-α-methylcysteine, L-α-methyl glutamic acid, L-α-A Histamine, L-α-methylisoleucine, L-α-methyl leucine, L-α-methylmethionine, L-α-methyl-proline, L- --methyl phenylalanine, L-α-methyl serine, L-α-methyltryptophan, L-α-methylproline, N-(N-(2,2-diphenyl) Ethyl)amine,mercaptomethylglycine, 1-carboxy-1-(2,2-diphenyl-ethylamino)cyclopropane, 4-hydroxyproline, ornithine, 2-amine Base benzene Anthracene (anthraniloyl), D-cyclohexylalanine, 4-phenyl-phenylalanine, L-citrulline, α-cyclohexylglycine, L-1,2,3 , 4-tetrahydroisoquinoline-3-carboxylic acid, L-thiazolidine-4-carboxylic acid, L-high tyrosine (homotyrosine), L-2-mercaptoalanine, L-histamine (3 -Methyl), N-(3-mercaptopropyl)glycine, O-methyl-L-tyrosine, O-dextran-serine, meta-tyrosine, Tyrosine acid, LN, N ' , N " -trimethyl lysine, high lysine, ortho-amine, N-glucan aspartic acid, 7-hydroxy-1, 2, 3 ,4-tetrahydro-4-fluorophenylalanine, 4-methylphenylalanine, bis-(2-methylpyridyl)amine, pentafluorophenylalanine, porphyrin-2-carboxylic acid, 2-aminobenzoic acid , 3-amino-2-naphthoic acid, asymmetric dimethyl arginine, L-tetrahydroisoquinoline-1-carboxylic acid, D-tetrahydroisoquinoline-1-carboxylic acid, 1-amino group -cyclohexaneacetic acid, D/L-allylglycine, 4-aminobenzoic acid, 1-amino-cyclobutanecarboxylic acid, 2 or 3 or 4-aminocyclohexanecarboxylic acid, 1 -Amino-1-cyclopentanecarboxylic acid, 1-aminoindoline-1-carboxylic acid, 4-amino-pyrrolidine-2-carboxylic acid, 2-aminotetrahydronaphthalene-2-carboxylic acid , Methyleneimine-3-carboxylic acid, 4-benzyl-pyrrolidine-2-carboxylic acid, tert-butylglycine, b-(benzothiazolyl-2-yl)-alanine, b-ring Propylalanine, 5,5-dimethyl-1,3-thiazolidin-4-carboxylic acid, (2R,4S)4-hydroxypiperidine-2-carboxylic acid, (2S,4S) and (2S, 4R)-4-(2-naphthylmethoxy)-pyrrolidine-2-carboxylic acid, (2S,4S) and (2S,4R)4-phenoxy-pyrrolidine-2-carboxylic acid, (2R , 5S) with (2S, 5R)-5-phenyl-pyrrolidine-2-carboxylic acid, (2S,4S)-4-amino-1-benzimidyl-pyrrolidine-2-carboxylic acid, Tributylalanine, (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-methyl- ortho-aminobenzoic acid, LN-methylalanine, LN-methyl Amine acid, LN-methyl aspartic acid, LN-methyl aspartic acid, LN-methylcysteine, LN-methyl glutamic acid, LN-methyl glutamic acid, LN- Methylhistamine, LN-methylisoleucine, LN-methyl lysine, LN-methyl-leucine, LN-methylornithine, LN-methylthreonine, LN- Methyl tyrosine, LN-methylproline, LN-methyl-t-butyl Glycine, L- valine, n, methyl alpha] -γ- amine butyrate, 4,4 '- with phenylalanine, alanine alpha] methylcyclopentyl, methyl alpha] -α- Naphthylalanine, α-methylpenicillamine, N-(4-aminobutyl)glycine, N-(2-aminoethyl)glycine, N-(3-aminopropyl) Glycine, N-Amino-α-methylbutyrate, α-naphthylalanine, N-benzylglycine, N-(2-aminoformateethyl)glycine, N-( Aminylmethyl)glycine, N-(2-carboxyethyl)glycine, N-(carboxymethyl)glycine, N-cyclobutylglycine, N-cyclodecane Glycine Acid, N-cycloheptylglycine, N-cyclohexylglycine, N-cyclodecylglycine, N-cyclododecylglycine, N-cyclooctylglycine, N-ring Propylglycine, N-cycloundecylglycine, N-(2,2-diphenylethyl)glycine, N-(3,3-diphenylpropyl)glycine, N-(3-mercaptopropyl)glycine, N-(1-hydroxyethyl)glycine, N-(hydroxyethyl)glycine, N-(imidazolylethyl)glycine Acid, N-(3-mercaptoethyl)glycine, N-methyl-γ-aminobutyrate, DN-methylmethionine, N-methylcyclopentylalanine, DN -methampheic acid, DN-methylproline, DN-methylthreonate, N-(1-methylethyl)glycine, N-methyl-naphthylalanine, N-methylpenicillamine, N-( p-Hydroxyphenyl)glycine, N-(thiomethyl)glycine, penicillamine, L-α-methylalanine, L-α-methylaspartic acid, L-α-methyl -T-butylglycine, L-methylethylglycine, L-α-methylglutamic acid, L-α-methyl homophenylalanine, N-(2-methylthioethyl) Glycine, L-α-methyl-aspartic acid, L-α-methyl-leucine, L-α-methylornithine, L-α-methylproline, L-α-A Baseuric acid, L-α-methyltyrosine, LN-methyl-homophenylalanine, N-(N-(3,3-diphenylpropyl)aminecarboxylic acid methylglycine, L -pyroglutamic acid, D-pyroglutamic acid, O-methyl-L-serine acid, O-methyl-L-homoserine, 5-hydroxyisamino acid, α-carboxy glutamic acid, benzene Glycine, L-hexahydronicotinic acid (high glutamic acid), L-high leucine, L-isoamine (dimethyl ester), L-2-naphthylalanine, L-dimethyl Gidopa or L-dimethoxy-phenylalanine, L-3-pyridyl alanine, L-histamine (benzyloxymethyl), N-cycloheptylglycine, L-di Amphetamine Acid, O- methyl-high -L- tyrosine, L-β- high lysine, O- dextran - threonine, tyrosine o- (ortho-tyrosine), LN, N '- dimethyl Amino acid, L-high arginine, neotryptophan, 3-benzothienyl alanine, isoquinoline-3-carboxylic acid, diaminopropionic acid, homocysteine, 3,4 -Dimethoxyphenylalanine, 4-chlorophenylalanine, L-1,2,3,4-tetrahydropalhalogen-3-carboxylic acid (L-1,2,3,4-tetrahydronorharman-3- Carboxylic acid),adamantylalanine,symmetric dimethyl arginine, 3-carboxythiomorpholine, D-1,2,3,4-tetrahydro-halogen Carboxylic acid (D-1,2,3,4-tetrahydronorharman-3-carboxylic acid), 3-aminobenzoic acid, 3-amino-1-carboxymethyl-pyridin-2-one, 1-amino group- 1-cyclohexanecarboxylic acid, 2-aminocyclopentanecarboxylic acid, 1-amino-1-cyclopropanecarboxylic acid, 2-aminoindoline-2-carboxylic acid, 4-amino-tetrahydrogen Thiopidine-4-carboxylic acid, azetidine-2-carboxylic acid, b-(benzothiazol-2-yl)-alanine, neopentylglycine, 2 -carboxymethylpiperidine, b-cyclobutylalanine, allylglycine, diaminopropionic acid, high - Cyclohexylalanine, (2S,4R)-4-hydroxypiperidine-2-carboxylic acid, octahydropurin-2-carboxylic acid, (2S,4R) and (2S,4R)-4-(2-naphthalene , 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-tritylmethylfluorenyl-pyrrolidine-2-carboxylic acid, (2S,4S)-4-mercaptoproline, Third butyl glycine, N,N-bis(3-aminopropyl)glycine, 1-amino-cyclohexane-1-carboxylic acid, N-decylethylglycine, and selenium Cysteine.

In certain embodiments, X1 is selected from the group consisting of methionine, oxymethionine or orthanoic acid residues or absent. In certain embodiments, X2 is selected from the group consisting of leucine and isoleucine or the absence of a residue. In certain embodiments, X9 is selected from the group consisting of phenylalanine, 1-amino-2-phenylcyclopropane-1-carboxylic acid, methionine, (O-benzyl) serine, 2-pyridylpropylamine Acid, 4-pyridylalanine residue. In certain embodiments, R ¹⁴ is -H. In certain embodiments, R ¹⁴ is —C(O)H. In certain embodiments, R ¹⁴ is —C(O)CH ₃ . In other embodiments, R ¹⁴ is -C(O)OCH ₂ CH(CH ₃ ) ₂ . In other embodiments, R ¹⁴ is -C(O)N-4-chlorophenyl. In various embodiments, each of the above selections regarding X1, X2, X9, and R ¹⁴ can be considered to be independent of each other and differently from each other.

In some embodiments, the chemotactic receptor ligand structure E is

In some embodiments, the chemotactic receptor ligand structure E is

In some embodiments, the chemotactic receptor ligand structure E has a structure selected from the group consisting of

In some embodiments, the chemotactic receptor ligand structure E has a structure selected from the group consisting of

In some embodiments, the chemotactic receptor ligand structure E has a structure selected from the group consisting of

In some embodiments, the compounds described herein can be used to make a chemotactic receptor ligand comprising, consisting essentially of, or consisting of:

J Exp Med 180, 2191-7 (1994) discloses methionine-based leucine-indenyl-alkamine-phenylalaninyl-phenylalanine (MNleLFF) as a FPR ligand, which is incorporated herein by reference. Bioorg Med Chem, 21, 668-675 (2013) discloses fMLX-OMe as a FPR ligand, incorporated herein by reference, wherein X-OMe has the following structure:

J. Peptide Res., 2000, 55, 102-109 discloses peptides containing N-terminal thiol or carbhydryl groups as FPR ligands, which are incorporated herein by reference, having the following structure:

IL FARMACO 59 (2004) 953-963 discloses β-peptido sulfonamide as a FPR ligand, which is incorporated herein by reference, including Boc-Met-Tau-Phe-OMe; HCO-Met-Tau- Phe-OMe; Met-Tau-Phe-OMe, Boc-Met-β ³ -HLeu-Phe-OMe; HCO-Met-β ³ -HLeu-Phe-OMe; Boc-Met-Leu-ψ[CH ₂ SO ₂ ]-Phe-OMe; HCO-Met-Leu-ψ[CH ₂ SO ₂ ]-Phe-OMe; Boc-Met-Tau-Phe-Phe-OMe; HCO-Met-Tau-Phe-Phe-OMe. European Journal of Pharmacology 436 (2002) 187-196 discloses peptides containing 3V,5V-dimethylphenyl-ureido as FPR ligands, incorporated herein by reference, including: 3V, 5V-dimethylphenyl- Urea-Phe-D-Leu-Phe-D-Leu-Phe-olo; 3V, 5V-dimethylphenyl-ureido-Phe-D-Leu-Phe-D-Leu-Glu; 3V, 5V- Dimethylphenyl-ureido-Phe-D-Leu-Phe-D-Leu-Tyr. Bioorganic & Medicinal Chemistry 14 (2006) 2253-2265 discloses peptides containing proline as FPR ligands, which are incorporated herein by reference, having the following structure:

Amino Acids (2008) 35 329-338 discloses peptides as FPR ligands, which are incorporated herein by reference, having the following structure:

Other peptides as FPR ligands are disclosed in Pept Res. 6, 298-307 (1993), incorporated herein by reference, having the following structure:

J. Peptide Sci. 10, 67-81 (2004) discloses a fluorine-modified peptide as a FPR ligand, which is incorporated herein by reference, HCO-Met-(S)-DfeGly-Phe-NH ₂ ; HCO-Met-( R)-DfeGly-Phe-NH ₂ ;HCO-Met-(S)-(αTfm)Ala-Phe-NH ₂ ;HCO-Met-(R)-(αTfm)Ala-Phe-NH ₂ ;HCO-Met- Aib-Phe-NH ₂ ; HCO-Met-(R)-(αDfm)Ala-Phe-NH ₂ . Further, Biochemistry 19, 2404-2410 (1980) further discloses peptides as FPR ligands, which are incorporated herein by reference, HCONle-Leu-Phe-OH; HCO-Nva-Leu-Phe-OH; HCO-Hep-Leu-Phe -OH; HCO-Ile-Leu-Phe-OH; HCO-Met-Ala-Leu-Phe-OH; HCO-Met-Leu-Phe-Lys-OH. Further peptides as FPR ligands are disclosed in Eur. J. Immunol. 35, 2486-2495 (2005), incorporated herein by reference. Amino Acids 30, 453-459 (2006) discloses a mixed alpha/beta peptide as a FPR ligand, which is incorporated herein by reference and has the following structure:

J. Peptide Sci. 10, 510-523 (2004) discloses a mixed αβ3-peptide as a FPR ligand, which is incorporated herein by reference, and includes the following structures:

J. Peptide Res., 59, 283-291 (2002) discloses peptides containing isopeptide bonds as FPR ligands, which are incorporated herein by reference. Arch. Pharm. Pharm. Med. Chem. 331, 170-176 (1998) discloses peptides containing a constrained mimetic of amphetamine as FPR ligands, which are incorporated herein by reference, including the following structures:

Bioorganic & Medicinal Chemistry 17, 251-259 (2009) discloses other proline-containing peptides as FPR ligands, which are incorporated herein by reference. J. Peptide Sci. 7, 56-65 (2002) discloses more peptides as FPR ligands, which are incorporated herein by reference, including the following structures:

J. Peptide Res. 58, 56-66 (2001) discloses pseudopeptides as FPR ligands, which are incorporated herein by reference, and include the following structures:

Other peptides are disclosed as FPR ligands by Bioorganic Chemistry 34, 298-318 (2006), which is incorporated herein by reference. Il Farmaco 58, 1121 (2003) discloses other peptides as FPR ligands, which are incorporated herein by reference, including: HCO-Met-β-Ala-Phe-OMe, Boc-Met-Tau-Phe-OMe, and HCO-Met -Tau-Phe-OMe. Il Farmaco 56, 851-858 (2001) discloses peptides having alkyl spacers as FPR ligands, which are incorporated herein by reference, and include the following structures:

Amino Acids 37, 285-295 (2009) discloses tetrapeptides as FPR ligands, which are incorporated herein by reference, including those having the following structures:

Eur. J. Med. Chem. 27, 19-26 (1992) discloses peptides comprising substituted glycine as FPR ligands, which are hereby incorporated by reference, including the following:

J. Pept. Sci. 18, 418-426 (2012) discloses peptides with para-substituted phenylalanine as FPR ligands, which are incorporated herein by reference. Pept Sci, 269-272 (2002) discloses other peptides as FPR ligands, which are incorporated herein by reference. Amino Acids 33, 477-487 (2007) discloses centrally modified pseudopeptides as FPR ligands, which are incorporated herein by reference. TRENDS in Immunology Vol. 23 No. 11 November 2002 discloses other peptides as FPR ligands, which are incorporated herein by reference. More peptides are disclosed as FPR ligands by Cytokine & Growth Factor Reviews 17 (2006) 501-519, which is incorporated herein by reference.

An additional example of a chemotactic receptor ligand is a phagocytosis (tuftsin) (also referred to herein as a phagocytic hormone peptide) by enzymatically Fc domain of the heavy chain of immunoglobulin G. Sexually cleaved tetrapeptide (Thr-Lys-Pro-Arg), for example

Phagocytic hormone

Phagocytic hormones bind to specific receptors on the surface of macrophages and polymorphonuclear leukocytes, stimulating their migration and endocytic activity. It also affects antibody formation.

Another example of a chemotactic receptor ligand is N-ethyl decyl-proline-glycine-proline (PGP) peptide, which is a chemotactic peptide, a collagen rupture product that attracts susceptibility. Neutral ball. In some aspects, the ethyl hydrazino-based PGP ligand is N-ethinyl-L-amidino-glycinyl-L-nonylamine having the following structure:

The phagocytic hormone or PGP peptide structure can be attached to the polyene antifungal structure via the carboxy terminus of the amino acid residue. The phagocytic hormone structure that can be joined to the polyene antifungal structure via the carboxy terminus of the phagocytic hormone structure comprises the following structure:

N-Ethyl-L-amidino-glycolyl-L-proline (PGP) peptide structure capable of binding to a polyene antifungal structure via a terminal carboxylic acid group of a PGP peptide structure, including the following structure:

Link

In some embodiments, the compound comprises a linker. The linker component is the simplest one-link, but usually provides a linear, circular or branched molecular skeleton with covalently linked two structures (eg, chemotactic receptor ligands and polyene antifungals) The pendant of the structure of the agent.

Thus, the linkage of a structure (e.g., the structure of a chemotactic receptor ligand to a polyene antifungal agent) is achieved by a covalent means involving the formation of a bond of one or more functional groups. Chemically reactive functional groups that may be employed in the examples of this application include, but are not limited to, amine groups, hydroxyl groups, mercapto groups, carboxyl groups, carbonyl groups, sugar groups, vicinal diols, thioethers, 2-amino alcohols, 2-amino groups. Mercaptan, mercapto, imidazolyl, and phenolic groups.

The covalent linkage of the structure can be effected by a linker comprising a reactive structure capable of reacting with a functional group in either structure. For example, the amine group of the structure and the carboxyl group of the linker or an activated derivative thereof act to form a guanamine linking the two structures.

A structure capable of reacting with a sulfhydryl group, for example, an α-haloethenyl compound including an XCH ₂ CO- (wherein, X = Br, Cl or I) type, which exhibits a particular reactivity to a thiol group, but Gurd , Methods Enzymol. 11: 532 (1967) describes that it can also be used to modify imidazolyl, thioether, phenol and amine groups. N-maleimide derivatives are also considered to be selective for sulfhydryl groups, but coupling with amine groups is considered more useful in certain situations. A reagent, for example, 2-iminothiolane (Traut et al., Biochemistry 12: 3266 (1973)), which converts an amine group to introduce a thiol group, if the linkage is via formation of a double Produced by a sulfur bridge, which can be considered a sulfhydryl reagent.

Examples of the reactive structure capable of reacting with an amine group include, for example, an alkylating group and a thiolating agent. Representative alkylating agents include: (i) an alpha-haloethyl fluorenyl compound which exhibits specificity for the amine group in the absence of a reactive thiol group and is XCH ₂ CO-type (where X = Br , Cl or I), as described in Wong Biochemistry 24: 5337 (1979); (ii) N-maleimide derivatives which can react with amine groups via Michael type reaction or by addition to a cyclic carbonyl group And thiolation, for example, as described by Smyth et al., J. Am . Chem . Soc. 82: 4600 (1960) and Biochem. J. 91: 589 (1964); (iii) haloaralkyl, for example, reactivity a nitrohalide aromatic compound; (iv) a halogenated alkane, such as described by McKenzie et al., J. Protein Chem . 7: 581 (1988); (v) an aldehyde and a ketone capable of forming a Schiff base with an amine group, the formation The adduct is usually reduced to a stable amine and stabilized; (vi) an epoxide derivative such as epichlorohydrin and bisoxirane, and an amine group, a mercapto group or a phenol Hydroxyl reaction; (vii)s-three a chlorine-containing derivative which is very reactive with nucleophiles such as amine groups, sulfhydryl groups and hydroxyl groups; (viii) based on the above s-three Aziridine of the compound, as described, for example, in Ross, J. Adv . Cancer Res . 2:1 (1954), which is reacted by a ring opening and a nucleophile such as an amine group; Ix) diethyl squarate, as described by Tietze, Chem . Ber. 124: 1215 (1991); and (x) α-haloalkyl ethers, which are activated by ether oxygen atoms, compared to the usual halo It is a more reactive alkylating agent as described by Benneche et al., Eur . J. Med. Chem. 28: 463 (1993).

Representative amine-based reactive guanylating agents, including: (i) isocyanates and isocyanates, especially aromatic derivatives, each forming a stable urea and thiourea derivative; (ii) sulfonium chloride, described in Herzig et al., Biopolymers 2: 349 (1964); (iii) hydrazine halide; (iv) active ester, for example, nitrophenyl ester or N-hydroxy amber imidate (v) Anhydride, for example, a mixed, symmetric or N-carboxy anhydride; (vi) other reagents useful for the formation of a guanamine bond, for example, as described in M. Bodansky, Principles of Peptide Synthesis , Springer-Verlag, 1984 (vii) acylazide, for example, wherein the azide group is produced by a hydrazine derivative pre-formed using sodium nitrite, such as Wetz et al., Anal . Biochem. 58:347 (1974). And (viii) an imidoester which reacts with an amine group to form a stable oxime, as described, for example, by Hunter and Ludwig, J. Am. Chem. Soc. 84:3491 (1962).

The aldehydes and ketones can be reacted with an amine to form a Schiff base which can be advantageously stabilized via reductive amination. The alkoxyamino structure readily reacts with a ketone and an aldehyde to produce a stable alkoxyamine, for example, as described by Webb et al., in Bioconjugate Chem . 1:96 (1990).

And examples can be reacted with a carboxyl reactive structure, include azo (Diazo) compounds, e.g., azo and azo acetate as acetamide, which will react with high specificity to generate ester groups, e.g. Herriot, Adv. Protein Chem. 3: 169 (1947). A carboxyl modifying agent can be employed, for example, carbodiimide, which will form a guanamine bond via the formation of O-decyl urea.

It should be understood that in each structure (eg, chemotactic receptor ligand knot The functional group of the structure or polyene antifungal structure may optionally be converted to other functional groups prior to the reaction, for example, to provide additional reactivity or selectivity. Processes for this use, for example, include the conversion of an amine to a carboxyl group using, for example, a dicarboxylic anhydride; the use of, for example, N-ethinyl homocysteine thiolactone, S-ethyl decyl succinic anhydride, 2-Asia An amine tetrahydrothiophene or a mercaptan-containing amber quinone derivative, which converts an amine to a thiol; uses, for example, an alpha-haloacetate to convert a thiol to a carboxy group; using, for example, an ethylenimine or a 2-bromoethyl group An amine that converts a thiol to an amine; the use of, for example, a carbodiimide, followed by the use of a diamine to convert the carboxyl group to an amine; the use of toluenesulfonyl chloride, followed by transesterification with thioacetate, and hydrolysis with sodium acetate a mercaptan to convert an alcohol to a mercaptan.

The compound here can be used as a so-called zero-length link as needed. Sub-, which involves direct covalent bonding of a reactive chemical group of one structure to a reactive chemical group of another structure, which does not introduce additional linking materials.

However, as mentioned above, the linker often includes 2 connected by a spacer element. One or more reactive structures. The presence of the spacer allows the bifunctional linker to react with a particular functional group in either structure (e.g., a chemotactic acceptor ligand structure or a polyene antifungal structure) to create a covalent linkage between the two. The reactive structures in the linker may be the same (same bifunctional linker) or different (heterobifunctional linkers, or heteromultimeric linkers when several dissimilar reactive structures are present), The diversity of covalently attached reagents between the two structures.

The spacer elements in the link are usually grouped by straight or branched chains. And may include C1-C10 alkylene, C2-C10 alkylene, C2-C10 alkynyl, C2-C6 extended heterocyclic, C6-C12 extended aryl, C7-C14 extended aralkyl, C3- C10 heterocyclic alkylene, C2-C100 polyethylene diol (polyethylene) Glycolene) or a C1-C10 heteroalkylene group. In some examples, the linker is described in any one of Formulas VII-XXII.

A homobifunctional linker for the preparation of a compound, including but not limited to The diamine and the diol may be selected from the group consisting of ethylenediamine, propylenediamine and hexamethyldiamine, ethylene glycol, diethylene glycol, propylene glycol, 1,4-butanediol, and 1,6-hexane. Alcohol, cyclohexanediol and polycaprolactone diol.

In certain embodiments, the chemotactic receptor ligand or (b) is attached to the linker via a guanamine bond (eg, at the C-terminus of the chemotactic peptide), a polyene antifungal agent, or (a) Amides key (e.g., at the end of primary or secondary amine, for example, in the formula II R ⁹ or R ¹¹ of formula IV) is attached to the linkers.

Treatment of fungal infections

The present disclosure includes compositions and methods for treating or preventing a disease or condition associated with a fungal infection by administering the compounds described herein. The compound can be administered by any suitable route for treating or preventing a disease or condition associated with a fungal infection. They can be administered to humans, domestic pets, livestock or other animals with pharmaceutically acceptable diluents, carriers or excipients. Administration can be local, parenteral, intravenous, intraarterial, subcutaneous, intramuscular, intracranial, intraorbital, intraocular, intraventricular, intracapsular, intraspinal, intracranial, intraperitoneal, intranasal, qi An aerosol, by suppository, or orally.

The compounds described herein are useful in the treatment of, for example, invasive prion, pulmonary prion, intra-abdominal abscess, peritonitis, pleural infection, esophagitis, candidemia, and invasive rosary Bacterial disease.

A method of treating a fungal infection in an individual, including for the individual A sufficient amount of the compound or pharmaceutical composition is administered to treat the infection. In a particular embodiment, the pharmaceutical composition is administered intravenously or topically. This pharmaceutical composition can be administered to treat bloodstream infections, tissue infections (e.g., lung, kidney or liver infections) in an individual or other types of infections described herein. The fungal infection to be treated may be an infection selected from the group consisting of invasive mycosis, pulmonary mite, intra-abdominal abscess, peritonitis, pleural infection, esophagitis, candidemia, and Invasive candidiasis.

In certain embodiments, the infection to be treated may be Candida albicans , C. parapsilosis , C. glabrata , C. guilliermondii , C. krusei , C. lusitaniae , C. tropicalis , Aspergillus fumigatus ) , A.flavus , A.terreus.A.niger , A.candidus , A.clavatus or A.ochraceus .

A method of prophylactically treating a fungal infection in an individual, comprising: administering A compound or pharmaceutical composition is administered to an individual. In a particular embodiment, the pharmaceutical composition is administered at least once during a period of 1-30 days (eg, administered 1, 2, 3, 4, or 5 times over a period of 1-30 days). For example, the method can be used for prophylactic treatment of an individual who is ready for an invasive medical procedure (eg, preparing for surgery, for example, undergoing transplantation, stem cell therapy, grafts, prostheses, receiving long-term or frequent intravenous catheters, or intensive care) The ward receives treatment), individuals with low immunity (for example, individuals with cancer, HIV/AIDS or individuals taking immunosuppressants) or individuals undergoing long-term antibiotic therapy.

A method of stabilizing or inhibiting fungal growth or killing fungi, including: The site of the fungus or fungus-producing fungus is contacted with a compound or pharmaceutical composition or a pharmaceutically acceptable salt thereof.

Pharmaceutical composition

When used to treat human and animal subjects, the compounds can be formulated as pharmaceutical or veterinary compositions. Depending on the individual to be treated, the mode of administration, and the form of treatment desired, for example, prevention, prevention or treatment, the compounds can be formulated in a variety of ways to meet these parameters. Remington: The Science and Practice of Pharmacy , 21 ^st Edition , Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology , eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York. This is incorporated herein by reference.

The compounds described herein may comprise from 1 to 95% by weight of the total composition. group The composition can be adapted for intra-articular, oral, parenteral (eg, intravenous, intramuscular), transrectal, transdermal, subcutaneous, topical, transdermal, sublingual, nasal, transvaginal Intravesical, transurethral, spinal, epidural, transaural, or transdermal administration, or by injection, inhalation or direct contact with nasal, urogenital, gastrointestinal, genital, or oral mucosa Provide it. Therefore, the pharmaceutical composition may be in the form of a tablet, a capsule, a pill, a powder, a granule, a suspension, an emulsion, a solution, a gel comprising a hydrogel, a paste, an ointment, a cream, a plaster, Infusion, osmotic delivery devices, suppositories, enemas, injections, implants, sprays, formulations suitable for iontophoretic delivery or aerosols. The composition can be formulated according to conventional pharmaceutical practice.

Generally, the compounds described herein can be used alone for therapeutic purposes. Use, in a mixture of two or more compounds, or in combination with other pharmaceuticals. Other pharmaceuticals combined with the compounds described herein, for example, Includes medicines to treat the same indications. Other potential medicines in combination with the compounds described herein, for example, may include pharmaceuticals for treating different related or related symptoms or indications. Depending on the mode of administration, the compound will be formulated into a suitable composition to enable easy delivery. Each compound in combination therapy can be formulated in a variety of ways known in the art. For example, the first and second agents in the combination therapy can be formulated together or separately. Preferably, the first and second medicaments are formulated together for administration of the medicaments simultaneously or nearly simultaneously.

The compound can be prepared and used in the form of a pharmaceutical composition, medicine The compositions comprise an effective amount of a compound described herein, as well as pharmaceutically acceptable carriers or excipients well known in the art. In some embodiments, the composition includes at least 2 different pharmaceutically acceptable excipients or carriers.

The formulation can be prepared for systemic administration or topical or Local (local) administration. Systemic formulations include those designed for injection (for example, intramuscular, intravenous or subcutaneous injection), or may be prepared for transdermal, transmucosal or oral administration. Formulations generally include a diluent, and in some cases, adjuvants, buffers, preservatives, and the like. The compounds can also be administered in the form of a liposome composition or a microemulsion.

For injection, the formulation can be prepared as a lipid solution or suspension. Some conventional forms, or solid forms, are suitable for conversion to a liquid such as a solution or suspension, or an emulsion, prior to injection. Suitable excipients include, for example, water, saline, dextrose, glycerol, and the like. Such compositions may also include some non-toxic auxiliary ingredients such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, monolauryl sorbitan, and the like.

Various drug sustained release systems have been designed. See, For example, U.S. Patent No. 5,624,677, incorporated herein by reference.

Systemic administration also includes relatively non-invasive methods, for example, Suppositories, transdermal patches, transmucosal delivery and intranasal administration are used. Oral administration is also suitable for the compound. Suitable forms include syrups, capsules and lozenges as are known in the art.

Each of the compounds in the combination therapy described herein can utilize the technique Formulations are made in a variety of ways known in the art. For example, the first and second agents in the combination therapy can be formulated together or separately.

Individual or separate formulas can be packaged together into a set group. Non-limiting examples of kits include, but are not limited to, for example: two pills, one pill and one powder, one suppository and one vial of liquid, two topical creams, and the like. The kit can include optional components that aid in administering a unit dose to the patient, for example, to reconstitute a vial in powder form, a syringe for injection, a custom IV delivery system, an inhaler, and the like. In addition, unit dose kits can include instructions for preparing and administering the compositions. The kit can be made into a single unit dose for a single patient, for multiple use in a specific patient (quantitative dose, or depending on the course of treatment, the potency of individual compounds may change); or the kit may include suitable Multiple doses ("big packages") administered to multiple patients. The kit components can be assembled in cartons, drum packs, bottles, tubes, and the like.

Oral formulations include: lozenges containing active ingredients and non-toxic A mixture of pharmaceutically acceptable excipients. Such excipients can be, for example, blunt diluents or fillers (for example, sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose , calcium phosphate, calcium sulfate or sodium phosphate); granulating agents and disintegrating agents (for example, cellulose derivatives including microcrystalline cellulose, starch including potato starch, cross-linking) Carboxymethylcellulose sodium, alginate or alginic acid); binders (eg, sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, Magnesium alumininate, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone or polyethylene glycol); and lubricants, glidants and anti-adhesion An agent (for example, magnesium stearate, zinc stearate, stearic acid, cerium oxide, hydrogenated vegetable oil or talc). Other pharmaceutically acceptable excipients may be coloring agents, flavoring agents, plasticizers, humectants, buffers, and the like.

Mix two or more compounds in lozenges, capsules or other In the carrier, or may be layered. For example, the first compound is contained on the inner side of the tablet and the second compound is on the outer side such that a substantial portion of the second compound is released earlier than the first compound.

Oral formulations can also be used in the form of chewable or hard gelatin capsules. Provided in which the active ingredient is mixed with a blunt solid diluent (for example, potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or in the form of a soft gelatin capsule, wherein the active ingredient and a water or oily medium, for example Mix with peanut oil, liquid paraffin or olive oil. The powders, granules and pellets in lozenges and capsules can be made using the above-mentioned ingredients using conventional tools such as mixers, fluid bed equipment or spray drying equipment.

Dissolution or diffusion controlled release can be achieved by appropriate lozenge, gel The compound of the capsule, pellet or granule formulation is coated or the compound is combined into a suitable matrix to achieve. The controlled release coating may comprise one or more of the above-described coating ingredients, and/or, for example, shellac, beeswax, glyco wax, ramie wax, carnauba wax, stearyl alcohol, glyceryl monostearate Ester, glyceryl distearate, glyceryl palmitate, ethyl cellulose, acrylic resin, dl-polylactic acid, fiber Acetic acid butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxy methacrylate, methacrylate water Gel, 1,3 butanediol, ethylene glycol methacrylate, and/or polyethylene glycol. In a controlled release matrix formulation, the matrix material can include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, Methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.

a liquid agent which may comprise a compound and a composition for oral administration Types include aqueous solutions, suitably flavored syrups, or oily suspensions, and flavored emulsions with edible oils, for example, cottonseed oil, sesame oil, coconut oil or peanut oil, and elixirs and similar pharmaceutical carriers.

In general, when administered to a human, the combination of any compound The oral dose will depend on the nature of the compound and can be readily determined by one of ordinary skill in the art. Usually, such a dose is normally from about 0.001 mg to 2000 mg per day, preferably from about 1 mg to 1000 mg per day, more preferably from about 5 to 500 mg per day. It may take up to 200mg per day.

Administration of each drug in combination therapy, as described herein, alone The site is 1 to 4 times a day for 1 day to 1 year and may even last for the rest of the patient's life. It can indicate chronic, long-term administration.

The following examples are used to illustrate the combination of several compounds represented. And the use of such compounds for inducing chemotaxis and antifungal activity. Accordingly, the examples are for illustrative purposes and are not intended to limit the disclosure. Other compounds not specifically exemplified can be synthesized using conventional methods and methods described herein.

Example General method

Analytical high performance liquid chromatography (HPLC) was performed using the following columns 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, Maintain 11min + 2min. Preparative HPLC was performed using the following column: Agilent ZORBAX SB-CN, 7 μm, 21.2 x 250 mm, CH ₃ CN/H ₂ O/0.1% acetic acid, and various linear gradients were performed at 20 mL/min as needed.

Fast LC: using Waters BEH C18, 3.0 x 30 mm, 1.7 μm, at 50 ° C and flow rate 1.5 mL/min, 2 μL injection volume, mobile phase: (A) water and 0.1% formic acid with 1% acetonitrile, mobile phase ( B) Methanol and 0.1% formic acid; residence time is expressed in minutes. Method details: (I) Run with Binary Pump G1312B with UV/Vis diode array detector G1315C, and Agilent 6130 mass spectrometer in positive and negative ion shower mode with UV PDA detection, gradient 15-95 %(B), 2.2min linear gradient; (II) maintained at 95% at 95% (B); (III) decreased from 95-15% (B) with a linear gradient of 0.1min; (IV) at 15% (B) Maintained for 0.29 min.

Polar Stop-Gap: using Agilent Zorbax Bonus RP, 2.1 x 50mm, 3.5μm, temperature 50°C, flow rate 0.8mL/min, injection volume 2μL, mobile phase: (A) water and 0.1% formic acid And 1% acetonitrile, mobile phase (B) methanol and 0.1% formic acid; retention time is expressed in minutes. Method details: (I) Run with Binary Pump G1312B with UV/Vis diode array detector G1315C and Agilent 6130 mass spectrometer in positive and negative ion shower mode with UV detection at 220 and 254 nm with gradient 5-95% (B), A linear gradient of 2.5 min; (II) maintained at 95% (B) for 0.5 min; (III) decreased from 95-5% (B) with a linear gradient of 0.1 min; (IV) maintained at 0.29 min at 5% (B).

Obtain NMR spectra from either instrument:

(1) Agilent (formerly Varian) UnityInova 400 MHz NMR spectrometer with 5 mm automatic three-bandwidth (ATB) probe. This ATB probe was simultaneously adjusted to 1H, 19F and 13C.

(2) Agilent (formerly Varian) UnityInova 500 MHz NMR spectrometer. A number of NMR probes can be used with a 500 MHz NMR spectrometer, including 3 mm and 5 mm 1H13 C15N probes and 3 mm X1H19F NMR probes (typically X is adjusted to 13 C). For a typical 1H NMR spectrum, the pulse angle was 45 degrees, a total of 8 scans were added, and the spectral width was 16 ppm (-2 ppm to 14 ppm). A total of 32,768 composite points were collected during the acquisition time of 5.1 seconds, and the recirculation delay was set to 1 second. The spectra were collected at 25 °C. The 1H NMR spectrum is typically widened and zero-filled to 131072 points with a 0.3 Hz line prior to Fourier transform.

Synthetic Peptide Fragment Coupling Partner: In some cases, a discreet coupling partner is isolated and purified. In other cases, the coupling partner was prepared and used directly without isolation.

Compounds can be made using methods known in the art, including steps similar to those disclosed below.

For some preparations, the following general conditions were used.

Preparative HPLC was performed using the following conditions: Teledyne Isco HP C18, 50 g column. Eluent: CH ₃ CN/H ₂ O/0.1% formic acid or 0.1% trifluoroacetic acid; various linear gradients as needed at 40 mL/min in Isco Combiflash Rf LC unit. UV is detected at 220 and 254 nm.

OR Luna 5micron C18, 100A°, AXIA 100 x 30mm.

Eluent: CH ₃ CN/H ₂ O/0.1% formic acid or 0.1% trifluoroacetic acid; various linear gradients as needed at 25 mL/min in Gilson system; 215 Liquid Handler, Gilson UV-VIS 155, Gilson 305 pump And detector. UV is detected at 220 and 254 nm.

Analytical LC/MS: High resolution liquid chromatography mass spectrometry (HRES-LC/MS) was performed using a Waters Q-TOF Premier mass spectrometer with an electrospray probe connected to an Agilent 1100 with a diode array detector The HPLC system was collected from 190 nm to 400 nm. A gradient of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B) was run from 15% B to 95% at 30 ° C for 15 minutes using a 100 x 3.0 2.6 u Phenomenex Kinetex C18 column.

Liquid chromatography mass spectrometry was performed using an Agilent 6120 mass spectrometer with an electrospray probe attached to an Agilent 1100 HPLC system with a variable wavelength detector set to 220 nm or 254 nm. A gradient of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B) was run from 15% B to 99% at 30 ° C for 3.5 minutes using a 50 x 3.0 2.6 u Phenomenex Kinetex C18 column.

1H-NMR spectra were acquired on a Bruker 300 MHz system using a 5 mm QNP probe.

Synthesis of peptide fragment coupling partner: In some cases, a discreet coupling partner is isolated and purified. In other cases, the coupled partner system was prepared and used directly without isolation. The isolated compounds are described in this section, and the coupling partners used directly are placed in the example of the final compounds.

Some peptides or derived peptides are obtained from a Contract Research Organization or other commercial source. Generally, peptides are believed to be readily available from such sources via standard peptide synthesis procedures.

The compounds described herein can be made using methods known in the art, including steps similar to those disclosed below.

Example 1: Synthesis of intermediates Synthetic fMLF-OSu(Int-1)

step 1

(N-Mercapto)-MLF-OH (100 mg, 0.23 mmol, 1 eq) was dissolved in 4 mL dry DMF. DCC (50 mg, 0.24 mmol, 1.05 eq) and N-hydroxysuccinimide (27 mg, 0.23 mol, 1 eq). The product was used directly in the next reaction without purification.

Step 2

To a solution of (N-methylmercapto)-MLF-OH (0.866 g, 1.49 mmol) in EtOAc (EtOAc) 48 hours, during which time additional HOSu (0.034 g, 0.30 mmol) and DCC (0.064 g, 0.31 mmol) were added at t = 24 hours. The reaction was used directly in the next reaction without previously separating fMLF-OSu. MS (M+H) 535.0. Alternatively, the solution can be removed under reduced pressure to separate the crude fMLF-OSu.

Synthesis (N-iso-BOC)-MLF-OSu(Int-2)

(N-iso-BOC)-MLF-OH (50 mg, 0.1 mmol, 1 eq) was dissolved in 1 mL dry DMF. EDCI (28 mg, 0.15 mmol, 1.5 eq) was added with N-hydroxysuccinimide (12 mg, 0.1 mmol, 1.05 eq). When HPLC analysis showed no (N-iso-BOC)-MLF-OH, the reaction was used directly in the next reaction without purification.

Synthetic N ^ε -fMLF-N ^α -FMOC-K(Int-3)

Step a) Preparation of N ^α -FMOC-N ^ε -Z-tert-butyl tributate N ^ε -Z-disuccinic acid tert-butyl ester (300 mg, 0.81 mmoles) and FMOC-OSu (299 mg, 0.89 mmoles, 1.1 eq) were dissolved in 3 mL dry DMF, and TEA (112 μL, 0.81 mmoles, 1 eq) was added. The reaction was stirred at room temperature for 1 hour. The reaction was diluted with 10% aq. LiCl solution and extracted with EtOAc EtOAc EtOAc. The organic extracts were combined and extracted with a 10% aqueous solution of LiCl. The organic solution was dried over sodium sulfate, filtered and evaporated. The yield was 519 mg. The target yield is 452 mg. LC/MS, 559.0 [M+H] ⁺ . ¹ H NMR d ₆ -DMSO was consistent with the desired product and showed a trace of DMF and ethyl acetate. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.38 (s, 10 H) 1.50-1.72 (m, 1 H) 2.92-3.05 (m, 1 H) 3.79 - 3.90 (m, 1 H) 4.16 - 4.25 (m,1 H)4.26-4.33(m,1 H)5.00(s,1 H)7.20-7.26(m,1 H)7.29-7.37(m,7 H)7.41(s,2 H)7.59-7.66 (m, 1 H) 7.72 (d, J = 7.42 Hz, 2 H) 7.89 (d, J = 7.42 Hz, 2 H) Step b) removing the Z-group

The product from step a) was dissolved in 20 mL ethanol and 2 mL acetic acid. 150 mg of 5% Pd/C was added and the reaction was placed under a hydrogen atmosphere (balloon pressure). After stirring overnight, the reaction was filtered and solvent was evaporated under reduced pressure. LC/MS, 425.2 [M+H] ⁺ . This crude product was used without purification.

Step c) Preparation of N ^ε -fMLF-N ^α -FMOC-K tert-butyl ester

The product from the previous step b) (344 mg, 0.81 mmol, 1.7 eq) was dissolved in 7 mL of dry DMF, and then taken to 2 mL of dry DMF of fMLF-OSu (Int-1) (246 mg, 0.46 mmol). After 10 minutes, the product was purified using preparative HPLC using a gradient of 60% to 100% methanol in water over 5 min. The yield was 120 mg. LC/MS, 844.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.80 (d, J = 6.64 Hz, 3 H) 0.85 (d, J = 6.64 Hz, 3 H) 1.09-1.34 (m, 5 H) 1.34-1.44 ( m,12 H)1.44-1.64(m,3 H)1.67-1.81(m,1 H)1.81-1.92(m,1 H)2.01(s,3 H)2.34-2.44(m,2 H)2.76- 2.86(m,1 H)2.87-2.98(m,2 H)2.99-3.14(m,1 H)3.77-3.88(m,1 H)4.16-4.36(m,4 H)4.36-4.48(m,2 H) 6.28 (s, 1 H) 7.17 (d, J = 7.22 Hz, 3 H) 7.22 (d, J = 6.25 Hz, 3 H) 7.33 (dd, J = 15.23, 7.61 Hz, 3 H) 7.42 (td , J = 7.42,0.98Hz, 3 H) 7.61 (d, J = 7.81Hz, 1 H) 7.72 (d, J = 7.22Hz, 2 H) 7.84 (d, J = 7.42Hz, 2 H) 7.89 (dd , J = 7.52, 2.44 Hz, 3 H) 7.93 (d, J = 8.20 Hz, 1 H) 7.99-8.03 (m, 1 H) 8.08 (d, J = 8.00 Hz, 1 H) 8.30 (d, J = 8.00Hz, 1 H)

Step d) removing the third butyl ester

The product from the above step c) (120 mg, 0.14 mmol) was dissolved in 20 mL of formic acid and stirred at room temperature for 2 hr. The formic acid was removed under reduced pressure. The residue was diluted twice with toluene and evaporated to remove residual formic acid. This product was used without further purification. The yield was 134 mg. LC/MS, 788.2 [M+H] ⁺ .

Synthesis of fMLF-diaminoethylguanamine (Int-4)

fMLF-OSu (Int-1) (246 mg, 0.46 mmol) was dissolved in 5 mL dry DMF and cooled to 0 °C. FMOC-2-(2-Aminoethoxy)-ethylamine HCl (184 mg, 0.51 mmol, 1.1 eq) was added, then DIPEA (88 uL, 65 mg, 0.51 mmol, 1.1 eq). This reaction was stirred until fMLF-OSu was consumed. Piperidine (250 uL, 5% V/V) was added and the reaction was stirred at 0 °C for 20 min. The reaction was filtered and the product was purified by preparative HPLC using 5% to 100% methanol in water (0.1% TEA) gradient. The yield is 150 mg. LC/MS, 524.2 [M+H] ⁺ .

Synthetic fMLF-N ^ε -FMOC- lysine (Int-5)

Step a) Preparation of fMLF-(N ^ε -Z-isoamino acid) tert- butyl ester

A solution of N ^ε -Z-isobutyl acid tert-butyl ester (0.852 g, 2.29 mmol) and fMLF (1.00 g, 2.29 mmol) in DMF (20 mL) was charged with HATU (0.869 g, 2.29 mmol) With 2,4,6-trimethylpyridine (2,4,6-collidine) (0.554 g, 4.57 mmol). After stirring at room temperature for 40 min the reaction was diluted in EtOAc (200mL), washed successively with saturated LiCl (3 x 50mL), washed with saturated NaHCO ₃ (2 x 50mL) and saturated NaCl (2 x 50mL), then dried over Na ₂ SO _4, filtered, and concentrated under reduced pressure. The crude material was chromatographed on a 40g Isco RediSep silica cartridge using 100% heptane to 100% EtOAc then 100% MeOH. Yield: 1.49 g, as a white solid. ¹ H NMR (400 MHz, Chloroform- d ) δ ppm 0.84 (d, J = 5.22 Hz, 3 H) 0.87 (d, J = 6.20 Hz, 3 H) 1.20-2.06 (m, 9 H) 1.44 (s, 9 H) 2.08 (s, 3 H) 2.50 (t, J = 7.35 Hz, 2 H) 2.81 (s, 1 H) 2.92-3.37 (m, 4 H) 4.30-4.75 (m, 4 H) 5.04-5.19 ( m,2 H)5.22-5.29(m,1 H)6.32-6.52(m,1 H)6.74(d, J =7.13Hz, 1 H)6.83-7.00(m,2 H)7.10-7.47(m, 10 H) 7.69-7.85 (m, 1 H) 8.04-8.20 (m, 1 H). MS (M+H) 756.2

Step b) Preparation of fMLFK-O-t- butyl ester

A solution of fMLF-(N ^ε -Z-isoamino acid) tert-butyl ester (1.96 g, 2.60 mmol) in EtOH (300 mL) was charged with 5% palladium on carbon (Pd on carbon) (5.52 g) Then, it was evacuated under a hydrogen balloon and blanketed 3 times by a balloon. After stirring at room temperature for 19 hours, the reaction was filtered with EtOAc EtOAc (EtOAc)EtOAc. The product containing fractions (1 and 2) were pooled and concentrated under reduced pressure. Yield: 1.38 g, as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.79 (d, J = 6.54 Hz, 3 H) 0.85 (d, J = 6.54 Hz, 3 H) 1.21-1.90 (m, 9 H) 1.40 (s, 9 H)2.01(s,3 H)2.31-2.44(m,2 H)2.58(t, J =6.76Hz, 2 H)2.75-3.10(m,2 H)3.19-3.50(m,2 H)3.99 - 4.70 (m, 6 H) 7.11 - 7.26 (m, 5 H) 7.93 (d, J = 8.25 Hz, 1 H) 8.00 (s, 1 H) 8.04 (d, J = 8.25 Hz, 1 H) 8.21. d, J = 7.52 Hz, 1 H) 8.29 (d, J = 8.00 Hz, 1 H). MS(M+H)622.2

Step c) Preparation of fMLF-(N ^ε -FMOC-isoamino acid) tert-butyl ester

A solution of fMLFK-O-tert- butyl ester (1.37 g, 2.20 mmol) in DMF (20 mL) was charged with <RTI ID=0.0>> After stirring at room temperature for 10 minutes, the reaction was diluted in EtOAc (250mL), saturated LiCl (3 x 50mL, MeOH was added as needed to break emulsion), dried, and then dried ₂ SO ₄ Na, filtered, and reduced pressure Concentrated under. The crude product was chromatographed on 40 g of Isco RediSep. Yield: 1.62 g, as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.77 (d, J = 6.54 Hz, 3 H) 0.82 (d, J = 6.54 Hz, 3 H) 1.15-1.90 (m, 9 H) 1.38 (s, 9 H)1.99(s,3 H)2.28-2.44(m,2 H)2.76-3.10(m,2 H)3.94-4.70(m,11 H)7.09-7.27(m,5 H)7.28-7.37( m,3 H) 7.40 (t, J = 7.49 Hz, 2 H) 7.68 (d, J = 7.52 Hz, 2 H) 7.88 (d, J = 7.47 Hz, 2 H) 8.00 (s, 1 H) 8.04 ( d, J = 8.30 Hz, 1 H) 8.15 (d, J = 8.39 Hz, 1 H) 8.28 (d, J = 7.17 Hz, 1 H) 8.33 - 8.46 (m, 1 H). MS(M+H)844.2

Step d) removing the third butyl ester to provide Int-5

A solution of fMLF-(N ^ε -FMOC- lyophilic acid) tert-butyl ester (1.61 g, 1.91 mmol) in EtOAc (20 mL) Under reduced pressure and the reaction was concentrated to 50g Isco Gold RediSep C-18 reverse phase silica Shixia to 99.9: 0.1 H ₂ O: HOAc to 99.9: 0.1 MeOH: HOAc gradient elution in chromatography. The product was isolated from a _{1: 1 H 2 O: CH} 3 CN (8mL) freeze-dried. Yield: 0.304 g. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.79 (d, J = 6.39 Hz, 3 H) 0.84 (d, J = 6.49 Hz, 3 H) 1.12-1.92 (m, 9 H) 2.00 (s, 3 H) 2.38 (t, J = 6.66 Hz, 2 H) 2.73-3.10 (m, 4 H) 3.31 (br.s., 2 H) 4.07-4.63 (m, 7 H) 7.09-7.36 (m, 8 H) 7.37-7.46 (m, 2 H) 7.68 (d, J = 7.27 Hz, 2 H) 7.83-7.97 (m, 3 H) 7.98-8.06 (m, 2 H) 8.07-8.14 (m, 1 H) 8.27 (d, J = 7.71 Hz, 1 H) 12.20-12.95 (m, 1 H). MS(M+H)788.2

Synthesis of amphotericin-B-2-(amino)-ethyl-decylamine (Int-6)

Icosamine (Mycosamine)-N-FMOC-Amphotericin B (prepared as in Example 1, step a) (256 mg, 0.224 mmoles) with ethylenediamine-mono-FMOC-HCl (107 mg, 0.335 mmoles, 1.5 eq Dissolved in 5 mL of dry DMF and cooled to 0 °C. DIPEA (97 μL, 72 mg, 0.559 mmoles, 2.5 eq) was added with COMU (96 mg, 0.224 mmoles, 1 eq). When no starting material remained, piperidine (66 uL, 57 mg, 0.671 mmoles, 3 eq) was added and the mixture was warmed to room temperature. When the intermediate product was consumed, the reaction was quenched with acetic acid (102 uL, 107 mg, 1.79 mmoles, 8 eq) and the product was used in preparative HPLC using a gradient of 20% to 100% methanol / 0.1% acetic acid in water / 0.1% acetic acid. purification. The yield was 48.6 mg. LC/MS, 988 [M+23] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.91 (d, J = 7.03 Hz, 3 H) 1.04 (d, J = 6.44 Hz, 3 H) 1.11 (d, J = 6.25 Hz, 4 H) 1.14 (d, J = 6.05 Hz, 4 H) 1.86 (s, 9 H) 2.54 (s, 4 H) 8.11 (t, J = 5.08 Hz, 1 H)

Synthesis of C2'-deoxyamphomycin B diamine ethyl ether decylamine (Int-7)

Step a) Synthesis of C2'-deoxy trehalose-N-FMOC-amphotericin B

C2'-deoxyamphomycin B is prepared in the manner described in the following references (and references cited therein): BCWilcock, et al . "C2 ' -OH of amphotericin B Plays an Important Role in Binding the Primary Sterol of Human Cells but Not Yeast Cells" J. Am. Chem. Soc. 2013, 135 , 8488-849.

C2'-deoxyamphomycin B (0.242 g, 0.266 mmol, 1 eq) was dissolved in 6 mL of dry DMF. FMOC-OSu (0.132 g, 0.319 mmol, 1.2 eq) was added and the mixture was stirred at room temperature for about 2 hours. The reaction was poured into about 60 mL of diethyl ether. The solid was filtered and washed with additional ether. Drying the solid in vacuum A product having a molecular weight of 1129.56 is produced.

Step b) Synthesis of C2'-deoxy trehalose-N-FMOC-Amphioxus -FMOC-2-(2-Aminoethoxy)-ethyl-decylamine

C2'-deoxy trehalylamine-N-FMOC-amphomycin B (0.287 g, 0.20 mmol, 1 eq) with FMOC-2-(2-aminoethoxy)-ethylamine HCl (0.109 g, 0.30 mmol, 1.5 eq) was dissolved in 6 mL dry DMF and cooled to 0 °C. COMU (0.128 g, 0.30 mmol, 1.5 eq) was added with DIPEA (0.091 g, 0.70 mmol, 3.5 eq). The reaction was stirred at 0 ° C for about 1 hr. The product was precipitated by the addition of ~60 mL of diethyl ether and MTBE. The solid was filtered and washed with additional ether. The solid was dried under vacuum to produce an impure product. The solid was washed with methanol to give the product having a molecular weight of 1437.71.

Step c) remove the FMOC group

The product of the above step b (0.2 g, 0.139 mmol, 1 eq) was dissolved in 1 mL DMF, and piperidine (41 uL, 36 mg, 0.42 mmol, 3 eq) was added. The reaction was stirred for about 30 minutes. The product was precipitated from the reaction and filtered. Wash the product with methanol The polyester was dried and vacuum dried to obtain a product having a molecular weight of 993.58.

Synthesis of amphotericin B diaminoethyl ether decylamine (Int-8)

step 1 Step a) Synthesis of trehalose-N-FMOC-amphotericin B

Amphotericin B (1 g, 1.082 mmol, 1 eq) was dissolved in 20 mL dry DMF. FMOC-OSu (0.445 g, 1.32 mmol, 1.22 eq) was added and the mixture was stirred at room temperature for 2 hr. The reaction was poured into ~200 mL of diethyl ether. The solid was filtered and washed with additional ether. The solid was dried under vacuum to give 1.09 g of product. LC / MS, 1168.2 [M + 23] +. HPLC (ELSD) T _R 3.395 min (100%). ¹ H NMR was consistent with the desired product, showing 4 methyl groups from 0.90 to 1.2 ppm, and 9.3 to 7.925 ppm showing FMOC aromatic protons. ^{1 H NMR (400MHz, DMSO-} d6) δ ppm 0.91 (d, J = 7.03Hz, 3 H) 1.04 (d, J = 6.05Hz, 3 H) 1.11 (d, J = 6.25Hz, 4 H) 1.17 ( d, J = 5.47 Hz, 3 H) 7.33 (dq, J = 7.61, 3.71 Hz, 1 H) 7.42 (t, J = 7.42 Hz, 2 H) 7.73 - 7.79 (m, 2 H) 7.89 (d, J =7.42Hz, 2 H)

Step b) Synthesis of trehalosamine-N-FMOC-amphoteric acid-FMOC-2-(2-aminoethoxy)-ethyl-decylamine

Trehalamide-N-FMOC-amphomycin (2.27 g, 1.98 mmol, 1 eq) with FMOC-2-(2-aminoethoxy)-ethylamine HCl (1.079 g, 2.97 mmol, 1.5 eq) Dissolve in 60 mL of dry DMF and cool to 0 °C. COMU (0.932 g, 2.18 mmol, 1.5 eq) was added with DIPEA (0.894 g, 6.9 mmol, 3.5 eq). The reaction was stirred at 0 ° C for 1 hour. The product was precipitated by the addition of ~600 mL of diethyl ether and MTBE. The solid was filtered and washed with additional ether. The solid was dried in vacuo to give 2.48 g of mp. The solid was washed with methanol to give 1.9 g of product. HPLC T _R 4.125 min (99%). TY 2.8 g, 68%.

Step c) remove the FMOC group

The product from step b (1.9 g, 1455 mmol, 1 eq) was dissolved in 8 mL DMF and EtOAc ( EtOAc, The reaction was stirred for 30 minutes. The product precipitated from the reaction and was filtered. The product was washed with methanol and dried in vacuo to give &lt LC/MS, 1010 [M+23] ⁺ . HPLC [ELSD] T _R 2.601 min (100%).

Step 2 Step a) Synthesis of trehalose-N-FMOC-amphotericin B

A solution of amphotericin B (5.00 g, 5.41 mmol) and Fmoc-OSu (2.01 g, 5.95 mmol) in DMF (100 mL) The reaction was diluted with t -butyl methyl ether (1.0 L). The filter cake was washed with additional butyl dimethyl ether (2 x 100 mL) and dried in vacuo. Yield: 5.77 g, as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.91 (d, J = 7.08 Hz, 3 H) 1.04 (d, J = 6.35 Hz, 3 H) 1.09-1.13 (m, 4 H) 1.17 (d, J = 5.27 Hz, 3 H) 6.92 (d, J = 8.44 Hz, 1 H) 7.28-7.38 (m, 2 H) 7.38-7.48 (m, 2 H) 7.76 (dd, J = 7.47, 3.76 Hz, 2 H) 7.89 (d, J = 7.52 Hz, 2 H). MS (M+Na) 1169.4.

Step b) Synthesis of trehalosamine-N-FMOC-amphoteric acid-FMOC-2-(2-aminoethoxy)-ethyl-decylamine

A solution of trehalosamine-N-FMOC-amphotericin B (4.56 g, 3.98 mmol) in DMF (90 mL) was cooled in ice/water bath to ~0 ° C then loaded with H ₂ NCH ₂ CH ₂ OCH ₂ CH ₂ NHFmoc - HCl (1.59 g, 4.38 mmol), COMU (1.87 g, 4.38 mmol) and DIPEA (1.54 g, 11.9 mmol). After warm to room temperature and stirred for 2 hours, diluted with third-butyl methyl ether (900 mL) and the reaction was, the mixture obtained was filtered through a sintered funnel. The filter cake was washed with additional butyl dimethyl ether (2 x 100 mL), dried in vacuo and without further purification. Yield: 6.05 g, yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.92 (d, J = 6.98 Hz, 3 H) 1.04 (d, J = 6.35 Hz, 3 H) 1.09-1.13 (m, 4 H) 1.16 (d, J = 4.49 Hz, 3 H) 6.86-6.99 (m, 1 H) 7.20-7.26 (m, 1 H) 7.28-7.36 (m, 4 H) 7.37-7.46 (m, 4 H) 7.61 (d, J = 7.52 Hz, 1 H) 7.71-7.79 (m, 4 H) 7.81 - 7.92 (m, 4 H). No clear molecular ions were observed by mass spectrometry.

Step c) remove the FMOC base to generate Int-8

The trehalose-N-FMOC-amphomycin-FMOC-2-(2-aminoethoxy)-ethyl-decylamine (6.05 g, th. 5.79 g, 3.98 mmol) from the above step b) The DMF (30 mL) solution was charged with piperidine (1.02 g, 11.9 mmol). After stirring at room temperature for 1.25 hours, diluted with tertiary butyl methyl ether (300 mL) and the reaction was, the mixture obtained was filtered through a sintered funnel. The filter cake was washed with additional butyl dimethyl ether (2 x 100 mL) and dried in vacuo. Int-1 yield: 4.12 g (>100% (102%)) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.91 (d, J = 7.03 Hz, 3 H) 1.04 (d, J = 6.30 Hz, 3 H) 1.08-1.13 (m, 4 H) 1.14 (d, J = 5.91 Hz, 3 H), 8.00-8.07 (m, 1 H). MS(M+H)1010.4.s

Synthesis of Nystatin Diamine Ethyl Ethylamine (Int-9)

Step a) Synthesis of N-FMOC-mycin

The mycin (0.246 g, 0.266 mmol, 1.0 eq) was dissolved in 6 mL of dry DMF. FMOC-OSu (0.132 g, 0.319 mmol, 1.2 eq) was added and the mixture was stirred at room temperature for about 2 hours. The reaction was poured into about 60 mL of diethyl ether. The solid was filtered and washed with additional ether. The solid was dried under vacuum to yield a product having a molecular weight of 1147.57.

Step b) Synthesis of N-FMOC-Nystatin-FMOC-2-(2-Aminoethoxy)-ethyl-decylamine

N-FMOC-mycin (0.230 g, 0.20 mmol, 1 eq) and FMOC-2-(2-aminoethoxy)-ethylamine HCl (0.109 g, 0.30 mmol, 1.5 eq) were dissolved in 6 mL dry DMF and cooled to 0 °C. COMU (0.128 g, 0.30 mmol, 1.5 eq) was added with DIPEA (0.091 g, 0.70 mmol, 3.5 eq). will The reaction was stirred at 0 ° C for about 1 hour. The product was precipitated by the addition of ~60 mL of diethyl ether and MTBE. The solid was filtered and washed with more ether. The solid was dried under vacuum to give a pure product. The solid was washed with methanol to give a product having a molecular weight of 1455.72.

Step c) remove the FMOC group

The product of the above step b (0.202 g, 0.139 mmol, 1 eq) was dissolved in 1 mL DMF, and piperidine (41 uL, 36 mg, 0.42 mmol, 3 eq) was added. The reaction was stirred for about 30 minutes. The product precipitated from the reaction and was filtered. The product was washed with methanol and dried in vacuo to give a product of molecular weight 101.

Preparation of N-methyl-decyl-D-methionamine-yl-D-alkamine-D-phenylalanine (Int-10)

Step a) Preparation of N-mercapto-D-methionine

D-methionine (3 g, 200 mmol) was added to a solution of 11 mL of acetic anhydride and 4.5 mL of formic acid in an ice water bath. Stir the mixture at room temperature for 4 hours The solution was then quenched with methanol and concentrated to provide the product which was used in the next step without purification

Step b) Preparation of methyl N-methyl decyl-D-methionamine decyl-D-leucine

(D)-N-Methylmercapto-methionine (1.8 g, 100 mmol) and D-ethyl leucine (1.5 g, 100 mmol) were dissolved in 20 mL THF then HATU (3.8 g, 10 mmol) was added The mixture was stirred and the reaction was stirred overnight. Next, the mixture was diluted with ethyl acetate and washed with a NaHCO ₃ and NH ₄ Cl solution, followed by brine. The organic phase was dried, concentrated and purified to give the title compound.

Step c) Preparation of (D, D, D)-fMLF methyl ester

The dipeptide from step b (1.5 g, 50 mmol) was dissolved in 15 mL of a mixture of 1:1:1 (THF/H2O/MeOH) then LiOH (140 mg, 1.1 eq) was added and the solution was stirred at room temperature 4 hours. The mixture was concentrated to dryness and the residue was dissolved in 20 mL DMF. Methyl D-phenylalanine (1.0 g, 55 mmol, 1.1 equi.) was added followed by HATU (2 g, 52 mmol). The solution was stirred overnight and diluted with ethyl acetate, washed NaHCO _3, followed by brine and then washed in a solution of NH ₄ Cl. The obtained organic solution was dried and purified to obtain 1.5 g of (D,D,D)-fMLF methyl ester.

Step d) hydrolyzing the methyl ester to obtain (D, D, D)-fMLF

(D, D, D)-fMLF methyl ester (1.5 g, 34 mmol) was dissolved in 15 mL of a 1:1:1 (THF/H.sub.2/MeOH) mixture. The solution was stirred at room temperature for 4 hours, the solution was removed and the residue was purified &lt ¹ H-NMR (300MHz, DMSO d6): 12.68 (1H, S), 8.28 (1H, d, J = 9 Hz), 8.12 (1H, d, J = 6 Hz), 8.04 (1H, d, J = 9 Hz) , 8.01 (1H, s), 7.25 (5H, m), 4.42 (1H, m), 4.31 (1H, m), 3.07 (1H, dd, J1 = 3 Hz, J2 = 12 Hz), 2.92 (1H, dd, J1=9Hz, J2=15Hz), 2.39(1H, t, J=6Hz), 1.742H, m), 1.55(1H,m), 1.43(2H,m),0.88(3H,d=6Hz),0.83 (3H,d,J=6Hz)

Step e) formation of N-Hydroxysuccinimide ester (Int-10)

(D, D, D)-(N-Methylmethyl)-MLF (100 mg, 0.23 mmol, 1.0 eq) was dissolved in 4 mL dry DMF. DCC (50 mg, 0.24 mmol, 1.05 eq) and N-hydroxysuccinimide (27 mg, 0.23 mol, 1.0 eq) were added and the mixture was stirred at room temperature overnight. The product was used directly in the next reaction without purification.

Synthesis of N-Ethyl-L-Amidino-Glysyl-L-Proline (Int-11)

Step a) Synthesis of Z-Gly-Pro tert-butyl ester

Z-Gly (1.087 g, 5.2 mmol) and N-methyl N-methylmorpholine (0.571 mL, 5.2 mmol) was cooled in EtOAc (15 mL) EtOAc. After stirring at -15 ° C for 10 minutes, the mixture was treated with L-proline tert-butyl ester-HCl (0.831 g, 4.0 mmol) and N-methyl. Treatment with porphyrin (0.571 mL, 5.2 mmol).

Finishing (work-up): The reaction mixture was diluted with ethyl acetate (50 mL), washed with 1N HCL, 1N NaHCO ₃ and brine, then dried over anhydrous Na ₂ SO _4. This solution was filtered and concentrated to give 1.45 g of a white solid. This material was used in the next step without further purification.

Step b) Synthesis of Gly-Pro tert-butyl ester

A mixture of Z-Gly-Pro tert-butyl ester (1.45 g, 5.2 mmol), 5% Pd/C (0.700 g) and methanol (20 mL) was stirred under a hydrogen atmosphere for 1 hour, at which time LCMS showed Z groups. Has been completely removed. The reaction was filtered to remove the palladium on carbon and concentrated to give 0.913 g of a solid. This material was used in the next step without further purification.

Step c) Synthesis of N-acetyl-L-Pro-Gly-L-Pro tert-butyl ester

N-Ethyl-L-proline (0.754 g, 4.80 mmol), N-methyl A solution of the morpholine (0.528 mL, 4. <RTI ID=0.0></RTI></RTI><RTIID=0.0> The mixture was stirred at this temperature for 15 min and then worked up with EtOAc EtOAc EtOAc. After stirring for 1 hour, the mixture was concentrated and washed with reverse-phase liquid chromatography (RPLC) using Isco CombiFlash liquid chromatography, eluting with 10% to 100% acetonitrile and water, using 0.1% formic acid as a modifier to obtain 0.439 g of product .

Step d) Synthesis of N-Ac-L-Amidoxime-glycine-L-nonylamine Acid (Int-11)

N-Ac-L-Pro-Gly-L-Pro-OtBu (0.439 g, 1.95 mmol) was dissolved in EtOAc (EtOAc) After 1 hour, the mixture was concentrated and purified by reverse phase liquid chromatography (RPLC) using Isco CombiFlash liquid chromatography eluting with 10% to 100% acetonitrile and water using 0.1% formic acid as a modifier. The product containing fractions were combined, concentrated and dried to give 0.240 g of product. ^{1 H-NMR (300MHz, CDCl} 3) δ 7.54 (s, 1H), 4.64-4.51 (m, 2H), 3.77-3.48 (m, 6H), 2.42-1.92 (m, 11H); LC / MS, 312.2 [M/2+H] ⁺ Calculated value: 312.15

Preparation of N-methyl-decyl-L-methylsulfanyl decyl-L-alkamine-L-phenylalaninyl-L-arginine Diaminoethylether monodecylamine (Int-12)

Step a)

Add N-Boc-Arg (300 mg, 1.1 mmol) to 10 ml of THF, then add FMOC-2-(2-aminoethoxy)-ethylamine HCl (400 mg, 1.1 mmol, 1.0 eq), EDCI (250 mg) , 1.2 eq) with HOBt (150 mg, 1.1 eq). The reaction mixture was cooled in an ice-br. EtOAc (EtOAc)EtOAc. The mixture was partitioned between 50 ml of ethyl acetate and 50 ml of brine. The organic layer was separated, washed with 10 mL of saturated NaHCO3, ammonium chloride and brine, and dried over anhydrous sodium sulfate. The organic layer was filtered and stripped to dryness. The residue obtained was treated with 5 ml of TFA to remove the Boc protecting group. The TFA solution was stirred for 0.5 hours, then concentrated and poured onto a C18 reverse phase ISCO chromatography column and eluted to afford 240 mg of the desired compound. ^{1 H NMR (300MHz, CDCl3)} δ ppm 8.61 (s, 1H), 8.46 (s, H0,7.75 (d, J = 7.5Hz, 2H), 7.61 (d, J = 7.2Hz, 2H), 7.40 (t , J=7.5Hz, 2H), 7.30 (t, J=7.5Hz, 2H), 4.40(m, 2H) 4.20~4.00(m,3H)3.35(m,6H),2.02(m,1H),1.60 (m, 3H)

Step b)

N-Methylmercapto-L-methionamine-yl-L-alkamine-L-phenylalanine (200 mg, 0.46 mmol) and the product from step a) above (200 mg, 0.41 mmol) were dissolved in 6 ml Dry in DMF and cool to 0 °C. COMU (250 mg, 0.5 mmol, 1.1 eq) was added with NMM (0.25 mL, 2 mmol, 4 eq). The reaction was stirred overnight. The DMF solution was bubbled into reverse phase C18 ISCO chromatography and eluted to give 170 mg of the desired product. ^{1 H NMR (300MHz, CDCl3)} δ ppm 8.37 (s, 1H0,8.14 (s, 1H) 7.81 (d, J = 6Hz, 2H) 7.67 (d, J = 9Hz, 2H) 7.43 (t, J = 6Hz, 2H)7.35(d,J=9Hz,2H)7.23(m,5H)4.54~4.22(m,4H),3.52(m,2H)3.19~2.88(m,6H)2.52(m,2H)2.03(s , 3H) 1.60~1.2 (m, 12H), 0.89 (m, 6H)

Step c)

The product from step b) above (90 mg, 0.10 mmol) and 0.05 ml of piperidine were added to 2 ml DMF. The obtained mixture was further stirred for 1 hour, and the reaction mixture was purified by C18 reversed phase chromatography (ISCO) to yield 60 mg of EtOAc. ¹ H NMR (300MHz, CDCl3) δ ppm 8.20(s,1H), 7.27(m,5H)6.30d,J=10.4Hz,1H)5.95(m,1H)5.49~5.17(m,2H)4.56~4.28 (m, 4H), 3.67~3.01 (m, 8H), 2.59~2.34 (m, 6H), 2.10 (s, 3H), 1.81-1.70 (m, 2H), 1.35 (m, 3H), 0.91 (d , J=6.3Hz, 3H), 0.85 (d, J=6.3Hz, 3H)

Preparation of N-succinyl-L-amidino-glycolyl-L-proline (Int-13)

Step a)

DCC (430 mg, 2.1 mmol) was added to a solution of Boc-Gly-L-Pro dipeptide (540 mg, 2.0 mmol) in 20 ml of THF at room temperature, followed by 9-fluorenylmethanol (400 mg, 2 mmol) with 15 mg DMAP. The reaction mixture was stirred overnight, then 20 g of saponin was added and the mixture was stripped to dryness. The residue was loaded into an empty sample iridium (ISCO) and the product was washed with 520 mg of product by gradually increasing the gradient of ethyl acetate to hexane. _{^{1 H NMR (300MHz, CDCl 3}} ) δ ppm 7.78 (d, J7.5Hz, 2H), 7.55 (d, J = 7.2Hz, 2H), 7.40 (t, J = 7.5Hz, 2H), 7.31 (t, J=5.7 Hz, 2H), 4.71 (m, 2H) 4.55 (ddd, J1=3 Hz, J2=6 Hz, J3=20 Hz, 1H) 4.23 (t, J=5.4 Hz, 1H) 4.48 (dd, J=3 Hz) , 1H), 3.90 (dd, J1 = 5.4 Hz, J2 = 17 Hz, 1H), 3.60 (dd, J1 = 4.0 Hz, J2 = 17 Hz), 2.02 (2H, m), 3.26 (1H, m), 1.72 ( m, 10H), 1.47 (1H, b)

Step b)

The product from the above step a) (450 mg, 1.0 mmol) was added to 5 ml of TFA and then this was stirred for 0.5 hour and was stripped to dryness. The residue obtained was redissolved in 15 mL THF followed by Boc-Pro-OH (230 mg, 1.1 eq), EDCI (200 mg, 1.05 eq) and HOBt (150 mg, 1.1 eq). The solution obtained was cooled in an ice water bath, 0.4 mL NMM (3 mmol, 3 eq) was then added and the mixture was stirred overnight. The mixture was layered into 50 ml of ethyl acetate and 50 ml of brine. The organic layer was separated, respectively, 20ml saturated NaHCO _3, brine and ammonium chloride washing. The organic layer was then dried over anhydrous sodium sulfate filtered and concentrated to dry. The residue obtained was treated again with 5 ml of TFA to remove the Boc protecting group. The TFA solution was stirred for 0.5 hours, then the TFA was removed, taken to a reversed phase C18 column (ISCO) and chromatographed to afford 230 mg of the desired product. _{^{1 H NMR (300MHz, CDCl 3}} ) δ ppm 7.75 (d, J = 7.2Hz, 2H), 7.56 (d, J = 7.2Hz, 2H), 7.36 (m, 4H), 4.64 (m, 2H) 4.21 ( m, 1H), 3.93 (1H, m), 3.34 (2H, m), 2.00~1.65 (6H, m), 1.30 (m, 2H)

Step c) Preparation of Int-13

The tripeptide from the above step b) (200 mg, 0.45 mmol) was dissolved in 10 ml of DCM containing 1 ml of pyridine. This solution was cooled in an ice water bath, then succinic anhydride (200 mg, 2 mmol) was added to this cooled solution and stirred overnight. The reaction was dried <RTI ID=0.0> ¹ H NMR (300MHz, CDCl3) δ ppm 7.83 (d, J = 6 Hz, 2H, 7.63 (d, J = 6 Hz, 2H), 7.43 - 7.41 (m, 4H), 4.64 (m, 2H), 4.46 (m) , 2H), 4.36~4.22 (3H, m) 4.0 (1H, m), 3.6 (m, 3H), 3.36 (m, 8H), 2.63 (m, 3H), 2.33 (m, 1H), 2.18~1.3 (m, 4H)

Preparation of N-Fmoc-L-threonyl-N-Fmoc-L-isoguanylidene-L-amidamine arginine diamine diethyl ether monodecylamine (Int-14)

Step a)

N-Boc-L-arginine (1.4 g, 5 mmol), azido-PEG1-amine (700 mg, 0.55 mmol, 1.1 eq) in 10 ml of DMF and COMU (2.30 g, 5 mmol, 1.0 eq) Cool in an ice water bath and add 0.3 ml of NMM (2.5 mmol, 2.5 eq). The reaction mixture was stirred overnight. The reaction was partitioned between 100 mL of ethyl acetate and 100 mL brine. The organic layer was separated, and ammonium chloride in 30ml saturated NaHCO ₃ and brine were washed, dried and then concentrated by rotary evaporation. The residue obtained was treated with 5 ml of TFA to remove the Boc protecting group. The TFA solution was stirred for 0.5 hours, then concentrated and the residue was taken to a C18 reversed ISCO column to give 1.2 g of desired product. MS(M+H) ⁺ 387

Step b)

2'Azidoethyloxaethyl argininylamide (300 mg, 1 mmol) and Boc-Pro-OH (220 mg, 1 mmol) from step a) above in 10 ml of DMF The COMU (430 mg, 1.0 eq) was cooled in EtOAc EtOAc. This mixture was partitioned between 50 ml of ethyl acetate and 50 ml of brine. The organic layer was separated to 10ml saturated NaHCO ₃ and ammonium chloride were washed brine, then dried, and concentrated on a rotary evaporator. The residue obtained was purified by C18 reverse phase chromatography (ISCO) to give 350 mg of product. ^{1 H NMR (300MHz, CDCl3)} δ ppm 4.44 (t, J1 = 6.9Hz, J2 = 15Hz, 2H, 4.27 (m, 1H), 3.68 (m, 1H), 3.44 (t, J = 6.9Hz, 4H) , 3.30 (m, 4H), 2.12~1.89 (m, 4H) 1.45 (s, 9H), 1.40 (t, j = 7.2 Hz, 4H)

Step c)

The product from step b) above (300 mg, 0.6 mmol) was treated with 5 ml of TFA for 1 hour and then the solution was stripped to dryness. The residue was redissolved in 10 mL of THF then EtOAc (EtOAc) (EtOAc (EtOAc) The mixture obtained was cooled in an ice water bath, then 0.3 mL of NMM (2.5 mmol, 4 eq) was added and the mixture was stirred overnight. The reaction was partitioned between 50 mL of ethyl acetate and 50 mL brine. The organic layer was separated, 10ml saturated NaHCO ₃ and ammonium chloride were washed brine, then dried over anhydrous sodium sulfate. The organic solution was filtered off and stripped to dryness. The residue obtained was eluted with 5 ml of TFA to remove the Boc protecting group. The TFA solution was stirred for 0.5 hours, then concentrated and passed to reverse phase C18 chromatography (ISCO) to afford 260 mg of the desired tripeptide. ¹ H NMR (300MHz, CDCl3) δ ppm 8.33 (s, 2H), 7.83 (d, J = 7.5 Hz, 2H) 7.65 (d, J = 7.5 Hz, 2H), 7.41 (t, J = 7.2 Hz, 2H) ) 7.32 (t, J = 7.5 Hz, 2H) 4.50 (m, 1H) 4.36 (m, 2H) 4.23 (m, 2H), 3.73 to 3.18 (8H, m), 2.25 (m, 2H), 2.09 (m) , 4H), 1.86 (m, 2H), 1.54 (m, 2H), 1.40 (m, 2H)

Step d)

Step c) (200 mg, 0.27 mmol), FMoc-Thr-OH (100 mg, 0.3 mmol), EDCI (100 mg, 0.4 mmol, 1.3 eq) and HOBt (70 mg, 0.5 mmol, 1.3 eq) were added to DMF. in. The mixture obtained was cooled in an ice water bath, 0.12 ml of NMM (1 mol, 3 eq) was added and then the mixture was stirred overnight. The mixture was partitioned between 50 ml of ethyl acetate and 50 ml of brine. The organic layer was separated, 10ml saturated NaHCO ₃ and ammonium chloride were washed brine, and dried over sodium sulfate. The organic layer was filtered and stripped to dryness and then subjected to reversed phase C18 chromatography (ISCO) to afford the desired product. ^{1 H NMR (300MHz, CDCl3)} δ ppm 7.73 (m, 4H), 7.55 (m, 4H), 7.36 (m, 4H), 7.26 (m, 4H), 7.15 (m, 2H), 4.33 ~ 4.17 (m , 4H), 4.02 (m, 1H), 3.90 (m, 1H), 3.78 (m, 1H), 3.52 to 3.04 (m, 10H), 2.37 (m, 1H), 2.05 (2H, m), 1.90 ( 2H, m), 1.64 (4H, m), 1.41 (m, 4H), 1.27 (m, 3H), 1.21 (d, J = 6 Hz, 3H), 1.13 (m, 2H), 0.8 (m, 2H)

Step e) Preparation of Int-14

The azide (0.100 mmol) prepared in the above step d) was treated with triphenylphosphine (0.105 mmol) in 5% aqueous THF (10 mL) and stirred until the starting azide disappeared completely. The mixture was concentrated and purified by reverse phase HPLC. Fractions containing exactly the compound having a molecular weight of 1030.5276 were combined and lyophilized to obtain this product.

Preparation of trehalase-N-FMOC-amphotericin B (Int-15)

A solution of amphotericin B (5.00 g, 5.41 mmol) and Fmoc-OSu (2.01 g, 5.95 mmol) in DMF (100 mL) The reaction was diluted with a third butyl methyl ether (1.0L). The filter cake was washed with additional EtOAc (2 x 100 mL). Yield: 5.77 g, as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.91 (d, J = 7.08 Hz, 3 H) 1.04 (d, J = 6.35 Hz, 3 H) 1.09-1.13 (m, 4 H) 1.17 (d, J = 5.27 Hz, 3 H) 6.92 (d, J = 8.44 Hz, 1 H) 7.28-7.38 (m, 2 H) 7.38-7.48 (m, 2 H) 7.76 (dd, J = 7.47, 3.76 Hz, 2 H) 7.89 (d, J = 7.52 Hz, 2 H). MS (M+Na) 1169.4

Preparation of N-FMOC-2'-deoxyamphomycin B (Int-16)

A solution of 2'-deoxy-amphomycin B (5.0 g, 5.5 mmol) and Fmoc-OSu (2.0 g, 6.0 mmol) in DMF (100 mL) was stirred at room temperature until a significant amount of polyene starting material was consumed . The reaction was diluted with a third-butyl methyl ether (1.0L), and the mixture was filtered through a sintered funnel. The filter cake with additional third-butyl methyl ether (2 x 100mL) washed, and dried in vacuo to give the precise molecular weight of 1129.5610 Int-16.

Example 2: Synthesis of Compound 1

Amphotericin B diaminoether decylamine (Int-8) (121 mg, 0.120 mmol, 1.00 eq) was dissolved in 4 mL dry DMF and cooled to 0 °C. (N-iso-BOC)-MLF-OSu (Int-2) was added dropwise to DMF (0.1 mmol, 0.8 eq). The reaction was stirred at 0 °C for 30 minutes. The product was purified by semi-preparative HPLC using a gradient of methanol / 0.1% acetic acid and water 0.1% acetic acid. The desired fractions were combined and evaporated in vacuo at 30 ° C to give &lt LC/MS, 1500 [MH] ^- . HPLC [ELSD] T _R 7.751 min (100%). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (d, J = 6.44 Hz, 3 H) 0.86 (t, J = 7.03 Hz, 8 H) 0.91 (d, J = 7.22 Hz, 3 H) 1.04 ( d, J = 6.44 Hz, 3 H) 1.11 (d, J = 6.44 Hz, 3 H) 1.14 (d, J = 5.86 Hz, 3 H) 1.88 (s, 5 H) 2.02 (s, 3 H) 2.73 ( s, 2 H) 2.89 (s, 2 H)

Example 3: Synthesis of Compound 2

step 1

Amphotericin B diaminoether decylamine (Int-8) (100 mg, 0.0990 mmol, 1.00 eq) was dissolved in 4 mL dry DMF and cooled to 0 °C. A 1 mL solution of DMLF-OSu (Int-1) from Step 1 of Int-1 was added dropwise to a DMF solution. After stirring for 1 hr, HPLC indicated that the compound had been consumed. DMF was removed under vacuum at room temperature and the residue was dissolved in 10 mL DMSO. The product was purified by semi-prep HPLC using a gradient of methanol / 0.1% acetic acid and water / 0.1% acetic acid. The desired fractions were combined and evaporated in vacuo to afford 47 mg of EtOAc. LC/MS, 1430 [M+H] ⁺ . HPLC [ELSD] T _R 6.727 min (100%). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (d, J = 7.03 Hz, 3 H) 0.85 (d, J = 6.64 Hz, 3 H) 0.91 (d, J = 7.22 Hz, 3 H) 1.04 ( d, J = 6.44 Hz, 4 H) 1.11 (d, J = 6.64 Hz, 4 H) 1.15 (d, J = 5.86 Hz, 4 H) 1.84-1.91 (m, 1 H) 2.01 (s, 3 H) 2.54(s,1 H)5.15-5.28

Step 2

fMLF-OSu (Int-1) from step 2 was charged with Int-8 (2.00 g, 1.98 mmol). After stirring at room temperature for 1.75 hours, diluted with tertiary butyl methyl ether (650 mL) and the reaction was, the mixture obtained was filtered through a sintered funnel. The filter cake was washed with additional third butyl methyl ether (2 x 100 mL) and dried in vacuo. The crude product was then and diatomaceous earth (10.8 g of) mixed and 99.9 on 50g Isco Gold RediSep C-18 reverse phase silica Shixia: 0.1 H ₂ O: HOAc to 99.9: 0.1 MeOH: HOAc gradient elution With chromatography. The product was separated from H ₂ O (~ 8mL) freeze-dried. Yield: 0.532 g, yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.80 (d, J = 6.44 Hz, 3 H) 0.85 (d, J = 6.54 Hz, 3 H) 0.91 (d, J = 7.03 Hz, 3 H) 1.04 (d, J = 6.49 Hz, 3 H) 1.07-1.13 (m, 4 H) 1.15 (d, J = 5.86 Hz, 3 H) 2.01 (s, 3 H) 7.08-7.28 (m, 5 H) 7.89 ( d, J = 7.91 Hz, 1 H) 7.95-8.00 (m, 2 H) 8.01 (s, 1 H) 8.08 (d, J = 8.00 Hz, 1 H) 8.27 - 8.35 (m, 1 H). MS (M+H) 1430.2. Analytical HPLC t _R = 7.265 min; purity = 100%, detected by ELSD

Example 4: Synthesis of Compound 3

Int-8 (26 mg, 0.03 mmol) and N ^ε -fMLF-N ^α -FMOC-K (Int-3) (20.3 mg, 0.03 mmol) were dissolved in 4 mL dry DMF and cooled to 0 °C. HATU (10.3 mg, 0.03 mmol, 1.1 eq) was added followed by 2,4,6-dimethylpyridine (6.8 μL, 6.24 mg, 0.05 mmol, 2 eq). After 30 minutes, piperidine (15 [mu]L, 12.8 mg, 0.15 mmol, 5 eq) was added and the mixture was warmed to room temperature. After stirring for 2 hours, the product was purified by preparative HPLC using a gradient of 40% to 100% methanol in water (0.1% acetic acid) for 5 min. The yield was 18.3 mg. LC / MS, 779.4 [(M + 2H) / 2] +. HPLC (UV at 220 nm), T _R 6.136 min (70.7%); 21.6% different isomers. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.79 (d, J = 6.44 Hz, 2 H) 0.84 (d, J = 6.64 Hz, 2 H) 0.91 (d, J = 7.03 Hz, 3 H) 1.04 (d, J = 6.25 Hz, 3 H) 1.12 (dd, J = 10.93, 6.25 Hz, 7 H) 2.02 (s, 2 H) 7.12-7.29 (m, 5 H) 7.80-7.87 (m, 1 H) 7.87-7.93(m,1 H)8.15-8.21(m,1 H)8.32-8.38(m,1 H).

Example 5: Synthesis of Compound 4

Step a) Preparation of N-FMOC Natamycin (Natamycin)

Natamycin (266 mg, 0.4 mmol) was slurried in 15 mL dry DMF and EtOAc (EtOAc) The reaction was stirred at room temperature until completion. The reaction was poured into 500 mL MTBE and filtered and then washed with additional MTBE. The product was dried under vacuum in the dark overnight. The yield was 311 mg. LC/MS, 910.0 [M+Na] ⁺ . ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 1.16 (d, J = 4.64Hz, 3 H) 1.25 (d, J = 5.98Hz, 3 H) 1.44-1.66 (m, 2 H) 1.84 (dd, J = 11.10, 3.90 Hz, 1 H) 1.89-2.04 (m, 3 H) 2.19 (dd, J = 23.67, 10.49 Hz, 1 H) 2.32-2.44 (m, 1 H) 2.74-2.78 (m, 1 H 3.16 (d, J = 5.74 Hz, 2 H) 3.23 (d, J = 7.08 Hz, 1 H) 3.42 (t, J = 8.54 Hz, 1 H) 3.56 - 3.65 (m, 1 H) 3.94 - 4.07 ( m,1 H)4.08-4.18(m,1 H)4.22(br.s.,3 H)4.32-4.45(m,2 H)4.59-4.75(m,2 H)5.24-5.45(m,1 H ) 5.54-5.69 (m, 1 H) 5.87 (dd, J = 15.13, 8.91 Hz, 1 H) 6.14 (s, 8 H) 6.51 (dd, J = 14.15, 11.10 Hz, 1 H) 6.91 (d, J =8.79 Hz, 1 H) 7.28-7.38 (m, 2 H) 7.42 (t, J = 7.32 Hz, 2 H) 7.76 (dd, J = 7.14, 3.97 Hz, 2 H) 7.89 (d, J = 7.57 Hz) , 2 H)

Step b) Coupling and deprotection

The N-FMOC natamycin (100 mg, 0.11 mmol) prepared in step a) was dissolved in 5 mL dry DMF and cooled to 0 °C. Add fMLF-diaminoethylguanamine (Int-5) (59 mg, 0.11 mmol, 1 eq). COMU (48 mg, 0.11 mmol, 1 eq) was added followed by DIPEA (41 uL, EtOAc. The reaction was stirred at 0 °C for 2 hours until N-FMOC Natamycin was consumed. Piperidine (325 uL, 6.5% V/V) was added and the reaction was stirred at 0 °C for 20 min. The reaction was quenched with 500 uL of acetic acid and the product was purified by preparative HPLC using a gradient of 30% to 100% methanol in water (0.1% acetic acid) for 5 min. The yield was 14 mg. LC/MS, 1171.2 [M+H] ⁺ . HPLC (UV at 220 nm), T _R 6.010 min (93%). HPLC (ELSD), T _R 6.156 min (100%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.79 (d, J = 6.48 Hz, 3 H) 0.85 (d, J = 6.59 Hz, 3 H) 1.14 (d, J = 6.04 Hz, 4 H) 1.21. -1.28(m,3H)1.33-1.44(m,3H)1.44-1.63(m,4H)1.67-1.79(m,1H)1.93(s,3H)2.19 (dd, J =21.19, 10.54 Hz, 1 H) 2.33 (dd, J = 9.44, 2.53 Hz, 1 H) 2.39 (d, J = 2.42 Hz, 3 H) 2.74 (d, J = 8.02 Hz, 1 H) 2.79-3.05 (m, 5 H) 3.08-3.20 (m, 2 H) 3.22 (dd, J = 7.63, 1.70 Hz, 2 H) 3.25-3.36 (m, 4 H) 3.39 (dd, J = 11.42, 5.71 Hz, 3 H) 3.59 (d, J = 2.42 Hz, 1 H) 4.05 (td, J = 10.57, 4.56 Hz, 2 H) 4.13 (t, J = 10.27 Hz, 2 H) 4.20 (d, J = 10.65 Hz, 1 H) 4.24 (s, 2 H) 4.25-4.33 (m, 2 H) 4.36-4.53 (m, 3 H) 4.60-4.72 (m, 2 H) 5.54-5.67 (m, 1 H) 5.85 (dd, J = 15.26, 8.68 Hz, 1 H) 5.97-6.33 (m, 9 H) 6.50 (dd, J = 14.39, 10.65 Hz, 1 H) 7.11-7.29 (m, 5 H) 7.97 (d, J = 8.13 Hz, 1 H) 7.99-8.07 (m, 3 H) 8.15 (d, J = 8.13 Hz, 1 H) 8.33 (d, J = 8.35 Hz, 1 H)

Example 6: Synthesis of acetate of compound 5

Step a) coupling of Int-8 to Int-5

Int-8 (0.078 g, 0.099 mmol), HATU (0.040 g, 0.10 mmol), and 2,4,6-trimethylpyridine were added to a solution of Int-8 (0.100 g, 0.0990 mmol) in DMF (3.0 mL). (0.024 g, 0.20 mmol). After stirring at room temperature for 1.3 hours, diluted with tertiary butyl methyl ether (30mL) and the reaction was, the mixture obtained was filtered through a sintered funnel. The filter cake was washed with additional butyl dimethyl ether (2 x 20 mL), dried in vacuo and dried. Yield: 0.208 g (>100% (118%)) as a yellow solid. MS(M+H+Na)/2 901.4

Step b) removing the FMOC protecting group to obtain compound 5

A solution of the coupling product from step a) (theoretical value: 0.176 g, 0.989 mmol) in DMF (3.0 mL) After stirring at room temperature for 2 hours, the crude product was directly by semi-preparative HPLC, to 30:70 A: B to 100% B (A = 99.9: 0.1 H 2 O: HOAc; B = 99.9: 0.1 MeOH: HOAc Gradient elution to purify. The product was isolated from a _{1: 1 H 2 O: CH} 3 CN (8mL) freeze-dried. Yield: 0.037 g, as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.80 (d, J = 6.49 Hz, 3 H) 0.85 (d, J = 6.54 Hz, 3 H) 0.91 (d, J = 6.88 Hz, 3 H) 1.04 (d, J = 6.39 Hz, 3 H) 1.09-1.12 (m, 4 H) 1.14 (d, J = 6.10 Hz, 3 H) 2.01 (s, 3 H) 7.11 - 7.33 (m, 5 H) 7.91 7.97(m,1H)7.99-8.04(m,2H)8.01(s,1H)8.06-8.11(m,1 H)8.11-8.17(m,1 H)8.32-8.38(m,1 H) . MS (M+H+H)/2 779.4. Analytical HPLC t _R = 5.931 min; purity = 97%, detected by ELSD

Example 7: Synthesis of Compound 6

Amphotericin-B-2-(amino)-ethyl-decylamine (Int-6) (15 mg, 0.0138 mmoles) was dissolved in 10 mL dry DMF and cooled to 0 °C. A solution of (N-isobutoxycarbonyl) MLF-OSu in DMF (Int-2) (0.0138 mmoles) was added dropwise until LC/MS showed no starting material remained. DMF was removed in vacuo and the product was purified by preparative HPLC using 30% to 100% methanol in water / 0.1% acetic acid gradient. The yield was 11 mg, 54%. LC/MS, 1458.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.80 (d, J = 6.44 Hz, 4 H) 0.86 (t, J = 6.64 Hz, 10 H) 0.91 (d, J = 7.03 Hz, 3 H) 1.04 ( d, J = 6.25 Hz, 3 H) 1.12 (dd, J = 12.10, 6.25 Hz, 6 H) 2.02 (s, 2 H) 2.54 (s, 20 H) 7.09 (t, J = 6.35 Hz, 1 H) 7.14 (d, J = 6.64 Hz, 1 H) 7.19 (d, J = 7.42 Hz, 3 H) 7.24 (d, J = 6.44 Hz, 2 H) 7.32 (d, J = 8.00 Hz, 1 H) 7.90 ( d, J = 8.79 Hz, 2 H) 8.00 (d, J = 8.79 Hz, 1 H) 8.24 (t, J = 7.20 Hz, 1 H)

Example 8: Preparation of Compound 7

fMLF-OSu (Int-1) (0.053 g, 0.1 mmol, 1.0 eq) in 1 mL dry DMF was loaded with &lt;RTI ID=0.0&gt; The mixture was stirred at room temperature for about 2 hours, the reaction was diluted with a third-butyl ether (about 60 mL), the obtained mixture was filtered in a sintered funnel. The filter cake with additional third-butyl methyl ether (about 2 x 10mL), and dried in vacuo. The crude product was then purified by reverse phase HPLC. Fractions containing the desired product were combined and lyophilized to give a product having a molecular weight of 1412.77.

Example 9: Preparation of Compound 8

To a solution of fMLF-OSu (Int-1) (0.053 g, 0.1 mmol, 1.0 eq) in 1 mL dry DMF. The mixture was stirred at room temperature for about 2 hours, the reaction was diluted with a third-butyl ether (about 60mL), and the resulting mixture was filtered through a sintered funnel. The filter cake was washed with additional tertiary butyl ether (about 2 x 10mL) and dried in vacuo. The crude product was then purified by reverse phase HPLC. The fractions containing the desired product were combined and lyophilized to give a product having a molecular weight of 1503.83.

Example 10: Preparation of Compound 9

Step a) Preparation of N-Amber-L-Amidino-Mercapto-L-Amidino-N-Hydroxysuccinate

N-Amber-L-Amidino-glycolyl-L-amidinoin (Int-13) (63 mg, 0.10 mmol, 1 eq) was dissolved in 2 mL dry DMF. DCC (22 mg, 0.11 mmol, 1.05 eq) was obtained eluted eluted elute The product was used directly in the next reaction without purification.

Step b)

A solution containing N-succinyl-L-amidoxime-glycine-L-amidoxime N-hydroxysuccinyl ester from step a) is supported on amphotericin-aminoethoxy- Ethylguanamine (Int-6) (100 mg, 0.1 mmol) was taken in 2 ml of DMF. After stirring at room temperature for 4 hours, 0.05 ml of piperidine was added and the mixture was stirred for further 1 hour, then purified by EtOAc EtOAc. ^{1 H NMR (300MHz, DMSO- d} 6) δ ppm 0.90 (d, J = 6.9Hz, 3 H) 1.01 (d, J = 7.2Hz, 3 H) 1.07 (d, J = 8Hz, 3 H), 1.15 (d, J = 4.5 Hz, 3H) 7.69 (s, 1H) 7.91 (s, 1H) 8.17 (s, 1 H), 8.36 (s, 1 H). MS 681 [M+H] ⁺ /2

Example 11. Preparation of Compound 10

Step a) Preparation of NAc-L-Amidoxime-glycinyl-L-proline N-hydroxyammonium imidate

NAc-L-Amidino-glycine-L-proline (63 mg, 0.20 mmol, 1 eq) was dissolved in 4 mL dry DMF. DCC (42 mg, 0.21 mmol, 1.05 eq.). The product was used directly in the next reaction without purification.

Step b): a solution of NAc-L-Amidoxime-glycidyl-L-proline N-hydroxyammonium imidate prepared in the above step a) is supported on amphotericin-amino ethoxylate Base-ethyl decylamine (Int-8) (200 mg, 0.2 mmol) was taken in 4 mL DMF. After stirring at room temperature for 4 hours, the mixture was purified by EtOAc EtOAc (EtOAc). ^{1 H NMR (300MHz, DMSO- d} 6) δ ppm 0.91 (d, J = 6.Hz, 3 H) 1.04 (d, J = 5.4Hz, 3 H) 1.11 (d, J = 6.3Hz, 3 H) , 1.15 (d, J = 6 Hz, 3H) 1.97 (s, 3H) 7.87 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H). MS 652 [M+H] ⁺ /2.

Example 12 Preparation of Compound 11

A procedure similar to that in Example 11 was used, but using Int-7 as a starting material. Compound 11 having a molecular weight of 1287.55 can be prepared.

Example 13. Preparation of Compound 12

D, D, D-fMLF-OSu (Int-10) (0.23 mmol) prepared according to the procedure of Example 1 for use in Int-10 was dried in DMF at 4 mLs, and loaded on amphotericin B-aminoethoxy B. Baseline amine (Int-8) (200 mg, 0.2 mmol). After stirring at rt for 4 h, EtOAcqqqqqqm ¹ H NMR (300 MHz, DMSO- d ₆ ) δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ , J=5.1 Hz, 3H1.11 (d, J=6 Hz, 3 H),) 1.04 (d, J = 6.0 9 Hz, 3 H) 0.90 (d, J = 6.9 Hz, 3 H) 0.74 (d, J = 6.3 Hz, 3 H) 0.70 (d, J = 7.5 Hz, 3 H). MS 715 [M+H] ⁺ /2.

Example 14. Preparation of Compound 13

The procedure of step b) of compound 4 was prepared in a similar manner to that in Example 5, but the starting materials were Int-14 (0.100 mmol) and Int-15 (0.100 mmol) to prepare amphotericin B-dioxin having a molecular weight of 1492.82. Aminoethyl ether-RPKT conjugate.

Example 15. Preparation of Compound 14

The procedure for preparing compound 13 is carried out in a similar manner to the above examples, but the starting materials are Int-14 and Int-16, and 2'-deoxyamphomycin B-diguanylaminoethyl ether-RPKT having a molecular weight of 1476.82 can be prepared. Joint.

Example 16. Preparation of Compound 15

A procedure similar to the above Example 14 for the preparation of compound 13 but starting materials of Int-12 and Int-15 was carried out to prepare an amphotericin B-diguanylaminoethyl ether-RFLfM conjugate having a molecular weight of 1585.96.

Example 17 Preparation of Compound 16

N-Methylmercapto-L-methylsulfanyl decyl-L-hamamine decyl-L-4-pyridylalanine (Int-17) (50 mg, 0.11 mmol), COMU (50 mg, 0.12 mmol, 1.1 Eq) and NMM (0.12 ml, 1 mmol, 2 eq) were added to 4 ml of DMF cooled in an ice water bath, then added to 4 mg of DMF in amphotericin-aminoethoxy-ethyl decylamine (Int-8) (200 mg, 0.2 mmol). After stirring overnight at rt, the title was purified eluting with EtOAc EtOAc ¹ H NMR (300 MHz, DMSO- d ₆ ) δ ppm 8.42 (d, J = 4.2 Hz, 2H) 8.30 (s, 2H) 8.01 (s, 1 H) 7.22 (d, J = 4.2 Hz, 2 H) 2.02 (s, 3 H) 1.15 (d, J = 6 Hz, 3H) 1.11 (d, J = 6 Hz, 3 H),) 1.04 (d, J = 5.4, 3H) 0.92 (d, J = 6.3 Hz, 3 H ) 0.86 (d, J = 6.3 Hz, 3 H) 0.80 (d, J = 6.3 Hz, 3 H). MS 715[M+H] ⁺ /2

Example 18: Antifungal activity of a compound Test organism

The test organism consisted of strains from the Micromyx Collection. Reference single exosomes were first obtained from the American Type Culture Collection (ATCC; Manassas, VA). The organisms obtained from Micromyx were pre-lined for purification on Sabouraud dextrose or potato dextrose agar. Colonies were picked from the culture medium with cotton swabs and resuspended in a suitable antifreeze-containing medium. The suspension was dispensed into a cryotube and stored at -80 °C.

Candida isolates were streaked from Saskatchewan glucose agar from cryotubes prior to testing. This yeast isolate was incubated overnight at 35 °C prior to use. Prior to collection, the fungal isolate was cultured on a Saskatchewan glucose agar slant at 35 ° C for at least 7 days.

Test medium

The isolates were tested in RPMI medium (Catalog No SH30011.04; Lot No. AWA92121B; HyClone Labs, Logan, UT) prepared according to the 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 μm PES filter and stored at 4 ° C until use.

Minimal Inhibitory Concentration (MIC) concentration analysis step

The MIC analysis method uses an automatic liquid manipulator for serial dilution and liquid transfer. Automated liquid operations include Multidrop 384 (Labsystems, Helsinki, Finland), Biomek 2000, and Biomek FX (Beckman Coulter, Fullerton CA). Fill the wells in columns 2-12 in a standard 96 well microdilution tray (Costar 3795) with 150 μl of the correct dilution (for test compounds) It is 50% DMSO and 100% DMSO for the comparative compound). These are referred to as 'master disks', whereby a "sub-disk" or a test disk can be prepared. The stock was diluted with the indicated solvent, diluted to 40 times the desired maximum concentration in the test plate (40X), and 300 μL of the 40X stock solution was dispensed into a suitable well of column 1 of the master. Biomek 2000 was used to make a 2-fold serial dilution in column 11 of the "master". The well of column 12 contains no drug as a biological growth control well.

Using Multidrop 384, 185 μL of the above RPMI was loaded into each well of the subdisk. Subdisks were prepared using Biomek FX, which transferred 5 [mu]L of drug solution from each well of the master disk to each well corresponding to the daughter disk in a single step.

Standard inoculum for each organism was prepared. For Candida, colonies were picked from the scribing tray and a suspension equal to 0.5 McFarland standard was prepared in RPMI medium, then diluted 1:100 in RPMI and transferred to length-divided Separation of sterile storage tanks (Beckman Coulter). For the sputum isolates, dilutions were prepared in RPMI using previously prepared and quantified suspensions to a final concentration of 20X. These dilutions were also transferred to a separate length of sterile storage tank (Beckman Coulter). The final concentration of the sputum isolate is about 0.2-2.5 x 10 ⁴ CFU/mL.

Inoculate the dish using Biomek 2000. The subdisks placed on the Biomek 2000 working surface were inverted so that the inoculation was carried out at low to high drug concentrations. Biomek 2000 added 10 μL of standardized vaccinogen to each well. Therefore, the well of the sub-disk finally contained 185 μL of RPMI, 5 μL of the drug solution, and 10 μL of the vaccination. In the test well, the final concentration of DMSO was 2.5% for the comparative agent evaluated and 1.25% for the test agent.

Stack 3 layers, cover the top plate, put it in a plastic bag, and read it The value was incubated at 35 ° C for about 24-48 hours. When the inoculation was confluent in the growing well, the disc was read. The disc is viewed from the bottom using a plate viewer. Unvaccinated soluble control disks were observed to demonstrate drug precipitation. The MIC was read when biovisible growth was inhibited (Table 1).

Example 19 Antifungal Activity of Compounds

MIC and MEC analyses were performed according to the CLSI medium microdilution guidelines (M27-A3, M27-S4, and M38-A2) with the exception that 100 μL of the assay volume was used and the stock solution compound was diluted to a final 50X concentration. Briefly, the starting concentrations of all antifungal agents were prepared as 100% DMSO. The stock concentration was 50X of the highest concentration analyzed last, then diluted in 2x series and diluted 12 times in a 96-well PCR disk (VWR 83007-374). Candida and sputum suspensions from Saskatchewan glucose agar plates were prepared in 0.85% saline at 0.5 McFarland standard (~0.1 OD ₅₃₀ nm). The Candida suspension was diluted 1:500 in RPMI (MP Biomedicals, cat no. 1060124; buffered with MOPS, adjusted to pH 7.0 with NaOH) to a concentration of ~0.5-2.5 x 10 ³ CFU/mL. The sputum suspension was diluted 1:50 in RPMI to a final concentration of ~0.4-5 x 10 ⁴ CFU/mL. 98 μL of each cell suspension in RPMI was added to a test well of a 96 well assay disk (Costar Model No. 3370). Each 2 [mu]L of 50X stock solution was dispensed using a Beckman Multimek 96 liquid handling robot into a dish containing each strain in 98 [mu]L RPMI (2% final solvent concentration). The plate was shaken and then incubated at 35 ° C for 24-48 hours before reading. For echinocandin, the MIC value can be read under 50% growth inhibition (24 hours) and for amphotericin B, it can be read under 100% growth inhibition (48 hours). The MEC value (24 hours) was read by a microscope at the lowest concentration of echinomycin, and a round/tight mycelium shape was observed. The data is shown in Tables 2a and 2b.

Example 20: Chemotaxis activity of a compound Human neutrophil migration analysis (Transwell Migration Assay) method 1.

Neutrophils were purified from human peripheral blood using PolymorphPrep. Red blood cells are solubilized in lysis buffer, and the cells are washed, counted, and resuspended in assay buffer. A neutrophil (approximately 50,000 to 100,000) was placed in a 24-well well with a 5-micon well, and the test compound was located in the bottom chamber of each well. In the bottom chamber there is only a negative control of the medium, which is established in three replicates. A positive control that directly adds the neutrophil to the bottom well is established in three replicates.

The plates were incubated at 37 ° C for 45 minutes to allow for migration. After this time passed, the migration was visually confirmed, and 1 part of the liquid (1/6 of the total cells) was taken from each well for ATP detection, which was quantitatively migrated by ATPlite (PerkinElmer). The average reading of the random migration detected in the negative control was subtracted from all readings to obtain the correct number of migrations. Then divide these values by the positive control. The average reading was taken to obtain the maximum migratory neutrophil movement %.

Method 2.

Neutrophils were purified from human peripheral blood using PolymorphPrep. Red blood cells are solubilized in lysis buffer, and the cells are washed, counted, and resuspended in assay buffer. A neutrophil (approximately 50,000 to 100,000) was placed in a 96-well well with a 5-micon size, and the test compound was located in the bottom chamber of each well. Each test compound was established in two replicates. The bottom chamber was only negative for the medium and was established in six replicates. A positive control that directly adds the neutrophil to the bottom well is established in six replicates.

The plates were incubated at 37 ° C for 45 minutes to allow for migration. After this time passed, the migration was visually confirmed, and 1 part of the liquid (1/6 of the total cells) was taken from each well for ATP detection, which was quantitatively migrated by ATPlite (PerkinElmer). The average reading of the random migration detected in the negative control was subtracted from all readings to obtain the correct number of migrations. These values were then divided by the average reading obtained from the positive control to obtain the maximum migratable neutrophil shift % at the specified concentration of the compound (nM) (Table 3).

Other embodiments

Although the present invention has been described with respect to the specific embodiments thereof, it is understood that the invention may be modified, and the application is intended to cover any change, use or adaptation of any of the general principles described herein. Deviations caused by known or common practice in the art, and which apply to the aforementioned essential features.

The entire disclosures of all of the documents, patents, and patent applications are hereby incorporated by reference in their entirety in their entireties in the entireties in the the the the the the the the The disclosure of U.S. Provisional Application Serial No. 61/982,134, the entire disclosure of which is incorporated herein by reference.

Claims (99)

A compound or a pharmaceutically acceptable salt thereof, comprising: a chemotactic receptor ligand structure E covalently linked to a polyene antifungal structure via linker L. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the linker is a polypeptide. The compound of claim 1 or 2, wherein the chemotactic receptor ligand structure is attached to the linker and/or the polyene antifungal structure via a guanamine bond, or a pharmaceutically acceptable salt thereof Attached to the linker via a guanamine bond. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the linker is attached to the carbonyl group of the chemotactic acceptor ligand structure E. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the linker of the compound is a diamine. A compound or a pharmaceutically acceptable salt according to claim 5, wherein the diamine linker is bonded to the carbonyl group of the polyene antifungal structure to form a guanamine bond. A compound or a pharmaceutically acceptable salt according to claim 5 or 6, wherein the diamine linker is bonded to the carbonyl group of the chemotactic acceptor ligand structure E to form a guanamine bond. The compound or pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein the polyene antifungal agent is 67-121-A, 67-121-C, amphotericin B , arenomvcin B, aurinin, aureofungin A, aureotuscin, candidin, chinin, demethoxyrapamycin, Dermostatin A, dermostatin B, DJ-400-B ₁ , DJ-400-B ₂ , elizabethin, eurocydin A, eurocidin B Filipin I, Filipin II, Filipino III, Filipino IV, fungichromin, gannibamycin, hamycin, levoin A ₂ , lennomycin, lusensomycin, mycoheptin, mycoticin A, mycoticin B, natamycin ( Natamycin), nystatin A, nystatin A ₃ , partricin A, partricin B, perimycin A, pimaricin (pimaricin), polifungin B, rapamycin, rectilavendomvcin, rimoidin, roflamycoin, tetramycin A, four Tetramycin B, tetrin A or tetrin B. A compound or a pharmaceutically acceptable salt according to claim 8 wherein the polyene antifungal agent is selected from the group consisting of amphotericin B, natamycin and nystatin. A compound or a pharmaceutically acceptable salt according to claim 9 wherein the polyene antifungal agent is amphotericin B. A compound or a pharmaceutically acceptable salt according to claim 9 wherein the polyene antifungal agent is natamycin. Such as a compound of claim 9 or a pharmaceutically acceptable salt, The chemotactic receptor ligand is a ligand of the forminyl peptide receptor family. The compound or pharmaceutically acceptable salt of any one of claims 1 to 12, wherein the chemotactic receptor ligand is a mercaptopeptide receptor 1 (FPR1), a thiol peptide receptor 2 (FPR2), mercaptopeptide receptor 3 (FPR3), methionyl peptide receptor 1 (FPRL1), methionin receptor 2 (FPRL2), neuropilin 1 Hormone receptor 1 (CXCR1), and/or chemokine receptor 2 (CXCR2). The compound or pharmaceutically acceptable salt according to any one of claims 1 to 12, wherein the chemotactic receptor ligand is selected from the group consisting of a chemotactic peptide, a phagocytic hormone peptide (tuftsin peptide), and Ethyl-proline-glycine-proline (PGP) peptide. The compound or pharmaceutically acceptable salt of any one of claims 1 to 14, wherein the chemotactic receptor ligand structure E is a chemotactic peptide comprising an amine of the formula Acid: R ¹⁴ -X1-X2-X3-X4-X5-X6-X7-X8-X9- wherein V1 is any amino acid residue; X2-X9 is any amino acid residue or absent; R ¹⁴ is hydrogen or Wherein X ₁₀ is a bond, NH or O; R ¹⁵ is hydrogen, a C1-C6 alkyl group which is optionally substituted, a C1-C6 heteroalkyl group which is optionally substituted, a C2-C6 alkenyl group which is optionally substituted, Optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally Substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 cycloalkynyl, optionally substituted fluorene, optionally substituted fluorene, optionally substituted C6-C12 aryl or alternatively substituted C2-C6 heterocycle. A compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein the chemotactic peptide comprises an amino acid of the formula: R ¹⁴ -X1-X2-X9-form VI wherein X1 is any amine group An acid residue; X2 is an leucine residue, an isoleucine residue; and X9 is an amino acid residue or is absent. The patentable scope of application of the compound of item 15 or a pharmaceutically acceptable salt, wherein the chemotactic peptide comprising the amino acid of the formula: R ¹⁴ -X1-X2-X9- formula VI wherein X1 and X9 each independently The residue is a hydrophobic amino acid residue, and X2 is a hydrophobic amino acid residue or is absent. A compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein X1 is a methionine residue, an oxidized methionine residue or a noralminic acid residue. A compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein X2 is an leucine residue, an isoleucine residue or is absent. A compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein X9 is a phenylalanine residue, a 1-amino-2-phenylcyclopropane-1-carboxylic acid residue, a methionine Residue, (O-benzyl)serine residue, 2-pyridylalanine residue or 4-pyridylalanine residue. The compound of any one of claims 15 to 20, wherein R ¹⁴ is -C(O)H, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 15 to 20, wherein R ¹⁴ is -C(O)CH ₃ , or a pharmaceutically acceptable salt thereof. The compound of any one of claims 15 to 20, wherein R ¹⁴ is -C(O)OCH ₂ CH(CH ₃ ) ₂ , or a pharmaceutically acceptable salt thereof. The compound of any one of claims 15 to 20, wherein R ¹⁴ is -C(O)NH-(4-chlorophenyl), or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein the chemotactic acceptor ligand structure E is selected from the group consisting of: Wherein R ²⁴ is H or C1-C3 alkyl; wherein q ¹ is 1 or 2; and wherein -NH-A ⁴ -C(O)- and -NH-A ⁵ -C(O)- are each independently a base Amino acid residue; Wherein R ²⁵ is H, C1-C6 alkyl or phenyl; wherein t ¹ is 1 or 2; wherein u ¹ is 1, 2, 3, 4, 5 or 6; and wherein v ¹ is 1 or 2; Wherein -NH-A ¹ -C(O)- and -NH-A ² -C(O)- are each independently a hydrophobic amino acid residue; wherein -NH-A ³ -C(O)- is hydrophobic Amino acid residue or absent; wherein R ²⁶ is H, C1-C6 alkyl, OR ²⁸ or NR ²⁹ ; wherein R ²⁷ is heterocyclyl, heteroaryl or heteroalkenyl; wherein R ²⁸ and R ²⁹ are each independently a C1-C10 alkyl or phenyl, optionally substituted with C1-C3 alkyl or halogen; wherein w ¹ is 0, 1 or 3. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein the chemotactic acceptor ligand structure E is selected from the group consisting of: Wherein R ²⁴ is H or C1-C3 alkyl; wherein q ¹ is 1 or 2; wherein -NH-A ⁴ -C(O)- and -NH-A ⁵ -C(O)- are each independently basic Amino acid residue; Wherein R ²⁵ is H, C1-C6 alkyl or phenyl; wherein t ¹ is 1 or 2; wherein u ¹ is 1, 2, 3, 4, 5 or 6; wherein v ¹ is 1 or 2; Wherein -NH-A ¹ -C(O)- and -NH-A ² -C(O)- are each independently a hydrophobic amino acid residue; wherein -NH-A ³ -C(O)- is hydrophobic a fatty amino acid residue or absent; wherein R ²⁶ is H, C1-C6 alkyl, OR ²⁸ or NR ²⁹ ; wherein R ²⁷ is heterocyclyl, heteroaryl or heteroalkenyl; wherein R ²⁸ and R ²⁹ are each independently a C1-C10 alkyl or phenyl, optionally substituted with C1-C3 alkyl or halogen; and wherein w ¹ is 0, 1 or 3. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein the chemotactic acceptor ligand structure E is Wherein R ²⁴ is H or methyl; wherein r ¹ and s ^{1 are} each ¹ , 2, 3 or 4; wherein q ¹ is 1 or 2; and wherein the basic amino acid residue is selected from the group consisting of Group: lysine residues, alanine residues, arginine residues, diaminobutyric acid residues, and diaminopropionic acid residues. A compound according to claim 27 or a pharmaceutically acceptable salt thereof, wherein R ²⁴ is methyl; and wherein the basic amino acid residue is an lysine or arginine residue. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein the chemotactic acceptor ligand structure E is Wherein R ²⁷ is a C3-C10 heteroalkyl, heteroaryl or heteroalkenyl group having from 1 to 5 O, S or N heteroatoms. A compound according to claim 25 or a pharmaceutically acceptable salt thereof, wherein R ²⁷ is piperidinyl, tetrahydrofuranyl, pyridyl or piperidin Base, pyrimidinyl, three Base, thienyl or bromo. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R ²⁷ is 2-pyridyl, 4-pyridyl or -NHC(NH)NH _{2 ;} wherein w ¹ is 3; wherein -NH -A ¹ -C(O)- is a methionine residue; and wherein -NH-A ² -C(O)- is an leucine residue. The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein the chemotactic acceptor ligand structure E is The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein the chemotactic acceptor ligand structure E is The compound or pharmaceutically acceptable salt of any one of claims 1 to 14, wherein the chemotactic acceptor ligand structure E has a structure selected from the group consisting of: Or wherein the chemotactic acceptor ligand structure E has a structure selected from the group consisting of: Or wherein the chemotactic acceptor ligand structure E has a structure selected from the group consisting of: The compound or pharmaceutically acceptable salt of any one of claims 1 to 34, wherein the linker comprises a non-reactive linking structure having a length of from 1 to 100 atoms. The compound or pharmaceutically acceptable salt of any one of claims 1 to 34, wherein the linker has the structure: G ¹ -(Z ¹ ) _b -(Y ¹ ) _c -(Z ² ) _d -(R ¹⁶ )-(Z ³ ) _e -(Y ² ) _f -(Z ⁴ ) _g -G ² Formula VII wherein G ¹ is a bond between the linker and the structure of the polyene antifungal agent; ² is a bond between the chemotactic acceptor ligand structure E and the linker; Z ¹ , Z ² , Z ³ and Z ^{4 are} each independently selected from: a C1-C4 alkylene group which is optionally substituted a selectively substituted C1-C3 heteroalkylene group, a selectively substituted C3-C9 cycloalkylene group, a selectively substituted C6-C12 extended aryl group, and a selectively substituted C2-C6 extended heterocyclic ring a group, O, S and NR ¹⁷ ; each R ^{17 is} independently hydrogen, a selectively substituted C 1 -C 4 alkyl group, a selectively substituted C 2 -C 4 alkenyl group, a selectively substituted C 2 -C 4 alkynyl group, Optionally substituted C2-C6 heterocyclyl, optionally substituted C6-C12 aryl or alternatively substituted C1-C7 heteroalkyl; Y ¹ and Y ^{2 are} independently carbonyl, thiocarbonyl, sulfonium sulfonate a base or a phosphate group; b, c, d, e, f and g are independently 0 or 1; and R ¹⁶ is a selectively substituted C1-C10 stretch An alkyl group, a selectively substituted C2-C10 alkenyl group, a selectively substituted C2-C10 alkynyl group, a selectively substituted C3-C9 cycloalkylene group, a selectively substituted C2-C6 extended group a cyclic group, a selectively substituted C6-C12 extended aryl group, a selectively substituted C2-C100 extended polyethylene glycol group or a selectively substituted C1-C10 heteroalkylene group or a chemical bond, if b, c , d, e, f and g are 0, then R ^{16 is} not a chemical bond; or G1-(Z ¹ ) _b -(Y ¹ ) _c -(Z ² ) _d -(R ¹⁶ )-(Z ³ ) _e - (Y ² ) _f -(Z ⁴ ) _g -G ² is a linkage linking the polyene antifungal structure to the chemotactic acceptor ligand structure. The compound or pharmaceutically acceptable salt of any one of claims 1 to 34, wherein the linker is selected from the group consisting of: Wherein i, k, l and m are independently 0 to 12; h is 1 to 6; j is 1 to 7; t is 1 to 5; u is 0 to 4; v is 1 to 4; w is 0 to 3 A is a selectively substituted C3-C8 cycloalkyl, a selectively substituted C2-C6 extended heterocyclic group or a selectively substituted C6-C12 extended aryl group; R ¹⁸ and R ^{19 are} independently hydrogen. Amino, fluoro, hydroxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 a heteroalkenyl group, a selectively substituted C2-C6 alkynyl group, a selectively substituted C2-C6 heteroalkynyl group, a selectively substituted C3-C10 cycloalkyl group, a selectively substituted C4-C10 cycloalkenyl group a selectively substituted C4-C10 cycloalkynyl group, a selectively substituted C6-C12 aryl group, a selectively substituted C2-C6 heterocyclic group, a selectively substituted C3-C10 cycloalkoxy group, and a choice a substituted C4-C10 cycloalkenyloxy group, a selectively substituted C4-C10 cycloalkynyloxy group, a selectively substituted C6-C12 aryloxy group or a selectively substituted C2-C6 heterocyclooxy group, or R ¹⁸ and R ¹⁹ with the carbon atoms bonded together to form a combined sum optionally substituted C3-C10 cycloalkyl , The optionally substituted C4-C10 cycloalkenyl, optionally substituted cycloalkyl of C4-C10 alkynyl group, the optionally substituted C6-C12 aryl group or optionally substituted heterocyclic group of C2-C6; and Z ¹ and Z ^{4 are} each independently selected from a C1-C4 alkylene group which is optionally substituted, a C1-C3 heteroalkyl group which is optionally substituted, a C3-C9 cycloalkyl group which is optionally substituted, and optionally Substituted C6-C12 extended aryl, optionally substituted C2-C6 extended heterocyclic group, O, S and NR ¹⁷ ; R ^{17 are} each independently hydrogen, optionally substituted C1-C4 alkyl, selected Substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C6 heterocyclyl, optionally substituted C6-C12 aryl or alternatively substituted C1 -C7 heteroalkyl. A compound or a pharmaceutically acceptable salt according to claim 37, wherein Z ¹ and Z ^{4 are} each independently a carbonyl group or NH. A compound or a pharmaceutically acceptable salt of claim 37, wherein the linker is Wherein m is 0, and wherein Z ¹ and Z ^{4 are} each independently NH. The compound or pharmaceutically acceptable salt of any one of claims 1 to 34, wherein the linker is selected from the group consisting of: Wherein n ¹ , o and p ¹ are 1 to 4; and R ¹⁸ and R ^{19 are} independently hydrogen, amine, fluorine, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 a heteroalkyl group, a selectively substituted C2-C6 alkenyl group, a selectively substituted C2-C6 heteroalkenyl group, a selectively substituted C2-C6 alkynyl group, a selectively substituted C2-C6 heteroalkynyl group, Optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 cycloalkynyl, optionally substituted C6-C12 aryl, optionally substituted Substituted C2-C6 heterocyclyl, optionally substituted C3-C10 cycloalkoxy, optionally substituted C4-C10 cycloalkenyloxy, optionally substituted C4-C10 cycloalkynyloxy, optionally a substituted C6-C12 aryloxy group or a selectively substituted C2-C6 heterocyclic oxy group or a combination of R ¹⁸ and R ¹⁹ with a carbon atom to which they are bonded form a C1-C10 cycloalkyl group which is optionally substituted, Optionally substituted C4-C10 cycloalkenyl, optionally substituted C4-C10 cycloalkynyl, optionally substituted C6-C12 aryl or alternatively substituted C2-C6 heterocyclyl. The compound or pharmaceutically acceptable salt of any one of claims 1 to 34, wherein the linker is: Wherein x is an integer between 0 and 12; wherein Z ¹ is a C1-C2 alkylene group which is optionally substituted, a C1-C3 heteroalkyl group which is optionally substituted, and a C3-C9 ring extension which is optionally substituted An alkyl group, a selectively substituted C6-C12 extended aryl group, a selectively substituted C2-C6 stretched heterocyclic group, O, S or NR ¹⁷ ; and each R ^{17 is} independently hydrogen, optionally substituted C1 a C4 alkyl group, a selectively substituted C2-C4 alkenyl group, a selectively substituted C2-C4 alkynyl group, a selectively substituted C2-C6 heterocyclic group, a selectively substituted C6-C12 aryl group or A substituted C1-C7 heteroalkyl group is optionally selected. A compound or a pharmaceutically acceptable salt according to claim 41, wherein Z1 is NH, and wherein x is 0. a compound selected from the group consisting of: Or a pharmaceutically acceptable salt thereof. A compound or pharmaceutically acceptable salt according to any of the preceding claims, having the following structure: Wherein each of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 is} independently hydrogen, hydroxy, -SH, amine, nitro, cyano, halo, optionally substituted C1 a C6 alkyl group, a selectively substituted C6-C10 aryl C1-C6 alkyl group, a selectively substituted C1-C6 alkoxy group, a selectively substituted C1-C6 alkyl fluorenyl group, a decylamine group, a carboxyl group, The ester or comprises -LE; wherein at least one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ comprises -LE; R ⁸ is hydrogen or optionally substituted C 2 -C 6 a ring group; m is an integer between 5 and 13; n is an integer between 3 and 8; p is 0, 1 or 2; A' is or Each of B' and C' is independently hydrogen, hydroxy, C1-C6 alkyl, pendant oxy or B' and C' combine to form -O-; wherein the dashed bond is a single bond or a double bond, if When the compound of formula I comprises at least 2 double bonds; or a pharmaceutically acceptable salt thereof. A compound or a pharmaceutically acceptable salt of claim 44, wherein R ⁷ comprises -LE. A compound or pharmaceutically acceptable salt according to any of the preceding claims, having the following structure: Wherein each of R ¹ , R ² , R ³ , R ⁵ and R ^{6 is} independently hydrogen, hydroxy, -SH, amine, nitro, cyano, halo, optionally substituted C1-C6 alkyl, selected a substituted C6-C10 aryl C1-C6 alkyl group, a selectively substituted C1-C6 alkoxy group, a optionally substituted C1-C6 alkyl fluorenyl group, a decylamine, a carboxyl group or an ester; R ⁴ is hydrogen , hydroxy, -SH, amine, nitro, cyano, halo, optionally substituted C1-C6 alkyl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted a C1-C6 alkoxy group, a selectively substituted C1-C6 alkyl fluorenyl group, a decylamine, a carboxy group or an ester or two adjacent R ⁴ groups together form -O-; wherein R ⁷ comprises -LE; R ⁸ is hydrogen Or optionally substituted C2-C6 heterocyclic group; m is an integer between 5 and 13; n is an integer between 3 and 8; p is 0, 1 or 2; A' is or Each of B' and C' is independently hydrogen, hydroxy, C1-C6 alkyl, pendant oxy or B' and C' combine to form -O-; wherein the dash bond is a single bond or a double bond, if The compound includes at least 2 double bonds; or a pharmaceutically acceptable salt thereof. A compound or pharmaceutically acceptable salt according to any of the preceding claims, having the following structure: Wherein each R ¹ , R ² and R ^{3 are} independently hydrogen, hydroxy, optionally substituted C1-C6 alkyl or alternatively substituted C6-C10 aryl C1-C6 alkyl; each R ^{4 is} independently Hydrogen, hydroxy, optionally substituted C1-C6 alkyl or pendant oxy; each R ⁵ and R ^{6 are} independently hydrogen, hydroxy or C1-C6 alkoxy; R ⁹ is -LE; R ¹⁰ is hydrogen or a hydroxyl group; R ¹¹ is a hydroxyl group or an amine; R ¹² is hydrogen or m is an integer between 5 and 13; n is an integer between 3 and 8; p is 0, 1 or 2; q is 1, 2 or 3; A' is or Each of B' and C' is independently hydrogen, hydroxy, C1-C6 alkyl, pendant oxy or B' and C' combine to form -O-; and wherein the dash bond is a single bond or a double bond, if The compound includes at least 2 double bonds. A compound or a pharmaceutically acceptable salt according to claim 47, wherein R ⁹ is -NR ¹³ (CH ₂ ) _a NR ¹³ E or -NR ¹³ (CH ₂ ) _a O(CH ₂ ) _a NR ¹³ E Each R ^{13 is} independently hydrogen or a C1-C3 alkyl group; and each a is independently 2, 3 or 4. A compound or pharmaceutically acceptable salt according to any of the preceding claims, having the following structure: , where R is -LE. A compound or a pharmaceutically acceptable salt according to claim 49, wherein R is -NR'(CH ₂ ) _a NR'E or -NR'(CH ₂ ) _a O(CH ₂ ) _a NR'E; Each R' is independently hydrogen or a C1-C3 alkyl group; and each a is independently 2, 3 or 4. A compound or pharmaceutically acceptable salt according to any of the preceding claims, having the following structure: , where R" is -LE. A compound or a pharmaceutically acceptable salt according to claim 51, wherein R" is -NHCH ₂ CH ₂ NHE or -NHCH ₂ CH ₂ OCH ₂ CH ₂ NHE. A compound or pharmaceutically acceptable salt according to any of the preceding claims, having the following structure: , where R is -LE. A compound or a pharmaceutically acceptable salt according to claim 53 wherein R is -NR'(CH ₂ ) _a NR'E or -NR'(CH ₂ ) _a O(CH ₂ ) _a NR'E; Each R' is independently hydrogen or a C1-C3 alkyl group; and each a is independently 2, 3 or 4. A compound or pharmaceutically acceptable salt according to any of the preceding claims, having the following structure: , where R" is -LE. A compound or a pharmaceutically acceptable salt according to claim 55, wherein R" is -NHCH ₂ CH ₂ NHE or -NHCH ₂ CH ₂ OCH ₂ CH ₂ NHE. A compound or pharmaceutically acceptable salt according to any of the preceding claims, having the following structure: , where R is -LE. A compound or a pharmaceutically acceptable salt according to claim 57, wherein R is -NR'(CH ₂ ) _a NR'E or -NR'(CH ₂ ) _a O(CH ₂ ) _a NR'E; Each R' is independently hydrogen or a C1-C3 alkyl group; and each a is independently 2, 3 or 4. A compound or pharmaceutically acceptable salt according to any of the preceding claims, having the following structure: , where R" is -LE. A compound or a pharmaceutically acceptable salt according to claim 59, wherein R" is -NHCH ₂ CH ₂ NHE or -NHCH ₂ CH ₂ OCH ₂ CH ₂ NHE. A compound or a pharmaceutically acceptable salt as claimed in claim 1 has the following structure: , where L is a linker. A compound or a pharmaceutically acceptable salt according to claim 61, wherein L is a linkage covalently linking the polyene antifungal structure to the chemotactic acceptor ligand structure E. A compound or pharmaceutically acceptable salt according to any of the preceding claims, having the following structure: Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 are} each independently hydrogen, hydroxy, -SH, amine, nitro, cyano, halo, optionally substituted C1 a C6 alkyl group, a selectively substituted C6-C10 aryl C1-C6 alkyl group, a selectively substituted C1-C6 alkoxy group, a selectively substituted C1-C6 alkyl fluorenyl group, a decylamine group, a carboxyl group, Ester or -LE; R ⁹ and R ^{10 are} each independently hydrogen, hydroxy, -SH, amine, nitro, cyano, halo, optionally substituted C1-C6 alkyl, optionally substituted C6 -C10 aryl-C1-C6 alkyl, optionally substituted alkoxy of C1-C6, optionally substituted alkyl of C1-C6 acyl, acyl amine, carboxyl, ester, -LE, R ⁹ and R ^10, or Forming -O- together; wherein at least one of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁹ and R ¹⁰ is -LE; R ⁸ is hydrogen or is optionally substituted a C2-C6 heterocyclic group; m is an integer between 3 and 13; n is an integer between 3 and 8; p is 0, 1 or 2; A' is or And B' and C' are each independently hydrogen, hydroxy, C1-C6 alkyl, pendant oxy or B' combined with C' to form -O-; or a pharmaceutically acceptable salt thereof. A compound or a pharmaceutically acceptable salt according to claim 63, wherein R ⁷ comprises -LE. A compound or pharmaceutically acceptable salt according to any of the preceding claims, having the following structure: Wherein R ¹ , R ² and R ^{3 are} each independently hydrogen, hydroxy, optionally substituted C1-C6 alkyl, or alternatively substituted C9-C10 aryl C1-C6 alkyl; R ⁴ independently Is hydrogen, hydroxy, optionally substituted C1-C6 alkyl or pendant oxy; R ⁵ and R ^{6 are} each independently hydrogen, hydroxy or C1-C6 alkoxy; R ⁹ and R ^{10 are} each independently hydrogen a hydroxyl group, a optionally substituted C1-C6 alkyl group, a pendant oxy group or a combination of R ⁹ and R ¹⁰ to form -O-; R ¹¹ is -LE; R ¹² is hydrogen or a hydroxyl group; R ¹³ is a hydroxyl group or an amine; ¹⁴ is hydrogen or m is an integer between 3 and 13; n is an integer between 3 and 8; p is 0, 1 or 2; A' is or And B' and C' are each independently hydrogen, hydroxy, C1-C6 alkyl, pendant oxy or B' combined with C' to form -O-. A compound or a pharmaceutically acceptable salt according to claim 65, wherein R ¹¹ is -NR ¹⁵ (CH ₂ ) _a NR ¹⁵ E or -NR ¹⁵ (CH ₂ ) _a O(CH ₂ ) _a NR ¹⁵ E R ^{15 is} each independently hydrogen or C1-C3 alkyl; and each a is independently an integer between 2 and 4. A compound or pharmaceutically acceptable salt according to any of the preceding claims, having the following structure: , where R is -LE. A compound or a pharmaceutically acceptable salt according to claim 67, wherein R is -NR'(CH ₂ ) _a NR'E or -NR'(CH ₂ ) _a O(CH ₂ ) _a NR'E; Each R' is independently hydrogen or a C1-C3 alkyl group; and each a is independently an integer between 2 and 4. A compound or pharmaceutically acceptable salt according to any of the preceding claims, having the following structure: , where R" is -LE. A compound or a pharmaceutically acceptable salt according to claim 69, wherein R" is -NHCH ₂ CH ₂ NHE or -NHCH ₂ CH ₂ OCH ₂ CH ₂ NHE. A compound or pharmaceutically acceptable salt according to any of the preceding claims, having the following structure , where L is a linker. A compound or a pharmaceutically acceptable salt according to claim 71, wherein L is covalently linked to the polyene antifungal structure to the chemotactic receptor ligand The bond of structure E. The compound or pharmaceutically acceptable salt of any one of claims 1 to 72, wherein the concentration of the compound or pharmaceutically acceptable salt that induces the greatest neutrophil shift is less than or equal to 10,000 nM. A compound or a pharmaceutically acceptable salt of claim 73, wherein the concentration of the compound or pharmaceutically acceptable salt that induces maximum neutrophil shift is less than or equal to 1,000 nM. A compound or a pharmaceutically acceptable salt of claim 74, wherein the concentration of the compound or pharmaceutically acceptable salt that induces maximum neutrophil shift is less than or equal to 100 nM. A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 75, wherein the compound or a pharmaceutically acceptable salt inhibits fungal growth. The compound or pharmaceutically acceptable salt of any one of claims 1 to 76, wherein the compound or pharmaceutically acceptable salt has an IC _{50 of} less than or equal to 1,000 nM. A compound or a pharmaceutically acceptable salt according to claim 77, wherein the compound or pharmaceutically acceptable salt has an IC _{50 of} less than or equal to 100 nM. A compound or a pharmaceutically acceptable salt according to claim 78, wherein the compound or pharmaceutically acceptable salt has an IC _{50 of} less than or equal to 10 nM. A pharmaceutical composition comprising a compound according to any one of claims 1 to 79, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. A method of treating an individual who has been or is presumed to have a fungal infection, the method comprising administering to the individual an effective amount of a compound or composition according to any one of claims 1 to 80. A method for the prophylactic treatment of a fungal infection in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound or composition according to any one of claims 1 to 80. The method of application of the first 81 or 82 patentable scope, wherein the fungal infections are a genus aspergillus (Aspergillus) or a fungus Candida genus (Candida) caused. The method of claim 81 or 82, wherein the fungal infection is a mildew disease. The method of claim 84, wherein the mold is an invasive mold. The method of claim 84, wherein the fungus disease is pulmonary mite. The method of claim 81, wherein the fungal infection is caused by Aspergillus fumigatus . The method of claim 81, wherein the fungal infection is candidiasis. The method of claim 88, wherein the candidiasis is intra-abdominal abscess, peritonitis, pleural infection, esophagitis, candidemia or invasive candidiasis. The method of claim 81, wherein the fungal infection is caused by Candida albicans . The method of claim 81, wherein the individual has low immunity. The method of claim 81, wherein the individual is diagnosed as a humoral immunodeficiency, a T cell deficiency, a neutropenia, a spleenless, or a complement deficiency. The method of claim 81, wherein the individual has been or will be treated with an immunosuppressive drug. The method of claim 81, wherein the individual has been diagnosed as having a disease that causes immunosuppression. The method of claim 94, wherein the disease is cancer or acquired immunodeficiency syndrome. The method of claim 95, wherein the cancer is leukemia, lymphoma or multiple myeloma. The method of claim 81, wherein the individual has experienced or will undergo a hematopoietic stem cell transplant. The method of claim 81, wherein the individual has experienced or will undergo an organ transplant. The method of claim 81 or 82, wherein the administration comprises intramuscular, intravenous, intradermal, intraarterial, intraperitoneal, intralesional, intracranial, intraarticular, intraprostatic, intrathoracic, intratracheal, Intranasal, vitreous, intravaginal, intrarectal, topical, intratumoral, peritoneal, subcutaneous, subconjunctival, vesicle, mucosa, pericardium, umbilical, intraocular, oral, topical, by inhalation, injection Or infusion.