Combinations of neoenactins with Anti-fungal agents with enhanced Anti-fungal activity

Abstract

The present disclosure relates to a compound of Formula (I): (I), or a pharmaceutically acceptable salt or solvate thereof, where A, A1, A2, R, R1, R2, R3, R4, k, and m are as described above. The present disclosure also relates to a method of treating a fungal infection in a subject and a method of inhibiting the growth of yeast types of fungi or filamentous types of fungi using a compound of Formula (I) or a combination therapeutic comprising a compound of Formula (I) and an antifungal agent.

Description

COMBINATIONS OF NEOENACTINS WITH ANTI-FUNGAL AGENTS WITH ENHANCED ANTI-FUNGAL ACTIVITY

[0001] This application claims the priority benefit of U.S. Provisional Patent Application Serial No. 63 / 638,573, filed April 25, 2024, which is hereby incorporated by reference in its entirety.FIELD

[0002] The present application relates to synthetic neoenactins and analogs and their use as antifungal agents.BACKGROUND

[0003] Fungal infections, especially those that are resistant to the limited set of antifungal agents, are a significant and growing public health concern. Since treatment of systemic fungal infections is currently limited to only a few classes of drugs (azoles, echinocandins, pyrimidines, allylamines, and polyenes) resistance creates an especially dire situation. The resulting morbidity is astounding in that fungal infections kill more than 1.6 million people every year. The situation is exacerbated by significant antifungal drug side effects, adverse drug-drug interactions and the frequent need for long courses of therapy. Consequently, there is a dire need for the development of new antifungal drugs or combination therapies.

[0004] In response to the rising threat of fungal infections, combined with existing and emerging resistance and treatability issues, the World Health Organization (WHO) developed the first WHO Fungal Priority Pathogens List (“WHO Fungal Priority Pathogens List to Guide Research, Development and Public Health Action,” Geneva, World Health Organization (2022)). This list was developed using a multicriteria decision analysis (MCDA) approach. The prioritization process was focused on fungal pathogens that can cause invasive acute and subacute systemic fungal infections for which drug resistance or other treatment and management challenges exist. The pathogens were ranked and then categorized into three priority groups (critical, high, and medium). According to the WHO Fungal Priority Pathogens List, the critical group includes Cryptococcus neoformans. Candida auris. Aspergillus fumigalus. and Candida albicans. The high group includes Nakaseomyces glabrata (Candida glabrala). Histoplasma spp., eumycetoma causative agents, Mucorales. Fusarium spp., Candida tropicalis. and Candida parapsilosis. The medium group includes Scedosporium spp., Lomentospora prolificans, Coccidioides spp., Pichia kudriavzeveii (Candida krusei). Cryptococcus gallii.- 2 - Talaromyces marneffei, Pneumocystis jirovecii, and Paracoccidioides spp. This further illustrates the significant need for improved treatment of fungal infections.

[0005] The present application is directed to overcoming these and other deficiencies in the art. SUMMARY

[0006] One aspect of the present disclosure relates to a compound of Formula (I):a pharmaceutically acceptable salt or solvate thereof, whereA2is optional, and if present iR is OH, OBn, or NH2; R1is selected from the group consisting of OH, i-Pr, C1-C6alkyl substituted with OH, C1-C6 alkyl substituted with OP(O)(ORa)2, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; R2is selected from the group consisting of H, -C(O)O-t-Bu (Boc), optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R1and R2can combine with the atoms to which they are attached to form an optionally substituted heterocyclyl; R3is selected from the group consisting of H, -C(O)O-t-Bu (Boc), optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; or 310888514v1- 3 - R2and R3can combine with the nitrogen atom to which they are attached to formR4is selected from the group consisting of H, cycloalkyl, optionally substituted C1-C16 alkyl, optionally substituted C2-C16 alkenyl, optionally substituted C2-C16 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; W is C or S; W1is optional, and if present is O or NH; k is 0 or 1; n is 0, 1, or 2; m is 0 or 1; X is optional, and if present is selected from the group consisting of O, N(OR5), N(OCH2COZR6), N(NHR7), N(NHCOR8), N(NHSO2NHR9), and N(NHSO2R10); Y is optional, and if present is selected from the group consisting of O, N(OR5), N(OCH2COZR6), N(NHR7), N(NHCOR8), N(NHSO2NHR9), and N(NHSO2R10); R5is H or optionally substituted C1-C6 alkyl; R6is H; R7is H or optionally substituted C1-C6 alkyl; R8is H or optionally substituted C1-C6 alkyl; R9is H or optionally substituted C1-C6alkyl; R10is H or optionally substituted C1-C6alkyl;is aryl or heteroaryl, wherein aryl and heteroarylaryl can be optionally substituted from 1 to 5 times with a substituent selected independently from OH, C1-C6 alkyl, - OP(O)(ORa)2, and -C1-C6 alkylene-OP(O)(ORa)2; Rais independently selected from H, C1-C6alkyl, aryl, or arylalkyl; Z is O or NH; and is an optionally present double bond, 310888514v1- 4 - with the proviso that i) when k is 1, R1is CH2OH, A is, W1is absent, and R4is H, C1- C12alkyl, or C1-C12alkyl substituted with OH, then X is not O, N(OH), or N(OMe); ii) when k is 1, and m is 0, then R1is not OH; and iii) the compound is not.

[0007] Another aspect of the present disclosure relates to a compound of Formula (IA):a pharmaceutically acceptable salt or solvate thereof, whereA2is optional, and if presentR1is selected from the group consisting of OH, i-Pr, C1-C6alkyl substituted with OH, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, substituted aryl, and optionally substituted heteroaryl; R2is selected from the group consisting of H, -C(O)O-t-Bu (Boc), optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R1and R2can combine with the atoms to which they are attached to form an optionally substituted heterocyclyl; 310888514v1- 5 - R3is selected from the group consisting of H, -C(O)O-t-Bu (Boc), optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; R4is selected from the group consisting of H, cycloalkyl, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; W is C or S; W1is optional, and if present is O or NH; n is 0, 1, or 2; m is 0 or 1; X is optional, and if present is selected from the group consisting of O, N(OR5), N(OCH2COZR6), N(NHR7), N(NHCOR8), N(NHSO2NHR9), and N(NHSO2R10); Y is optional, and if present is selected from the group consisting of O, N(OR5), N(OCH2COZR6), N(NHR7), N(NHCOR8), N(NHSO2NHR9), and N(NHSO2R10); R5is H or optionally substituted C1-C6alkyl; R6is H; R7is H or optionally substituted C1-C6 alkyl; R8is H or optionally substituted C1-C6 alkyl; R9is H or optionally substituted C1-C6alkyl; R10is H or optionally substituted C1-C6 alkyl; Z is O or NH; and is an optionally present double bond, with the proviso that i) when R1is CH2OH, A is, W1is absent, and R4is H, C1-C12alkyl, or C1-C12alkyl substituted with OH, then X is not O, N(OH), or N(OMe); ii) when m is 0, then R1is not OH; and iii) the compound is not.

[0008] Yet another aspect of the present disclosure relates to a compound of Formula (IB): 310888514v1- 6 -A2is optional, and if present iR1is CH2OH or CH(CH3)OH; R2is H; or R1and R2can combine to formR3is H; R4is selected from the group consisting of H, cycloalkyl, and C1-C12alkyl; W is C; W1is optional, and if present is O or NH; n is 0, 1; X is optional, and if present is O, =N-OH, =N-NH2; and is an optionally present double bond, with the proviso that i) when R1is CH2OH, W1is absent, and R4is H or C1-C12 alkyl, then X is not O and ii) the compound is not.

[0009] Another aspect of the present disclosure relates to a compound of Formula (II): 310888514v1- 7 -a pharmaceutically acceptable salt or solvate thereof, wherein Z1is O, NH, or CH2; and R´is C1-C30alkyl.

[0010] Yet another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any aspect of the present disclosure and a pharmaceutically acceptable carrier.

[0011] A further aspect of the present disclosure relates to a method of treating a fungal infection in a subject. This method involves administering to the subject in need thereof a compound according to any aspect of the present disclosure.

[0012] Another aspect of the present disclosure relates to a method of treating a fungal infection in a subject. This method involves administering to the subject in need thereof a combination therapeutic comprising: (i) a compound according to any aspect of the present disclosure; and (ii) an antifungal agent.

[0013] Another aspect of the present disclosure relates to a method of inhibiting the growth of yeast types of fungi or filamentous types of fungi. This method involves contacting yeast types of fungi or filamentous types of fungi with a compound according to any aspect of the present disclosure under conditions effective to inhibit the growth of yeast types of fungi or filamentous types of fungi.

[0014] Yet another aspect of the present disclosure relates to a method of inhibiting the growth of yeast types of fungi or filamentous types of fungi. This method involves contacting yeast types of fungi or filamentous types of fungi with a combination therapeutic comprising: (i) a compound according to any aspect of the present disclosure; and (ii) an antifungal agent.

[0015] Another aspect of the present disclosure relates to a combination therapeutic comprising: (i) a compound according to any aspect of the present disclosure; and (ii) an antifungal agent.

[0016] The present disclosure describes an innovative class of antifungal agents (neoenactins and analogs) and demonstrates their anti-fungal activity. Additionally, combinations of the antifungal agents with known antifungal agents synergistically augment the antifungal activity to provide significant improvements in activity and efficacy. The resulting combinations allow for use of significant reduction in the dose of current antifungal agents needed and thus may minimize adverse effects. 310888514v1- 8 - BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 shows representative Enactins (ENs) and Neoenactins (NEs) L-serine hydroxamic acid-based antifungal compounds from Streptomyces roseoviridis and Streptoverticillium olivoreticuli.

[0018] Figure 2 shows the structures of known neoenactins and their analogs.

[0019] Figures 3A-3B shows structures of Neoenactin A and synthetic analogs. Figure 3A shows head group modifications and Figure 3B shows tail group modifications.

[0020] Figures 4A-4B show Minimum Inhibitory Concentration (“MIC”) values (µg / mL) of Neoenactin A and Synthetic Analogs Against Dermatophytes. DETAILED DESCRIPTION

[0021] Enactins (EN) and neoenactins (NE) are L-serine hydroxamic acid (N-hydroxy amide)-based antimycotic antibiotics produced by the bacteria Streptomyces roseoviridis and Streptoverticillium olivoreticuli. These compounds have been shown to be potent antifungal agents (Yamamoto et al., “A New Group of Antibiotics, Hydroxamic Acid Antimycotic Antibiotics. IV. Structures of Enactins Ia, Ib1, Ib2and Va,” Chem. Pharm. Bull.39(6):1436-1439 (1991); Okada et al., “A New Group of Antibiotics, Hydroxamic Acid Antimycotic Antibiotics. II. The Structure of Neoenactins NL1 and NL2 and Structure-Activity Relationship,” J. Antibiot. 42:276-282 (1989), which are hereby incorporated by reference in their entirety). Several congeners of NEs have been isolated (Figure 1) and all of them are comparably active against many strains of pathogenic fungi (Roy et al., “Isolation, Structural Elucidation and Biological Properties of Neoenactins B1, B2, M1 and M2, Neoenactin Congeners,” J. Antibiot.40:266-274 (1987), which is hereby incorporated by reference in its entirety).

[0022] The present disclosure describes the structure-activity-relationships (SAR) of synthetic neoenactin analogs and combinations of neoenactins with known anti-fungal compounds that produce synergistic anti-fungal activity. The resulting enhanced anti-fungal activity reduces the amounts of compounds needed to inhibit growth of pathogenic fungi. The SAR studies also provided new compounds with superior activity against dermatophytes.

[0023] One aspect of the present disclosure relates to a compound of Formula (I):310888514v1- 9 - a pharmaceutically acceptable salt or solvate thereof, whereA2is optional, and if present iR is OH, OBn, or NH2; R1is selected from the group consisting of OH, i-Pr, C1-C6 alkyl substituted with OH, C1-C6 alkyl substituted with OP(O)(ORa)2, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6alkynyl, substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; R2is selected from the group consisting of H, -C(O)O-t-Bu (Boc), optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R1and R2can combine with the atoms to which they are attached to form an optionally substituted heterocyclyl; R3is selected from the group consisting of H, -C(O)O-t-Bu (Boc), optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; or R2and R3can combine with the nitrogen atom to which they are attached to formR4is selected from the group consisting of H, cycloalkyl, optionally substituted C1-C16 alkyl, optionally substituted C2-C16 alkenyl, optionally substituted C2-C16 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; W is C or S; W1is optional, and if present is O or NH; k is 0 or 1; 310888514v1- 10 - n is 0, 1, or 2; m is 0 or 1; X is optional, and if present is selected from the group consisting of O, N(OR5), N(OCH2COZR6), N(NHR7), N(NHCOR8), N(NHSO2NHR9), and N(NHSO2R10); Y is optional, and if present is selected from the group consisting of O, N(OR5), N(OCH2COZR6), N(NHR7), N(NHCOR8), N(NHSO2NHR9), and N(NHSO2R10); R5is H or optionally substituted C1-C6 alkyl; R6is H; R7is H or optionally substituted C1-C6 alkyl; R8is H or optionally substituted C1-C6 alkyl; R9is H or optionally substituted C1-C6alkyl; R10is H or optionally substituted C1-C6alkyl; A is aryl or heteroaryl, wherein aryl and heteroarylaryl can be optionally substituted from 1 to 5 times with a substituent selected independently from OH, C1-C6 alkyl, - OP(O)(ORa)2, and -C1-C6 alkylene-OP(O)(ORa)2; Rais independently selected from H, C1-C6alkyl, aryl, or arylalkyl; Z is O or NH; and is an optionally present double bond, with the proviso that i) when k is 1, R1is CH2OH, A is, W1is absent, and R4is H, C1- C12alkyl, or C1-C12alkyl substituted with OH, then X is not O, N(OH), or N(OMe); ii) when k is 1, and m is 0, then R1is not OH; and iii) the compound is not.

[0024] As used above, and throughout the description herein, the following terms, unless otherwise indicated, shall be understood to have the following meanings. If not defined otherwise herein, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this technology belongs. In the 310888514v1- 11 - event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0025] As used herein, the term “alkane” refers to aliphatic hydrocarbons of formula CnH2n+2, which may be straight or branched having about 1 to about 40 (e.g., 1–2, 1–3, 1–4, 1–5, 1–6, 1–7, 1–8) carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkyl chain. Exemplary alkanes include methane, ethane, n-propane, i-propane, n-butane, t-butane, n-pentane, and 3-pentane. The term “alkylene” refers to a divalent group formed from an alkane by removal of two hydrogen atoms. Exemplary alkylene groups include, but are not limited to, divalent groups derived from the alkanes described above.

[0026] The term “alkyl” means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 30 carbon atoms in the chain, or any number of carbons between 1 and 30, or however many carbons are indicated. For example, a straight or branched carbon alkyl chain could have 1 to 16 carbon atoms, in which case the alkyl is described as a C1- C16alkyl, meaning the alkyl possesses any number of carbons between 1 and 16. In another example, a straight or branched carbon alkyl chain could have 1 to 6 carbon atoms, in which case the alkyl is described as a C1-C6 alkyl, meaning the alkyl possesses any number of carbons between 1 and 6. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n- propyl, i-propyl, n-butyl, t-butyl, n-pentyl, and 3-pentyl.

[0027] The term “alkylene” refers to a divalent group formed from an alkane by removal of two hydrogen atoms. Exemplary alkylene groups include, but are not limited to, methylene, ethylene, propylene, and other divalent groups derived from the alkanes described above.

[0028] The term “alkenyl” means an aliphatic hydrocarbon group containing a carbon— carbon double bond and which may be straight or branched having about 2 to about 24 carbon atoms in the chain, or any number of carbons between 2 and 24, or however many carbons are indicated. For example, a straight or branched carbon alkenyl group could have 2 to 16 carbon atoms, in which case the alkenyl group is described as a C2-C16alkenyl, meaning the alkenyl possesses any number of carbons between 2 and 16. In another example, a straight or branched carbon alkenyl group could have 2 to 6 carbon atoms, in which case the alkenyl is described as a C2-C6alkenyl, meaning the alkenyl possesses any number of carbons between 2 and 6. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkenyl chain. Exemplary alkenyl groups include ethenyl, propenyl, n- 310888514v1- 12 - butenyl, and i-butenyl. The term “alkenyl” means the hydrocarbon chain contains at least one carbon-carbon double bond.

[0029] The term “alkynyl” means an aliphatic hydrocarbon group containing a carbon- carbon triple bond and which may be straight or branched having about 2 to about 24 carbon atoms in the chain, or any number of carbons between 2 and 24, or however many carbons are indicated. For example, a straight or branched carbon alkynyl group could have 2 to 16 carbon atoms, in which case the alkynyl is described as a C2-C16 alkynyl, meaning the alkynyl possess any number of carbons between 2 and 16. In another example, a straight or branched carbon alkynyl group could have 2 to 6 carbon atoms, in which case the alkynyl is described as a C2-C6 alkynyl, meaning the alkynyl possesses any number of carbons between 2 and 6. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkynyl chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl. The term “alkynyl” means the hydrocarbon chain contains at least one carbon-carbon triple bond.

[0030] The term “cycloalkyl” means a non-aromatic mono- or multicyclic ring system of about 3 to about 12 carbon atoms, or of any number of carbon atoms between about 3 to about 12. Exemplary and non-limiting monocyclic cycloalkyls include cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.1]pentyl, adamantly, and the like.

[0031] The term “aryl” means an aromatic monocyclic or multi-cyclic ring system of 6 to about 14 carbon atoms, or of any number of carbon atoms between 6 and about 14. Representative and non-limiting aryl groups include phenyl and naphthyl.

[0032] The term “arylalkyl” or “alkylaryl” means an alkyl substituted with one or more aryl groups, wherein the alkyl and aryl groups are as herein described. One particular example is an arylmethyl or arylethyl group, in which a single or a double carbon spacer unit is attached to an aryl group, where the carbon spacer and the aryl group can be optionally substituted as described herein. Representative arylalkyl groups include.

[0033] The term “benzyl” or “Bn” means a benzyl group as shown below 310888514v1- 13 -.

[0034] The term “heteroaryl” means an aromatic monocyclic or multi-cyclic ring system of about 5 to about 14 ring atoms, in which one or more of the atoms in the ring system is / are element(s) other than carbon, for example, nitrogen, oxygen, or sulfur. In the case of multi- cyclic ring system, only one of the rings needs to be aromatic for the ring system to be defined as “heteroaryl”. In some embodiments, a “heteroaryl” contains about 5 to 6 ring atoms. The prefix aza, oxa, thia, or thio before heteroaryl means that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. A nitrogen atom of a heteroaryl is optionally oxidized to the corresponding N-oxide. Representative, non-limiting heteroaryls include pyridyl, 2-oxo- pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, 2-oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro- benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 6,7-dihydro-4H- pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 3-oxo-[1,2,4]triazolo[4,3- a]pyridin-2(3H)-yl, and the like.

[0035] The term “heteroarylalkyl” or “alkylheteroaryl” means an alkyl substituted with one or more heteroaryl groups, wherein the alkyl and heteroaryl groups are as herein described. One particular example is an heteroarylmethyl or heteroarylethyl group, in which a single or a double carbon spacer unit is attached to a heteroaryl group, where the carbon spacer and the 310888514v1- 14 - heteroaryl group can be optionally substituted as described herein. Representative heteroarylalkyl groups include

[0036] As used herein, “heterocyclyl” or “heterocycle” refers to a stable 3- to 18- membered ring (radical) which includes carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. For purposes of this disclosure, the heterocycle may be a monocyclic or a polycyclic ring system, which may include fused, bridged, or spiro ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycle may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the ring may be partially or fully saturated. Non-limiting examples of heterocycles include, without limitation, oxiranyl, azepinyl, azocanyl, pyranyl dioxanyl, dithianyl, 1,3-dioxolanyl, tetrahydrofuryl, dihydropyrrolidinyl, decahydroisoquinolyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, 2-oxoazepinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone.

[0037] Further heterocycles and heteroaryls are described in Katritzky et al., eds., Comprehensive Heterocyclic Chemistry: The Structure, Reactions, Synthesis and Use of Heterocyclic Compounds, Vol.1-8, Pergamon Press, N.Y. (1984), which is hereby incorporated by reference in its entirety.

[0038] The term “monocyclic” used herein indicates a molecular structure having one ring.

[0039] The term “polycyclic” or “multi-cyclic” used herein indicates a molecular structure having two or more rings, including, but not limited to, fused, bridged, or spiro rings.

[0040] The term “halogen” means fluoro, chloro, bromo, or iodo.

[0041] The term “alkoxy” means groups of from 1 to 8 carbon atoms of a straight, branched, or cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. Lower-alkoxy refers to groups containing one to four carbons. For purposes of the present disclosure, alkoxy also includes methylenedioxy and ethylenedioxy in which each oxygen atom is bonded to the atom, chain, or ring from which the methylenedioxy or 310888514v1- 15 - ethylenedioxy group is pendant so as to form a ring. Thus, for example, phenyl substituted by alkoxy may be, for example,.

[0042] The term “substituted” or “substitution” of an atom means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom’s normal valency is not exceeded.

[0043] The term “optionally substituted” is used to indicate that a group may have a substituent at each substitutable atom of the group (including more than one substituent on a single atom), provided that the designated atom’s normal valency is not exceeded, and the identity of each substituent is independent of the others. Up to three hydrogen (H) atoms in each residue are replaced with alkyl, halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.

[0044] “Unsubstituted” atoms bear all of the hydrogen atoms dictated by their valency.

[0045] When a substituent is keto (i.e., =O), then two hydrogens on the atom are replaced. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. The terms “stable compound” or “stable structure” mean a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.

[0046] As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds where the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral (i.e., HCl or other halogen or non-halogen acids including sulfates, hemisulfates, and the like) or organic acid salts of basic residues such as, but not limited to, amines; alkali or organic salts of acidic residues such as, but not limited to, carboxylic acids; and the like. The pharmaceutically acceptable salts include, but are not limited to, the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts can be synthesized from the parent compound, which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a 310888514v1- 16 - mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile may be preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418 and Journal of Pharmaceutical Science, 66:2 (1977), each of which is incorporated herein by reference in its entirety.

[0047] The phrase “pharmaceutically acceptable” means those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0048] A “solvate” refers to a physical association of a compound provided herein with one or more solvent molecules. A suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions.

[0049] The term “compounds of the disclosure”, and equivalent expressions, are meant to embrace compounds of general Formula (I), Formula (I´), Formula (I´´), Formula (IA), Formula (IB), or Formula (II) as described herein, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g., hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. For the sake of clarity, particular instances when the context so permits are sometimes indicated in the text, but these instances are purely illustrative and it is not intended to exclude other instances when the context so permits.

[0050] Compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The compounds described herein are meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the 310888514v1- 17 - compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0051] In some embodiments, the compound of Formula (I) has a Formula (IA):a pharmaceutically acceptable salt or solvate thereof, whereA2is optional, and if presentR1is selected from the group consisting of OH, i-Pr, C1-C6 alkyl substituted with OH, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, substituted aryl, and optionally substituted heteroaryl; R2is selected from the group consisting of H, -C(O)O-t-Bu (Boc), optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R1and R2can combine with the atoms to which they are attached to form an optionally substituted heterocyclyl; R3is selected from the group consisting of H, -C(O)O-t-Bu (Boc), optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; R4is selected from the group consisting of H, cycloalkyl, optionally substituted C1-C12alkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; W is C or S; W1is optional, and if present is O or NH; n is 0, 1, or 2; m is 0 or 1; 310888514v1- 18 - X is optional, and if present is selected from the group consisting of O, N(OR5), N(OCH2COZR6), N(NHR7), N(NHCOR8), N(NHSO2NHR9), and N(NHSO2R10); Y is optional, and if present is selected from the group consisting of O, N(OR5), N(OCH2COZR6), N(NHR7), N(NHCOR8), N(NHSO2NHR9), and N(NHSO2R10); R5is H or optionally substituted C1-C6alkyl; R6is H; R7is H or optionally substituted C1-C6 alkyl; R8is H or optionally substituted C1-C6alkyl; R9is H or optionally substituted C1-C6 alkyl; R10is H or optionally substituted C1-C6 alkyl; Z is O or NH; and is an optionally present double bond, with the proviso that i) when R1is CH2OH, A is, W1is absent, and R4is H, C1-C12alkyl, or C1-C12 alkyl substituted with OH, then X is not O, N(OH), or N(OMe); ii) when m is 0, then R1is not OH; and iii) the compound is not.

[0052] In some embodiments, the compound of Formula (I) has a Formula (IB):310888514v1- 19 - R1is CH2OH or CH(CH3)OH; R2is H; or R1and R2can combine to form ; R3is H; R4is selected from the group consisting of H, cycloalkyl, and C1-C12 alkyl; W is C; W1is optional, and if present is O or NH; n is 0, 1; X is optional, and if present is O, =N-OH, =N-NH2; and is an optionally present double bond, with the proviso that i) when R1is CH2OH, W1is absent, and R4is H or C1-C12 alkyl, then X is not O and ii) the compound is not.

[0053] In some embodiments, the compound of Formula (IB) is selected from the group consisting of: ,, , 310888514v1- 20 -.

[0054] In some embodiments, k is 0 and the compound of Formula (I) has a Formula (I´):

[0055] In some embodiments, k is 1 and the compound of Formula (I) has a Formula (I´´):

[0056] In some embodiments, the compound of Formula (I) has a Formula (I´):a pharmaceutically acceptable salt or solvate thereof, whereA2is optional, and if present i310888514v1- 21 - R is OH, OBn, or NH2; R1is optionally substituted heteroaryl or and optionally substituted heterocyclyl; R4is selected from the group consisting of H, cycloalkyl, optionally substituted C1-C16 alkyl, optionally substituted C2-C16 alkenyl, optionally substituted C2-C16 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; W is C or S; W1is optional, and if present is O or NH; n is 0, 1, or 2; X is optional, and if present is selected from the group consisting of O, N(OR5), N(OCH2COZR6), N(NHR7), N(NHCOR8), N(NHSO2NHR9), and N(NHSO2R10); Y is optional, and if present is selected from the group consisting of O, N(OR5), N(OCH2COZR6), N(NHR7), N(NHCOR8), N(NHSO2NHR9), and N(NHSO2R10); R5is H or optionally substituted C1-C6 alkyl; R6is H; R7is H or optionally substituted C1-C6alkyl; R8is H or optionally substituted C1-C6 alkyl; R9is H or optionally substituted C1-C6 alkyl; R10is H or optionally substituted C1-C6alkyl;is aryl or heteroaryl, wherein aryl and heteroarylaryl can be optionally substituted from 1 to 5 times with a substituent selected independently from OH, C1-C6alkyl, - OP(O)(ORa)2, and -C1-C6 alkylene-OP(O)(ORa)2; Rais independently selected from H, C1-C6 alkyl, aryl, or arylalkyl; Z is O or NH; and is an optionally present double bond.

[0057] In some embodiments, the compound of Formula (I) has a Formula (I´´):a pharmaceutically acceptable salt or solvate thereof, where 310888514v1- 22 -A2is optional, and if present iR is OH, OBn, or NH2; R1is selected from the group consisting of OH, i-Pr, C1-C6alkyl substituted with OH, C1-C6 alkyl substituted with OP(O)(ORa)2, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, and substituted aryl; R2is selected from the group consisting of H, -C(O)O-t-Bu (Boc), optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R1and R2can combine with the atoms to which they are attached to form an optionally substituted heterocyclyl; R3is selected from the group consisting of H, -C(O)O-t-Bu (Boc), optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; or R2and R3can combine with the nitrogen atom to which they are attached to formR4is selected from the group consisting of H, cycloalkyl, optionally substituted C1-C16 alkyl, optionally substituted C2-C16 alkenyl, optionally substituted C2-C16 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; W is C or S; W1is optional, and if present is O or NH; k is 0 or 1; n is 0, 1, or 2; m is 0 or 1; 310888514v1- 23 - X is optional, and if present is selected from the group consisting of O, N(OR5), N(OCH2COZR6), N(NHR7), N(NHCOR8), N(NHSO2NHR9), and N(NHSO2R10); Y is optional, and if present is selected from the group consisting of O, N(OR5), N(OCH2COZR6), N(NHR7), N(NHCOR8), N(NHSO2NHR9), and N(NHSO2R10); R5is H or optionally substituted C1-C6alkyl; R6is H; R7is H or optionally substituted C1-C6 alkyl; R8is H or optionally substituted C1-C6alkyl; R9is H or optionally substituted C1-C6 alkyl; R10is H or optionally substituted C1-C6 alkyl; A is aryl or heteroaryl, wherein aryl and heteroarylaryl can be optionally substituted from 1 to 5 times with a substituent selected independently from OH, C1-C6 alkyl, - OP(O)(ORa)2, and -C1-C6alkylene-OP(O)(ORa)2; Rais independently selected from H, C1-C6 alkyl, aryl, or arylalkyl; Z is O or NH; and is an optionally present double bond, with the proviso that i) whenalkyl, or C1-C12alkyl substituted with OH, then X is not O, N(OH), or N(OMe); ii) when m is 0, then R1is not OH; and iii) the compound is not.

[0058] The following embodiments apply to any of the above aspects of the present disclosure.

[0059] In some embodiments, R is OH.

[0060] In some embodiments, R is OBn.

[0061] In some embodiments, R is NH2. 310888514v1- 24 -

[0062] In some embodiments, R1is selected from the group consisting of OH; i-Pr; C1-C6alkyl substituted with OH; C1-C6alkyl substituted with OP(O)(ORa)2; C2-C6alkenyl; C2-C6alkynyl; aryl; heteroaryl; and heterocyclyl, wherein C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, and heterocyclyl can be optionally substituted 1, 2, 3, or 4 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, haloalkyl, OH, alkoxy, cyano, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, acylamino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, and heteroaryloxy.

[0063] In some embodiments, R1is selected from the group consisting of OH; i-Pr; C1-C6alkyl substituted with OH; C2-C6 alkenyl; C2-C6 alkynyl; aryl; and heteroaryl, wherein C2-C6 alkenyl, C2-C6 alkynyl, aryl, and heteroaryl can be optionally substituted 1, 2, 3, or 4 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, haloalkyl, OH, alkoxy, cyano, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, acylamino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, and heteroaryloxy.

[0064] In some embodiments, R1is selected from the group consisting of OH; i-Pr; C1-C6alkyl substituted with OH; C1-C6alkyl substituted with OP(O)(ORa)2; C2-C6alkenyl; C2-C6alkynyl; aryl; heteroaryl; and heterocyclyl, wherein C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, and heterocyclyl can be optionally substituted 1, 2, 3, or 4 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, OH, NH2, and alkoxy.

[0065] In some embodiments, R1is selected from the group consisting of OH; i-Pr; C1-C6 alkyl substituted with OH; C2-C6alkenyl; C2-C6alkynyl; aryl; and heteroaryl, wherein C2-C6alkenyl, C2-C6alkynyl, aryl, and heteroaryl can be optionally substituted 1, 2, 3, or 4 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, OH, and alkoxy.

[0066] In some embodiments, R1is selected from the group consisting of OH,

[0067] In some embodiments, R1is selected from the group consisting of OH,, CH2OH, and CH(CH3)OH. 310888514v1- 25 -

[0068] In some embodiments, R1is CH2OH or CH(CH3)OH.

[0069] In some embodiments,.

[0070] In some embodiments, R2is H.

[0071] In some embodiments, R1and R2combine to form an optionally substituted heterocyclyl, such as morpholinyl, piperidinyl, or piperazinyl. In some embodiments, R1and R2some embodiments, R1and R2combine to formoptionally substituted with -C(O)OC1-C6alkyl. In some embodiments, R1

[0072] In some embodiments, R3is H.

[0073] In some embodiments, R3is heteroarylalkyl optionally substituted from 1 to 3 times with a substituent selected independently from OH, C1-C6 alkyl, -OP(O)(ORa)2, and -C1-C6 alkylene-OP(O)(ORa)2.

[0074] In some embodiments, R3is -CH2-pyridinyl optionally substituted from 1 to 3 times with a substituent selected independently from OH, C1-C6 alkyl, -OP(O)(ORa)2, and -C1-C6 alkylene-OP(O)(ORa)2.

[0075] In some embodiments,. 310888514v1- 26 -

[0076] In some embodiments, R2and R3combine with the nitrogen atom to which they are attached to formpyridine optionally substituted from 1 to 3 times with a substituent selected independently from OH, C1-C6alkyl, and -CH2-OP(O)(ORa)2.

[0077] In some embodiments, R2and R3combine with the nitrogen atom to which they are attached to form.

[0078] In some embodiments, R4is selected from the group consisting of H, cycloalkyl, and C1-C16alkyl.

[0079] In some embodiments, R4is selected from the group consisting of H, cycloalkyl, and C1-C12 alkyl.

[0080] In some embodiments, R4is selected from the group consisting of H, C3-C12 cycloalkyl, and C1-C16alkyl.

[0081] In some embodiments, the compound of Formula (I) is selected from the group consisting of:310888514v1- 27 - ,310888514v1- 28 -

[0082] In some embodiments, the compound of Formula (I) is selected from the group consisting of: ,, 310888514v1- 29 -.

[0083] Compounds of Formula (I), Formula (I´), Formula (I´´), Formula (IA), Formula (IB), and Formula (II) may be defined and claimed herein by any combination of substituents disclosed herein. For example, compounds of Formula (I) include compounds with the generic structure of Formula (I) defined by various substituents (e.g., A, A1, A2,, R, R1-R10, Ra, W, W1, k, n, m, X, Y, and Z), each of which is defined as encompassing a listed group of molecular entities (e.g., OH, i-Pr, C1-C6 alkyl, C, S, or a many other molecular entities), and compounds of the present disclosure include compounds defined by the complete list of entities described above (the broadest defined scope of Formula (I), Formula (I´), Formula (I´´), Formula (IA), and Formula (IB)), or less than the complete list of entities, or any combination of complete 310888514v1- 30 - or less than complete list of molecular entities describing the particular substituent. Thus, for example, a compound of the present disclosure includes compounds that may include only one of the R1substituents defined herein and multiple of the R3substituents described herein, or any other combination of complete, partial, or singular substituent identified herein (i.e., compounds of a lesser scope than the broadest scope defined herein and a broader scope of individual compounds described herein).

[0084] Compounds of Formula (I), Formula (I´), Formula (I´´), Formula (IA), and Formula (IB) of the present disclosure can be prepared as shown in Schemes 1-9, as follows.

[0085] The syntheses and antifungal studies of neoenactin A (3, neoenactin A) and analogs (specifically its N-deshydroxy derivative (5), nor-neoenactin (4) and 13C- desketoneoenactin (6)) have been previously reported (Darwish et al., “Synthesis of the Antifungal Agent Norneoenactin A,” J. Org. Chem.58(22):6072-6075 (1993); Darwish et al., “Synthesis of the Antifungal Agent Neoenactin A and Its N-Deshydroxy Derivative,” J. Org. Chem.59:451-454 (1994); Bernier et al., “Desketoneoenactin-Siderophore Conjugates for Candida: Evidence of Iron Transport-Dependent Species Selectivity,” J. Antimicrobial Agents & Chemotherapy 49:241-248 (2005), which are hereby incorporated by reference in their entirety) (Scheme 1). Specific examples of compounds that were previously prepared and studied are shown in Figure 2. Antifungal assays indicated that some variation of the structure of the neoenactins still retains comparable anti-fungal activity. Specifically, some changes in the length of the hydrocarbon chain (nor-neoenactin, 4) and its degree of oxidation (desketoneoenactin, 6) do not negatively affect anti-fungal activity, but the hydroxamate moiety may be essential as the N-deshydroxy analog 5, is devoid of activity. Scheme 1310888514v1- 31 -

[0086] Neoenactin syntheses first requires preparation of appropriate alkylating agents (typically Michael acceptors, like 2a or 2b, for conjugate additions) that react with the protected amino acid derived hydroxamic acid “head” group (i.e., serine hydroxamate 1).

[0087] Scheme 2 illustrates the syntheses of six representative Michael acceptor precursors (10a-f) for new serine hydroxamate derived neoenactin analogs. These components are herein designated as the “tail” group. Scheme 2a. Oxalyl chloride, DMF, DCM. b. N,O-dimethyl hydroxylamine HCl, pyridine, DCM, 0˚C. c. Mg, vinyl bromide, I2, THF.

[0088] Michael acceptors with different tail groups can also be prepared as shown in Scheme 3 (R1 groups are the same as in Scheme 2 above). These compounds can be used to prepare new serine hydroxamate derived neoenactin analogs. The Boc protecting group on the amino acid head group (with serine as the preferred group) and a benzyl protecting group can be used for the hydroxamate. Other compatible protecting groups commonly used in peptide syntheses can also be utilized. Representative R1 groups are shown, but can also include additional linear, branched and cyclic alkyl groups, unsaturated alkyl groups, aryl, mixed alkyl aryl and heteroaryl groups. 310888514v1- 32 - Scheme 3a. HATU, DIPEA, DMF, 70˚C. b. KOtBu, a form of 10, dioxane, 100˚C. c. Pd / C, H2, EtOH. d. TFA.

[0089] Additional tail groups can also be derived from simple alkyl groups to provide the corresponding di-deoxy neoenactin analogs (Scheme 4). In this case the N-Boc, O-benzyl protected hydroxylamine (16) is first prepared and alkylated with commercially available alkyl iodides (1-iododecane, R2=CH3and 1-iodotetradecane, R2=C6H13as representative examples). Removal of the Boc protecting group is followed by coupling with the Boc protected amino acid (i.e., Boc-serine) and final deprotections to give analogs designated with structures shown as compound 20. 310888514v1- 33 - Scheme 4a. BOC anhydride, NMM, DCM, 0˚C. b. R2 = CH3; 1-Iododecane or R2 = C6H13; 1-iodotetradecane, KOtBu, dioxane, 100˚C. c. TFA, DCM. d. HATU, DIPEA, DMF, 70˚C. e. Pd / C, H2, EtOH. f. TFA.

[0090] Other electrophilic tail precursors including maleimides, sulfinyl ethenes, sulfonyl ethenes, acrylates, acrylamides and others can also be used (Schemes 5a-5b). Scheme 5a310888514v1- 34 - Scheme 5b

[0091] The natural neoenactins all contain an L-serine derived hydroxamic acid. The amino acid derived hydroxamic acid containing head group can be modified as shown in Scheme 6. This allows preparation of neoenactin analogs containing other amino acid (glycine, alanine, threonine, valine) hydroxamate. The analog in which the L-serine derived hydroxamic acid I (41c , L-serine) is replaced with D-serine 41c, D-serine) can also be prepared in the same manner. Scheme 6a. HATU, DIPEA, DMF, 70˚C. 310888514v1- 35 - b. KOtBu, hexadec-1-en-3-one, dioxane, 100˚C. c. Pd / C, H2, EtOH

[0092] Both unnatural or less common amino acids, like isoserine (Scheme 7) or cyclized amino acid analogs (Scheme 8) can be used. Scheme 7a. HATU, DIPEA, DMF, 70˚C. b. KOtBu, hexadec-1-en-3-one, dioxane, 100˚C. c. Pd / C, H2, EtOH. 310888514v1- 36 -

[0093] Since natural neoenactins and synthetic deoxy neoenactins contain two or one keto group, respectively, they can be directly derivatized with standard carbonyl chemistry (Scheme 9). Each keto group can be converted to ketals, oximes, hydrazones, and related analogs. Scheme 9

[0094] Another aspect of the present disclosure relates to a compound of Formula (II): 310888514v1- 37 -a pharmaceutically acceptable salt or solvate thereof, wherein Z1is O, NH, or CH2; and R´is C1-C30alkyl.

[0095] In some embodiments, Z1is O.

[0096] In some embodiments, the compound of Formula (II) is.

[0097] Compounds of Formula (II) of the present disclosure can be prepared as shown in Scheme 10. Scheme 10b. KOtBu, dioxane, reflux. c. Piperidine, DMF.

[0098] Scheme 10 illustrates the synthesis of compounds of Formula (II) from FMOC protected cycloserine (A) and an appropriate Michael acceptor (B) followed by the deprotection 310888514v1- 38 - reaction. Other compatible protecting groups commonly used in peptide synthesis can also be utilized.

[0099] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount a compound described herein and a pharmaceutically acceptable carrier.

[0100] The term “therapeutically effective amount” is meant to describe an amount of compound of the present disclosure effective to produce the desired therapeutic effect. Such amounts generally vary according to a number of factors well within the purview of ordinarily skilled artisans given the description provided herein to determine and account for. These include, without limitation: the particular subject, as well as its age, weight, height, general physical condition, and medical history; the particular compound used, as well as the carrier in which it is formulated and the route of administration selected for it; and the nature and severity of the condition being treated.

[0101] The term “pharmaceutical composition” means a composition comprising a compound according to any aspect of the present disclosure (e.g., a compound of Formula (I), Formula (I´), Formula (I´´), Formula (IA), Formula (IB), or Formula (II)) and at least one component comprising pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. Examples of suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar—agar and tragacanth, or mixtures of these substances. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monosterate and gelatin. Examples of suitable carriers, diluents, solvents, or vehicles include water, ethanol, polyols, suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Examples of excipients include lactose, milk sugar, sodium citrate, calcium carbonate, and dicalcium phosphate. Examples of disintegrating agents include starch, alginic acids, and certain complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulphate, talc, as well as high molecular weight polyethylene glycols. 310888514v1- 39 -

[0102] A “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0103] The term “pharmaceutically acceptable dosage forms” means dosage forms of the compound of the disclosure, and includes, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations, including suspensions, sprays, inhalants tablets, lozenges, emulsions, solutions, granules, capsules, and suppositories, as well as liquid preparations for injections, including liposome preparations. Techniques and formulations generally may be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., latest edition.

[0104] Another aspect of the present disclosure relates to a combination therapeutic comprising: (i) a compound described herein (e.g., a compound of Formula (I), Formula (I´), Formula (I´´), Formula (IA), Formula (IB), or Formula (II); and (ii) an antifungal agent.

[0105] Any suitable antifungal agent can be used in combination with one or more compounds described herein. Antifungal agents that can be used include, but not limited to azoles (imidazoles and / or triazoles), polyenes, allylamines, echinocandins, and orotomides, or combinations thereof.

[0106] Suitable imidazoles that can be used include, but are not limited to, ketoconazole, clotrimazole, and miconazole. Suitable triazoles that can be used include, but are not limited to, fluconazole, itraconazole, posaconazole, terbinafine, isavuconazole, voriconazole, and echinocandin B. Suitable polyenes that can be used include, but are not limited to, amphotericin B and nystatin. Suitable allylamines that can be used include, but are not limited to terbinafine. Suitable echinocandins that can be used include, but are not limited to, anidulafungin, caspofungin, and micafungin.

[0107] In some embodiments, the antifungal agent is selected from the group consisting of ketoconazole, clotrimazole, miconazole, fluconazole, itraconazole, posaconazole, terbinafine, isavuconazole, voriconazole, echinocandin B, amphotericin B, nystatin, terbinafine, anidulafungin, caspofungin, micafungin, flucytosine, and griseofulvin, or combinations thereof.

[0108] In some embodiments of any of the above aspects of the present disclosure, a compound described herein (e.g., a compound of Formula (I), Formula (I´), Formula (I´´), Formula (IA), Formula (IB), or Formula (II) is used in combination with one or more antifungal 310888514v1- 40 - agents. For example, the compound described herein can be used in combination with one antifungal agent, two antifungal agents, three antifungal agents, or four antifungal agents.

[0109] In some embodiments of any of the above aspects of the present disclosure, one or more compounds described herein (e.g., a compound of Formula (I), Formula (I´), Formula (I´´), Formula (IA), Formula (IB), or Formula (II) is used in combination with an antifungal agent. For example, the antifungal agent can be used in combination with one compound of the present disclosure, two compounds of the present disclosure, three compounds of the present disclosure, or four compounds of the present disclosure.

[0110] In some embodiments of any of the above aspects of the present disclosure, the use of a combination therapeutic comprising: (i) a compound described herein (e.g., a compound of Formula (I), Formula (I´), Formula (I´´), Formula (IA), Formula (IB), or Formula (II); and (ii) an antifungal agent results in a synergistic effect.

[0111] As used herein, the term “synergy” or “synergistic effect” when used in connection with a description of the efficacy of a combination of agents or compounds, means any measured effect of the combination which is greater than the effect predicted from a sum of the effects of the individual agents or compounds. For example, as described herein, there are synergistic effects of treating a fungal infection by a combination of a known antifungal agent (e.g., allylamines, polyenes, echinocandins, azoles, or orotomides) and a compound of the present disclosure (e.g., a compound of Formula (I), Formula (I´), Formula (I´´), Formula (IA), Formula (IB), or Formula (II)).

[0112] In some embodiments, when a compound according to any aspect of the present disclosure is administered in combination with an antifungal agent, the antifungal agent can be administered in an amount that is less than a therapeutically effective amount of the antifungal agent needed to treat the fungal infection.

[0113] Another aspect of the present disclosure relates to a method of treating a fungal infection in a subject. This method includes administering to the subject in need thereof a compound according to any aspect of the present disclosure.

[0114] The term “method of treating” means amelioration or relief from the symptoms and / or effects associated with the disorders described herein. As used herein, reference to “treatment” of a patient is intended to include prophylaxis.

[0115] Another aspect of the present disclosure relates to a method of treating a fungal infection in a subject. This method includes administering to the subject in need thereof a combination therapeutic comprising: (i) a compound according to any aspect of the present disclosure; and (ii) an antifungal agent. 310888514v1- 41 -

[0116] In some embodiments, the fungal infection is caused by fungal pathogen. Fungal pathogens include, but are not limited to, Cryptococcus neoformans, Candida auris (C.au), Aspergillus fumigatus, Candida albicans, Nakaseomyces glabrata (Candida glabrata), Histoplasma spp., eumycetoma causative agents, Mucorales, Fusarium spp., Candida tropicalis, Candida Parapsilosis (C.Para), Candida Albicans (C.Albi), Scedosporium spp., Lomentospora prolificans, Coccidioides spp., Pichia kudriavzeveii (Candida krusei), Cryptococcus gattii, Cryptococcus Neoformans (C. Neo), Talaromyces marneffei, Pneumocystis jirovecii, and Paracoccidioides spp.

[0117] In some embodiments, the fungal infection is selected from the group consisting of head ringworm, body ringworm, foot ringworm, onychomycosis, perionychomycosis, pityriasis versicolor, phlegm, vaginal candidiasis, airway candidiasis, biliary tract Candidiasis, esophageal candidiasis, urinary tract candidiasis, systemic candidiasis, mucocutaneous candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastosis, histoplasmosis, coccidioidomycosis, sporotrichosis, and fungal sinusitis.

[0118] In some embodiments of any of the above aspects of the present disclosure, the fungal infection is resistant to treatment using the antifungal agent alone. For example, the fungal infection is resistant to treatment using ketoconazole, clotrimazole, miconazole, fluconazole, itraconazole, posaconazole, terbinafine, isavuconazole, voriconazole, echinocandin B, amphotericin B, nystatin, terbinafine, anidulafungin, caspofungin, micafungin, flucytosine, and / or griseofulvin. The combination therapeutic comprising: (i) a compound according to any aspect of the present disclosure; and (ii) an antifungal agent can be used to treat the resistant fungal infection.

[0119] Another aspect of the present disclosure relates to a method of inhibiting the growth of yeast types of fungi or filamentous types of fungi. This method includes contacting yeast types of fungi or filamentous types of fungi with a compound according to any aspect of the present disclosure under conditions effective to inhibit the growth of yeast types of fungi or filamentous types of fungi.

[0120] Another aspect of the present disclosure relates to a method of inhibiting the growth of yeast types of fungi or filamentous types of fungi. This method includes contacting yeast types of fungi or filamentous types of fungi with a combination therapeutic comprising: (i) a compound according to any aspect of the present disclosure; and (ii) an antifungal agent.

[0121] In some embodiments, the yeast types of fungi are selected from a species of Candida, Cryptococcus, Aspergillus, Brettanomyces, Saccharomyces, Torulopsis, and Kluyveromyces, and combinations thereof. Exemplary yeast types of fungi include Aspergillus 310888514v1- 42 - niger, Aspergillus flavus, Aspergillus fumiqatus, Aspergillus oryzae, Aspergillus luchensis, Aspergillus versicolor, Aspergillus sydowi, Aspergillus nidulans, Aspergillus flaucus, Aspergillus terreus, Brettanomyces bruxellensis, Brettanomyces clausenii, Brettanomyces custerii, Brettanomyces anomalous, Brettanomyces naardenensis, Candida albicans, Candida parapsilosis, Candida tropicalis, Candida pseudotropicalis, Candida krusei, Candida rugosa, Candida quilliermondii, Candida stellatoidea, Saccharomyces bayanus, Saccharomyces cerevisiae, Saccharomyces dairiensis, Saccharomyces exigus, Saccharomyces uinsporus, Saccharomyces uvarum, Saccharomyces oleaginosus, Saccharomyces boulardii, Torulospora hansenii, Torulopsis glabrata, Cryptococcus albidus, Cryptococcus laurentii, Kluyveromyces lactis, and Kluyveromyces fragilis.

[0122] In some embodiments, the filamentous types of fungi are selected from a species Aspergillus, Trichophyton, Microsporum, Acremonium, Aureobasidium, Bjerkandera, Ceriporiopsis, Chrysosporium, Coprinus, Coriolus, Cryptococcus, Filibasidium, Fusarium, Humicola, Magnaporthe, Mucor, Myceliophthora, Neocallimastix, Neurospora, Paecilomyces, Penicillium, Phanerochaete, Phlebia, Piromyces, Pleurotus, Schizophyllum, Talaromyces, Thermoascus, Thielavia, Tolypocladium, Trametes, and Trichoderma. Exemplary filamentous types of fungi include Aspergillus Spp, Aspergillus awamori, Aspergillus foetidus, Aspergillus fumigatus, Aspergillus japonicus, Aspergillus nidulans, Aspergillus niger, Aspergillus oryzae, Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum gypseum, Bjerkandera adusta, Ceriporiopsis aneirina, Ceriporiopsis caregiea, Ceriporiopsis gilvescens, Ceriporiopsis pannocinta, Ceriporiopsis rivulosa, Ceriporiopsis subrufa, Ceriporiopsis subvermispora, Chrysosporium inops, Chrysosporium keratinophilum, Chrysosporium lucknowense, Chrysosporium merdarium, Chrysosporium pannicola, Chrysosporium queenslandicum, Chrysosporium tropicum, Chrysosporium zonatum, Coprinus cinereus, Coriolus hirsutus, Fusarium bactridioides, Fusarium cerealis, Fusarium crookwellense, Fusarium culmorum, Fusarium graminearum, Fusarium graminum, Fusarium heterosporum, Fusarium negundi, Fusarium oxysporum, Fusarium reticulatum, Fusarium roseum, Fusarium sambucinum, Fusarium sarcochroum, Fusarium sporotrichioides, Fusarium sulphureum, Fusarium torulosum, Fusarium trichothecioides, Fusarium venenatum, Humicola insolens, Humicola lanuginosa, Mucor miehei, Myceliophthora thermophila, Neurospora crassa, Penicillium purpurogenum, Phanerochaete chrysosporium, Phlebia radiata, Pleurotus eryngii, Thielavia terrestris, Trametes villosa, Trametes versicolor, Trichoderma harzianum, Trichoderma koningii, Trichoderma longibrachiatum, Trichoderma reesei, and Trichoderma viride. 310888514v1- 43 -

[0123] In practicing the methods of the present disclosure, agents (compounds described herein) suitable for treating a subject can be administered using any method standard in the art. The agents, in their appropriate delivery form, can be administered to a subject by any route, including systemic, local, oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, topical (including ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal), ocular, or the implantation of a slow-release device, e.g., a mini-osmotic pump. Parenteral administration includes, e.g., intravenous, intraarterial, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intrathecal, intraventricular, and intracranial. The compositions of the present disclosure may be administered alone or with suitable pharmaceutical carriers, and can be in solid or liquid form, such as tablets, capsules, powders, solutions, suspensions, or emulsions.

[0124] In some embodiments, the agents, in their appropriate delivery form, can be administered orally, intravenously, topically, including skin, vaginal, otic, ophthalmic, nasal, rectal, oral mucosal, or esophageal, intradermally, intramuscularly, intraperitoneally, subcutaneously, or intranasally. In some embodiments, the agents, in their appropriate delivery form, can be administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, intrathecally, topically, or intranasally.

[0125] The agent(s) may be orally administered, for example, with an inert diluent, or with an assimilable edible carrier, or it may be enclosed in hard or soft shell capsules, or it may be compressed into tablets, or they may be incorporated directly with the food of the diet. Agents may also be administered in a time release manner incorporated within such devices as time-release capsules or nanotubes. Such devices afford flexibility relative to time and dosage. For oral therapeutic administration, the agent(s) may be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like. Such compositions and preparations should contain at least 0.1% of the agent, although lower concentrations may be effective and indeed optimal. The percentage of the agent in these compositions may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of an agent of the present disclosure in such therapeutically useful compositions is such that a suitable dosage will be obtained. 310888514v1- 44 -

[0126] Also specifically contemplated are oral dosage forms of the agent(s). The agent(s) may be chemically modified so that oral delivery is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of proteolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the component or components and increase in circulation time in the body. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline (Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts,” In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp.367-383 (1981), which are hereby incorporated by reference in their entirety). Other polymers that could be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane. In some embodiments, preferred for pharmaceutical usage, as indicated above, are polyethylene glycol moieties.

[0127] The tablets, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, sucrulose, or saccharin. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

[0128] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar, or both. A syrup may contain, in addition to active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor.

[0129] The agent(s) may also be administered parenterally. Solutions or suspensions of the agent can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols, such as propylene glycol or polyethylene glycol, may be preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0130] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile 310888514v1- 45 - injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0131] When it is desirable to deliver the agent(s) systemically, it may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi- dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

[0132] Intraperitoneal or intrathecal administration of the agents of the present disclosure can also be achieved using infusion pump devices such as those described by Medtronic, Northridge, CA. Such devices allow continuous infusion of desired compounds avoiding multiple injections and multiple manipulations.

[0133] In addition to the formulations described previously, the agent(s) may also be formulated as a depot preparation. Such long-acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0134] The agent(s) may also be administered directly to the airways in the form of an aerosol. For use as aerosols, the agent(s) in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants. The agent of the present disclosure also may be administered in a non-pressurized form such as in a nebulizer or atomizer.

[0135] The percentage of active ingredient in the compositions of the present disclosure may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 250 mg / kg body weight, about 0.001 to about 200 mg / kg body weight, about 0.01 to about 150 mg / kg body weight, about 0.01 to about 100 mg / kg body weight, about 0.01 to about 70 mg / kg body weight, 310888514v1- 46 - about 0.01 to about 50 mg / kg body weight, about 0.01 to about 10 mg / kg body weight, about 0.001 to about 10 mg / kg body weight, about 0.001 to about 5 mg / kg body weight, about 0.001 to about 2 mg / kg body weight, about 0.001 to about 1 mg / kg body weight, about 0.001 to about 0.5 mg / kg body weight, about 0.001 to about 0.25 mg / kg body weight, about 0.001 to about 0.1 mg / kg body weight, about 0.01 to about 0.1 mg / kg body weight. Preferably about 0.01 to about 10 mg / kg body weight per day by inhalation, from about 0.01 to about 100 mg / kg body weight, preferably 0.1 to 70 mg / kg body weight, more especially 0.1 to 10 mg / kg body weight per day by oral administration, and from about 0.01 to about 50 mg / kg body weight, preferably 0.01 to 10 mg / kg body weight per day by intravenous administration. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health, and other characteristics which can influence the efficacy of the medicinal product.

[0136] The products according to the present disclosure may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. It goes without saying that, for other patients, it will be necessary to prescribe not more than one or two doses per day.

[0137] In various embodiments of the methods described herein, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a child, including an unborn fetus, a newborn, an infant, or a toddler. In some embodiments, the subject is an adult. In some embodiments, treating an unborn fetus using methods described herein may involve treating a pregnant female carrying the unborn fetus.

[0138] The above disclosure is general. A more specific description is provided below in the following examples. The examples are described solely for the purpose of illustration and are not intended to limit the scope of the present application. Changes in form and substitution of equivalents are contemplated as circumstances suggest or render expedient. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitation. 310888514v1- 47 - EXAMPLES

[0139] The following Examples are presented to illustrate various aspects of the present application, but are not intended to limit the scope of the claimed application. Example 1 – Biological Assays Test Organisms (Fungi)

[0140] Candida Parapsilosis (C.Para): ATCC 22019. Candida Albicans (C.Albi): ATCC 10231, MYA574 (Fluconazole-resistant), Y537 (Amp B-resistant), 64124 (Ketoconazole- resistant), Candida Auris (C.Auris): ATCC 0381 (Type strain), 0384 (MDR), and 0389 (MDR). Cryptococcus Neoformans (C. Neo): ATCC 208821 (H99), Jec20, Jec21, DUMC118.00, DUMC158.03, and Cryptococcus Gattii (R265) Trichophyton rubrum ATCC MYA-4438, MMX 5723, MMX 11212, Trichophyton mentagrophytes ATCC MYA-4439, and Microsporum gypseum MMX 5719, MMX 5720, and E. floccosum MMX 5721, MMX 5722. Test Medium

[0141] For an evaluation of in vitro potency using a single drug, all fungal pathogens were tested in RPMI-1640 from Thermo Fisher Scientific Laboratories (Waltham, MA) buffered with MOPS from Sigma-Aldrich (St. Louis, MO). Broth Microdilution: Inoculum Preparation

[0142] A standardized inoculum of each test organism was prepared per CLSI methods (M38).

[0143] Candida and Cryptococcus. Spp (Cryptococcus Neoformans (C. Neo): ATCC 208821 (H99), Jec20, Jec21, DUMC118.00, DUMC158.03, and Cryptococcus Gattii (R265)) overnight culture were measured at an optical density (OD) of 530 nm using a spectrophotometer microplate reader (Bio Tek: Winooski, VT). A final concentration of 105CFU / mL was achieved by serially diluting the initial inoculum in a corresponding media. Broth Microdilution: Drug Plates Preparation

[0144] For an evaluation of in vitro potency by a single drug, the wells in columns 2 through 12 of a standard 96-well microdilution plate (3799 Corning® 96-well Clear Round Bottom Polystyrene Treated Microplate) were filled with 100 μL of diluent. The drugs (200 μL) were added to column 1 and titrated horizontally using two-fold serial dilutions to a final concentration of 0.03 μM. Column 12 contained no drug and served as the growth control wells.

[0145] For an evaluation of in vitro potency by two drugs, the wells in columns 2 through 12 of a standard 96-well microdilution plate (3799 Corning® 96-well Clear Round 310888514v1- 48 - Bottom Polystyrene Treated Microplate) were filled with 50 μL of diluent. The drugs (100 μL) were added to column 1 and titrated horizontally using two-fold serial dilutions to a final concentration of 0.03 μM. Subsequently, a second (companion) drug (50 µL) was added at the indicated concentration. Column 12 contained no drug and served as the growth control wells.

[0146] The prepared plates were covered with a sterile lid and incubated aerobically at 37ºC for 24 and 48 hours. Modal Minimum Inhibitory Concentration (MIC) values were recorded by visually observing 90% growth inhibition at 18-24 hours. MIC values were determined using a broth microdilution procedure described by CLSI (M38). Example 2 – Neoenactin Structure-Activity-relationships (SAR) and Synergistic Antifungal Activity with Clinical Drugs

[0147] SAR studies on Neoenactins and their analogs were conducted using microbiological assays. The original Neoenactin A and synthetic analogs were first screened for independent activity against sets of strains of Candida and Cryptococcus (Tables 1 and 2). The antifungal activity is shown in Table 3. The original Neoenactin A was most active against all strains tested. Most analogs had decreased activity against the strains of Candida but several retained activity against Cryptococcus. 310888514v1- 49 - Table 1. Activity of Neoenactin A Against Various Candida Spp. MIC Testing range 0.03 - 30 µMTable 2. Activity of Neoenactin A Against Various Cryptococcus Spp. MIC Testing range <0.002 - 30 µMTable 3. Anti-Fungal Activity of Neoenactin Analogs310888514v1- 50 -310888514v1- 51 -310888514v1- 52 -310888514v1- 53 -310888514v1- 54 -310888514v1- 55 -n.d. indicates greater than the testing limit Neo – A is Neoenactin-A

[0148] Notably, analogs with simple alkyl groups (017584 and 01700) (Figures 3A-3B) and ester or amide groups (176997 and 018003, respectively) retained good anti-fungal activity (Table 4) (MIC similar to neonactin A).017997 018003 ester amide Table 4. Anti-Fungal Activity

[0149] Notably, analogs with keto groups converted to oximes retained good activity (Table 5) (018041, Compound 60 in Scheme 9). 310888514v1- 56 - Table 5. Anti-Fungal Activity of Oxime DerivativeActivity of Neoenactin A and Synthetic Analogs Against Pathogenic Dermatophyes

[0150] Neoenactin A and several of the synthetic analogs were also tested for activity against dermatophytes. The resulting data (Figures 4A-4B) indicates excellent activity that also indicates the value of the structure-activity relationship (SAR) studies as in many cases, synthetic analogs were superior to the natural Neoenactin A, most notably 017700 with the simple long alkyl chain. Synergistic Anti-Fungal Activity of Neoenactins with Other Classes of Anti-Fungal Agents

[0151] Combinations of Neoenactin A with other classes of anti-fungal agents demonstrated a significant synergistic activity with added neoenactin. As shown in Table 6, combination of Neoenactin A with traditional clinically used anti-fungal drugs resulted in drastic improvement of MIC values. 310888514v1- 57 - Table 6. Synergism of Neoenactin A and Synthetic Analogs in Combination with Known Anti-Fungal Agents Improves MIC ValuesC. Albicans 10231C. Albicans 64124 (Ketaconazole-R)310888514v1- 58 - Example 3 – Synthesis of Neoenactin Analogsa. KOtBu, dioxane, 90 °C b. Pd / C, H2, EtOH c. TFA, DCM

[0152] To a sealed tube containing compound 11 (0.10 g, 0.32 mmol) and dodecyl prop- 2-enoate (0.08 g, 0.32 mmol) in dioxane (5 mL) was added KOtBu (0.007 g, 0.064 mmol) and the resulting solution was bubbled with argon and stirred at reflux overnight. The resulting solution was concentrated in vacuo, diluted with 10 mL DCM, washed with 10 mL 2% AcOH, 10 mL brine, dried over Na2SO4, and concentrated in vacuo. The resulting oil was purified by column chromatography on SiO2 to yield dodecyl compound 67 as a colorless oil (100.0 mg, 56 % yield).

[0153] Compound 67 (0.08 g, 0.16 mmol) was dissolved in EtOH (30 mL) and Pd / C (0.02 g, 0.02 mmol) was added under argon. The reaction mixture was bubbled with H2 and stirred under an atmosphere of H2 for 1 hour. Once complete by TLC, reaction mixture was filtered through glass paper and the organics were concentrated. The resulting oil was taken up in 20 mL DCM and washed with 20 mL H2O, 20 mL brine, dried over Na2SO4, and concentrated in vacuo. The resulting oil was purified by column chromatography to yield compound 68 as a colorless oil (25.0 mg, 95 % yield).

[0154] To a round bottom flask containing compound 68 (0.02 g, 0.043 mmol) in DCM (5 mL) was added TFA (0.03 mL, 0.43 mmol) and the resulting solution was stirred for 2 hours whereupon it was concentrated in vacuo to yield dodecyl 3-((2S)-2-aminohydroxy-3- hydroxypropanoylamino)propanoate (69) as a pink solid and TFA salt (99 % yield). 310888514v1- 59 - Synthesis of (2S)-2-Amino-N-[2-(N-dodecylcarbamoyl)ethyl]-3-hydroxy-N- hydroxypropanamide (73)a. KOtBu, dioxane, 90 °C. b. TFA, DCM. c. L-BOC-Serine, HATU, DIPEA, DMF, 45 °C. d. Pd / C, H2, EtOH e. TFA, DCM

[0155] To a vial containing (tert-butoxy)-N-(phenylmethoxy)carboxamide (0.10 g, 0.45 mmol) and N-dodecylprop-2-enamide (0.11 g, 0.45 mmol) in dioxane (5 mL) bubbled with Ar was added KOtBu (0.06 g, 0.54 mmol) and the resulting suspension was heated to 90 °C and stirred overnight. The resulting suspension was concentrated in vacuo, diluted with 20 mL DCM, washed with 20 mL 2 % AcOH, 20 mL brine, dried over Na2SO4, and concentrated in vacuo. The resulting oil was purified by column chromatography on SiO2 to yield compound 70 as a colorless oil (75.0 mg, 36 % yield).

[0156] To a round bottom flask containing compound 70 (0.075 g, 0.16 mmol) in DCM (10 mL) was added TFA (0.12 mL, 1.62 mmol) and the resulting solution was stirred for 2 hours whereupon it was concentrated in vacuo, diluted with 20 mL DCM, washed with 20 mL saturated aqueous NaHCO3, dried over Na2SO4, and concentrated in vacuo to yield 71 as an oil (58.0 mg). Used crude as 100 % in the next step.

[0157] To a vial containing (L)-BOC-serine (0.03 g, 0.17 mmol) and compound 71 (0.06 g, 0.17 mmol) in DMF (5 mL) was added HATU (0.08 g, 0.20 mmol) and DIPEA (0.06 mL, 0.33 mmol) and the resulting brown solution was heated to 45 °C with stirring overnight. The resulting brown suspension was concentrated in vacuo, diluted with DCM (30 mL), washed successively with 5 % HOAc (2 x 30 mL), saturated aqueous NaHCO3(2 x 30 mL), and brine 310888514v1- 60 - (30 mL), dried over Na2SO4, and concentrated in vacuo. The resulting oil was purified by column chromatography on SiO2to yield compound 72 as a colorless oil (60.0 mg, 62 % yield).

[0158] Compound 72 (0.06 g, 0.11 mmol) was dissolved in EtOH (20 mL) and then Pd / C (0.03 g, 0.03 mmol) was added under argon. The reaction was bubbled with H2 and stirred under an atmosphere of H2for 1 hour. Once complete by TLC, the reaction was filtered through glass paper and the organics were concentrated in vacuo. The resulting oil was taken up in 20 mL DCM, washed with 20 mL H2O, 20 mL brine, dried over Na2SO4, and concentrated in vacuo to yield compound 72int as an off white solid (50.0 mg, 95 % yield).

[0159] To a round bottom flask containing compound 72int (0.05 g, 0.11 mmol) in DCM (10 mL) was added TFA (0.08 mL, 1.09 mmol) and the resulting solution stirred for 2 hours whereupon it was concentrated in vacuo, diluted with 20 mL DCM, washed with 20 mL NaHCO3, dried over Na2SO4, and concentrated in vacuo to yield (2S)-2-amino-N-[2-(N- dodecylcarbamoyl)ethyl]-3-hydroxy-N-hydroxypropanamide (73) as an off white solid (10.0 mg, 25 % yield). Synthesis of (2S)-2-Amino-N(4,4-dimethyl-3-oxotetradecyl)-3-hydroxy-N- hydroxypropanamide (80)310888514v1- 61 - a. LDA, THF, -10 °C – rt. b. NaOH, MeOH, reflux. c. Oxalyl chloride, DCM, DMF. d. N,O-dimethylhydroxylamine, pyridine, DCM. e. Mg, I2, vinyl bromide, THF. f. KOtBu, dioxane, reflux. g. Pd / C, H2, EtOH. h. HCl, DCM.

[0160] To a stirred solution of LDA (2.26 mL, 4.52 mmol) in THF (5 mL) at -10 °C was added ethyl 2-methylpropanoate (0.58 mL, 4.30 mmol) and the resulting solution stirred for 1 hour whereupon iododecane (0.95 mL, 4.43 mmol) was added and the solution warmed to rt overnight. The reaction mixture was subsequently poured over ice water and extracted with 2 x 30 mL Et2O. The crude oil was washed with 20 mL brine, dried over Na2SO4, and concentrated in vacuo. The resulting oil 74 was used without purification in the next step.

[0161] To a stirred solution of compound 74 (1.11 g, 4.33 mmol) in MeOH (20 mL) was added 4M NaOH (4.33 mL, 17.32 mmol) and the resulting suspension was heated to reflux with stirring until the reaction was complete by TLC. The solution was subsequently cooled to rt, diluted with 10 mL H2O, and extracted with 2 x 50 mL Et2O. The aqueous layer was then acidified to pH=1 with 12 M HCl, and further extracted with 3 x 50 mL Et2O. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting oil was purified by column chromatography on SiO2 to yield compound 74int as a colorless oil (980.0 mg, 99 % yield).

[0162] To a stirred rt solution of 74int (0.98 g, 4.29 mmol) in DCM (50 mL) was added 1 drop of DMF and oxalyl chloride (0.50 mL, 5.58 mmol) and the resulting solution was stirred overnight whereupon it was concentrated in vacuo. The resulting crude oil 75 was used without purification in next step.

[0163] To a stirred solution of N,O-dimethylhydroxylamine HCl (0.37 g, 6.08 mmol) in DCM (10 mL) cooled to 0 °C was added pyridine (0.66 mL, 8.10 mmol) and stirring continued for 30 minutes whereupon compound 75 (1.00 g, 4.05 mmol) was added and stirring continued at 0 °C for 30 minutes whereupon it was warmed to room temperature. Upon completion by TLC, the reaction mixture was diluted with 50 mL DCM, washed with 50 mL 0.1 M HCl, 2 x 50 mL brine, dried over Na2SO4, and concentrated in vacuo. The resulting crude oil was subsequently purified by column chromatography on SiO2to yield compound 76 as a tan oil (1.09 g, 99 % yield). 310888514v1- 62 -

[0164] To a flame dried round bottom flask containing vinyl bromide (1M in THF) (9.21 mL, 9.21 mmol) was added Mg (0.22 g, 9.21 mmol) and one crystal of iodine and the suspension was stirred until iodine color disappears and magnesium dissolves. The Mg solution was then added dropwise via cannula to a solution of compound 76 (2.00 g, 7.37 mmol) in THF (10 mL) at - 10 °C and the resulting solution was stirred with warming to rt until the reaction was complete by TLC. The solution was then diluted with 50 mL 0.5 M HCl, extracted with 3 x 50 mL EtOAc, dried over Na2SO4, and concentrated in vacuo. The resulting oil was purified by column chromatography on SiO2to yield compound 77 as a colorless oil (500.0 mg, 57 % yield).

[0165] To a sealed tube containing compound 1 (0.24 g, 0.76 mmol) and compound 77 (0.20 g, 0.84 mmol) in dioxane (5 mL) was added KOtBu (0.02 g, 0.15 mmol) and the resulting solution was bubbled with Argon, capped, and stirred at reflux overnight. The resulting solution was concentrated in vacuo, diluted with 30 mL DCM, washed with 20 mL 2 % aqueous AcOH, 20 mL brine, dried over Na2SO4, and concentrated in vacuo. The resulting oil was purified by column chromatography on SiO2to yield compound 78 as a colorless oil (146.0 mg, 33 % yield).

[0166] Compound 78 (0.15 g, 0.27 mmol) was dissolved in EtOH (20 mL) and then Pd / C (0.08 g, 0.08 mmol) was added under argon. The reaction was bubbled with H2 and stirred under an atmosphere of H2 until the reaction was complete by TLC. Once complete by TLC, reaction was filtered through glass paper and the organics were concentrated. The resulting oil was taken up in 30 mL DCM and washed with 30 mL H2O, 30 mL brine, dried over Na2SO4, and concentrated in vacuo. The resulting oil was purified by column chromatography on SiO2 to yield compound 79 as a colorless oil (122.0 mg, 94 % yield).

[0167] To a round bottom flask containing compound 79 (0.06 g, 0.13 mmol) in DCM (10 mL) was added 4M HCl in Et2O (1.31 mL, 1.31 mmol)) and the resulting solution was stirred until the reaction was complete by TLC. The resulting solution was concentrated in vacuo to yield (2S)-2-amino-N(4,4-dimethyl-3-oxotetradecyl)-3-hydroxy-N- hydroxypropanamide (80) as a red solid (25.0 mg, 50 % yield). 310888514v1- 63 - Synthesis of Dodecyl 3-[(2S)-2-aminohydroxy-3-a. Pyridine, - 10 °C. b. Pt / C, H2, AcOH c. HCl, DCM

[0168] To a round bottom flask containing compound 67 (0.05 g, 0.09 mmol) in pyridine (1 mL) at - 10 °C was added chlorodiphenoxyphosphino-1-one (0.05 mL, 0.26 mmol) and the resulting solution was warmed to rt over 2 hours and stirred overnight. The resulting solution was subsequently quenched with H2O (1 mL) and the resulting mixture was stirred for a further 30 minutes whereupon it was diluted with 20 mL 1M HCl, extracted with 2 x 20 mL DCM, dried over Na2SO4, and concentrated in vacuo. The resulting crude solid was then purified by column chromatography on SiO2to yield compound 81 as an off white solid (100.0 mg, 55 % yield).

[0169] To a round bottom flask containing compound 81 (0.07 g, 0.09 mmol) dissolved in AcOH (2 mL) under an atmosphere of argon was added Pt / C (0.05 g, 0.03 mmol). The reaction mixture was subsequently bubbled with H2and stirred under an atmosphere of H2for 1 hour. Once complete by TLC, the reaction mixture was filtered through glass paper. The resulting solution was diluted with 20 mL H2O, extracted with 3 x 20 mL DCM, washed with 20 mL H2O, 2 x 20 mL saturated aqueous NaHCO3, 20 mL brine, dried over Na2SO4, and concentrated in vacuo. The resulting solution was purified by column chromatography on SiO2 to yield compound 82 as a colorless oil (40.0 mg, 79 % yield).

[0170] To a round bottom flask containing 82 (0.04 g, 0.04 mmol) was added DCM (5 mL) and HCl (1M in Et2O) (0.48 mL, 0.48 mmol) and the resulting solution stirred until the reaction was complete by TLC. The resulting solution was concentrated in vacuo to yield 310888514v1- 64 - dodecyl 3-[(2S)-2-aminohydroxy-3-(oxyphosphinyloxyphosphinyl)propanoylamino]propanoate (83) as a HCl salt (35.0 mg, 99 % yield). Synthesis of Dodecyl 3-[(2S)-2-aminohydroxy-3- (methoxyphosphinyl)propanoylamino]propanoate (86a) and Dodecyl 3-[(2S)-2-amino-3- (ethoxyphosphinyl)hydroxypropanoylamino]propanoate (86b)a. Pyridine, - 10 °C. b. Pd / C, H2, EtOH. c. HCl, DCM.

[0171] To a round bottom flask containing compound 67 (0.08 g, 0.15 mmol) in pyridine (1 mL) at - 10 °C was added the appropriate chloro phoshinone (0.18 mmol) and the resulting solution was stirred for overnight whereupon it was quenched with H2O (1 mL) and stirred for a further 30 minutes. 1M HCl (5 mL) was then added and the reaction mixture was extracted with 2x 10 mL DCM, dried over Na2SO4, and concentrated in vacuo. The crude oil was then purified by column chromatography on SiO2 to yield compound 84 as a colorless oil.

[0172] Compound 84 (0.05 g, 0.07 mmol) was dissolved in EtOH (20 mL), the solution was purged with Ar, and Pd / C (0.05 g, 0.02 mmol) was added in one portion. H2was bubbled through the solution for 5 minutes and the resulting mixture was stirred under an atmosphere of 1atm H2 until the reaction was complete by TLC. The resulting solution was subsequently filtered through glass paper and concentrated in vacuo. The residue was diluted with 20 mL DCM, washed with 20 mL H2O, dried over Na2SO4, and concentrated in vacuo to yield compound 85.

[0173] To a round bottom flask containing compound 85 (0.05 g, 0.10 mmol) was added DCM (20 mL) and HCl (1M in Et2O (0.88 mL, 0.88 mmol)) and the resulting solution was 310888514v1- 65 - stirred until complete by TLC. The resulting solution was concentrated in vacuo to yield compound 86 as a HCl salt.

[0174] Compound 86a was prepared according to the procedure described above from compound 67 (0.08 g, 0.15 mmol) and chlorodimethoxyphosphino-1-one (0.020 mL, 0.18 mmol). Dodecyl 3-[(2S)-2-aminohydroxy-3-(methoxyphosphinyl)propanoylamino]propanoate (86a) was obtained as a tan solid (47 % over 3 steps).

[0175] Compound 86b was prepared according to the procedure described above from compound 67 (0.07 g, 0.13 mmol) and chlorodiethoxyphosphino-1-one (0.024 mL, 0.18 mmol). Dodecyl 3-[(2S)-2-amino-3-(ethoxyphosphinyl)hydroxypropanoylamino]propanoate (86b) was obtained as a tan solid (45 % over 3 steps). Synthesis of Dodecyl 3-[(2S)-2-aminohydroxy-3-(phenoxyphosphinyl)propanoyl- amino]propanoate (89)a. Pyridine, - 10 °C. b. Pt / C, H2, EtOH. c. HCl, DCM.

[0176] To a round bottom flask containing compound 67 (0.05 g, 0.09 mmol) in pyridine (1 mL) at - 10 °C was added chlorodiphenoxyphosphino-1-one (0.05 mL, 0.26 mmol) and the resulting solution was warmed to rt over 2 hours and stirred overnight. The resulting solution was subsequently quenched with H2O (1 mL) and the resulting mixture was stirred for a further 30 minutes whereupon it was diluted with 20 mL 1M HCl, extracted with 2 x 20 mL DCM, dried over Na2SO4, and concentrated in vacuo. The resulting crude solid was then purified by column chromatography on SiO2 to yield compound 87 as an off white solid (100.0 mg, 55 % yield). 310888514v1- 66 -

[0177] Compound 87 (0.07 g, 0.09 mmol) was dissolved in EtOH (20 mL) and then Pd / C (0.03 g, 0.03 mmol) was added under argon. The reaction mixture was bubbled with H2and was stirred under an atmosphere of H2 for 1 hour. Once complete by TLC, the reaction mixture was filtered through glass paper and the organics were concentrated in vacuo. The resulting oil was taken up in 20 mL DCM, washed with 20 mL H2O, 20 mL brine, dried over Na2SO4, and concentrated in vacuo. The resulting oil was purified by column chromatography on SiO2 to yield compound 88 as a colorless oil (40.0 mg, 61 % yield).

[0178] To a round bottom flask containing compound 88 (0.01 g, 0.01 mmol) was added DCM (5 mL) and HCl (1M in Et2O (0.12 mL, 0.12 mmol) and the resulting solution was stirred until the reaction was complete by TLC. The resulting solution was concentrated in vacuo to yield dodecyl 3-[(2S)-2-aminohydroxy-3-(phenoxyphosphinyl)propanoyl-amino]propanoate (89) as a HCl salt (45.0 mg, 99 % yield). Synthesis of Dodecyl 3-((3E)(2S)hydroxy-4-{3-hydroxy-2-methyl-5- [(oxyphosphinyloxyphosphinyl)methyl](4-pyridyl)}-2-(hydroxymethyl)-3-azabut-3- enoylamino)propanoate (90)a. Sodium acetate, DCM / MeOH.

[0179] To a stirred solution of pyridoxyl 5-phosphate (0.03 g, 0.11 mmol) in 1:1 DCM / MeOH (5 mL) was added compound 69 (0.04 g, 0.11 mmol) and the pH of the resulting solution was adjusted to pH 5 with sodium acetate (0.02 g, 0.22 mmol). The reaction mixture was stirred until the reaction was complete by TLC. The resulting reaction mixture was concentrated in vacuo, diluted with 10 mL DCM, and the sodium acetate was filtered off. This procedure was repeated until no sodium acetate remained. The resulting solution was concentrated in vacuo to yield dodecyl 3-((3E)(2S)hydroxy-4-{3-hydroxy-2-methyl-5- [(oxyphosphinyloxyphosphinyl)methyl](4-pyridyl)}-2-(hydroxymethyl)-3-azabut-3- enoylamino)propanoate (90) as a yellow solid (50.0 mg, 77 % yield). 310888514v1- 67 - Synthesis of Dodecyl 3-{(2S)hydroxy-3-hydroxy-2-[({3-hydroxy-2-methyl-5- [(oxyphosphinyloxyphosphinyl)methyl](4-pyridyl)}methyl)amino]propanoylamino}propanoate (91)a. Sodium borohydride, DCM / MeOH.

[0180] To a stirred solution of compound 90 (0.05 g, 0.09 mmol) in 1:1 DCM / MeOH (5 mL) was added sodium borohydride (0.004 g, 0.11 mmol) and the resulting solution was stirred until the reaction was complete by TLC. The resulting solution was concentrated in vacuo and purified by column chromatography on SiO2to yield dodecyl 3-{(2S)hydroxy-3-hydroxy-2-[({3- hydroxy-2-methyl-5-[(oxyphosphinyloxyphosphinyl)methyl](4- pyridyl)}methyl)amino]propanoylamino}propanoate (91) as an off white solid (6.0 mg, 11 % yield). Synthesis of Dodecyl 3-((4S)-4-amino-3-oxo-2,4,5-trihydroisoxazol-2-yl)propanoate (94)a. NaHCO3, DIPEA, dioxane, 0 °C. b. KOtBu, dodecyl prop-2-enoate, dioxane, reflux. 310888514v1- 68 - c. Piperidine, DMF.

[0181] To a stirred solution of L-cycloserine (0.2 g, 1.96 mmol) in dioxane (20 mL) under argon at 0 °C was added NaHCO3(0.18 g, 2.15 mmol) and DIPEA (0.34 mL, 1.96 mmol) followed by FMOC-Cl (0.43 g, 1.96 mmol) and the resulting suspension was stirred overnight. The resulting reaction mixture was diluted with 20 mL DCM, washed with 20 mL 5% AcOH, 20 mL saturated aqueous NaHCO3, 20 mL brine, dried over Na2SO4, and concentrated in vacuo. The resulting mixture was purified by column chromatography on SiO2 to yield compound 92 as a white solid (95.0 mg, 15 % yield).

[0182] To a sealed tube containing compound 92 (0.1 g, 0.29 mmol) and dodecyl prop-2- enoate (0.08 g, 0.32 mmol) in dioxane (5 mL) was added KOtBu (0.01 g, 0.06 mmol) and the resulting solution was bubbled with argon and stirred at reflux overnight. The resulting solution was concentrated in vacuo, diluted with 20 mL DCM, washed with 20 mL 2% AcOH, 20 mL brine, dried over Na2SO4, and concentrated in vacuo. The resulting oil was purified by column chromatograph on SiO2 to yield compound 93 as a colorless oil (100.0 mg, 60 % yield).

[0183] To a flask containing compound 93 (0.10 g, 0.18 mmol) was added a solution of 20 % piperidine in DMF (2.5 mL) and the resulting solution was stirred until the reaction was complete by TLC. The reaction was concentrated, diluted with 20 mL EtOAc, washed with 20 mL 0.1 M HCl, 20 mL H2O, 20 mL brine, dried over Na2SO4, and concentrated in vacuo. The resulting oil was purified by column chromatography on SiO2to yield dodecyl 3-((4S)-4-amino- 3-oxo-2,4,5-trihydroisoxazol-2-yl)propanoate (94) as a yellow solid (16.0 mg, 95 % yield).310888514v1- 69 - a. EDC-HCl, DMAP, MeCN. b. KOtBu, hexadec-1-en-3-one, dioxane, reflux. c. HCl, DCM.

[0184] To a vial containing (tert-butyl)oxycarbohydrazide (0.13 g, 0.97 mmol) and BOC- serine (0.2 g, 0.97 mmol) in MeCN (5 mL) was added EDC-HCl (0.22 g, 1.17 mmol) and DMAP (0.14 g, 1.17 mmol) and the resulting solution was stirred at room temperature until the reaction was complete by TLC. The resulting solution was concentrated in vacuo, diluted with DCM (30 mL), washed successively with 2 % HOAc (2 x 30 mL), saturated aqueous NaHCO3 (2 x 30 mL) and brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The resulting oil was purified by column chromatography on SiO2 to yield compound 95 as an off white solid (78.0 mg, 25 % yield).

[0185] To a vial containing hexadec-1-en-3-one (0.06 g, 0.24 mmol) and compound 95 (0.08 g, 0.24 mmol) in dioxane (5 mL) was added KOtBu (0.01 g, 0.05 mmol) and the resulting solution was stirred overnight. The resulting solution was concentrated in vacuo and purified by column chromatography on SiO2to yield compound 96 as a colorless oil (100.0 mg, 70 % yield).

[0186] To a stirred solution of compound 96 (0.10 g, 0.18 mmol) in DCM (10 mL) was added HCl (1M in Et2O) (1.79 mL, 1.79 mmol) and the resulting solution was stirred overnight at room temperature. The resulting solution was then concentrated in vacuo to yield (2S)-2- amino-N-amino-3-hydroxy-N-(3-oxohexadecyl)propenamide (97) as a tan oil (30.0 mg, 43% yield). Synthesis of Dodecyl 3-(hydroxy-1,3-oxazol-5-ylcarbonylamino)propanoate (100a), Dodecyl 3- (hydroxypyrrol-2-ylcarbonylamino)propanoate (100b) and Dodecyl 3-(hydroxy-1,3-oxazol-4- ylcarbonylamino)propanoate (100c) 310888514v1- 70 -a. EDC-HCl, DMAP, MeCN. b. KOtBu, dodecyl prop-2-enoate, dioxane, reflux. c. Pd / C, H2, EtOH.

[0187] To a vial containing carboxylic acid (0.10 g, 0.88 mmol) and oxybenzylamine HCl (0.14 g, 0.88 mmol) in MeCN (5 ml) was added EDC-HCl (0.20 g, 1.06 mmol) and DMAP (0.13 g, 1.06 mmol) and the resulting solution was stirred at room temperature until the reaction was complete by TLC. The resulting solution was concentrated in vacuo, diluted with DCM (30 mL), washed successively with 5 % HOAc (2 x 30 mL), saturated aqueous NaHCO3(2 x 30 mL), and brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The resulting oil was purified by column chromatography on SiO2 to yield compound 98.

[0188] To a sealed tube containing compound 98 (0.07 g, 0.32 mmol) and dodecyl prop- 2-enoate (0.08 g, 0.32 mmol) in dioxane (5 mL) was added KOtBu (0.01 g, 0.06 mmol) and the resulting solution was bubbled with argon and stirred at reflux overnight. The resulting solution was concentrated in vacuo, diluted with 20 mL DCM, washed with 20 mL 2% AcOH, 20 mL brine, dried over Na2SO4, and concentrated in vacuo. The resulting oil was purified by column chromatography on SiO2 to yield compound 99.

[0189] Compound 99 (0.016 g, 0.034 mmol) was dissolved in EtOH (30 mL) and then Pd / C (0.01 g, 0.01 mmol) was added under argon. The reaction mixture was bubbled with H2 and stirred under an atmosphere of H2 until the reaction was complete by TLC. Once complete by TLC, the reaction mixture was filtered through glass paper and the organics were 310888514v1- 71 - concentrated in vacuo. The resulting oil was taken up in 20 mL DCM, washed with 20 mL H2O, 20 mL brine, dried over Na2SO4, and concentrated in vacuo to yield compound 100.

[0190] Compound 100a was prepared according to the procedure described above from 1,3-oxazole-5-carboxylic acid (0.10 g, 0.88 mmol). Dodecyl 3-(hydroxy-1,3-oxazol-5- ylcarbonylamino)propanoate (100a) was obtained as an off white solid (12.0 mg, 3 % yield over 3 steps).

[0191] Compound 100b was prepared according to the procedure described above from pyrrole-2-carboxylic acid (0.10 g, 0.90 mmol). Dodecyl 3-(hydroxypyrrol-2- ylcarbonylamino)propanoate (100b)was obtained as a brown oil (120.0 mg, 66 % yield over 3 steps).

[0192] Compound 100c was prepared according to the procedure described above from 1,3-oxazole-4-carboxylic acid (0.10 g, 0.88 mmol). Dodecyl 3-(hydroxy-1,3-oxazol-4- ylcarbonylamino)propanoate (100c)was obtained as an orange solid (55.0 mg, 16 % yield over 3 steps).

[0193] Although certain embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the disclosure and these are therefore considered to be within the scope of the disclosure as defined in the claims which follow. 310888514v1

Claims

- 72 - WHAT IS CLAIMED:

1. A compound of Formula (I):a pharmaceutically acceptable salt or solvate thereof, whereinA2is optional, and if present iR is OH, OBn, or NH2; R1is selected from the group consisting of OH, i-Pr, C1-C6alkyl substituted with OH, C1-C6 alkyl substituted with OP(O)(ORa)2, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6alkynyl, substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; R2is selected from the group consisting of H, -C(O)O-t-Bu (Boc), optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R1and R2can combine with the atoms to which they are attached to form an optionally substituted heterocyclyl; R3is selected from the group consisting of H, -C(O)O-t-Bu (Boc), optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; or 310888514v1- 73 - R2and R3can combine with the nitrogen atom to which they are attached to formR4is selected from the group consisting of H, cycloalkyl, optionally substituted C1-C16 alkyl, optionally substituted C2-C16 alkenyl, optionally substituted C2-C16 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; W is C or S; W1is optional, and if present is O or NH; k is 0 or 1; n is 0, 1, or 2; m is 0 or 1; X is optional, and if present is selected from the group consisting of O, N(OR5), N(OCH2COZR6), N(NHR7), N(NHCOR8), N(NHSO2NHR9), and N(NHSO2R10); Y is optional, and if present is selected from the group consisting of O, N(OR5), N(OCH2COZR6), N(NHR7), N(NHCOR8), N(NHSO2NHR9), and N(NHSO2R10); R5is H or optionally substituted C1-C6 alkyl; R6is H; R7is H or optionally substituted C1-C6 alkyl; R8is H or optionally substituted C1-C6 alkyl; R9is H or optionally substituted C1-C6alkyl; R10is H or optionally substituted C1-C6alkyl;is aryl or heteroaryl, wherein aryl and heteroarylaryl can be optionally substituted from 1 to 5 times with a substituent selected independently from OH, C1-C6 alkyl, - OP(O)(ORa)2, and -C1-C6 alkylene-OP(O)(ORa)2; Rais independently selected from H, C1-C6alkyl, aryl, or arylalkyl; Z is O or NH; and is an optionally present double bond, 310888514v1- 74 - with the proviso that i) when k is 1, R1is CH2OH, A is, W1is absent, and R4is H, C1- C12alkyl, or C1-C12alkyl substituted with OH, then X is not O, N(OH), or N(OMe); ii) when k is 1, and m is 0, then R1is not OH; and iii) the compound is not.

2. The compound according to claim 1, wherein R is OH.

3. The compound according to claim 1, wherein R is NH2.

4. The compound according to claim 1, wherein R1is selected from the5. The compound according to claim 1, wherein R1is OH,, CH2OH, or CH(CH3)OH.

6. The compound according to claim 1, wherein R1is CH2OH or CH(CH3)OH.

7. The compound according to claim 1, wherein A is. 310888514v1- 75 - 8. The compound according to claim 1, wherein R1and R2combine to form.

9. The compound according to claim 1, wherein R2is H.

10. The compound according to claim 1, wherein R3is H.

11. The compound according to claim 1, wherein R3is heteroarylalkyl optionally substituted from 1 to 3 times with a substituent selected independently from OH, C1- C6alkyl, -OP(O)(ORa)2, and -C1-C6alkylene-OP(O)(ORa)2.

12. The compound according to claim 1, wherein R3is -CH2-pyridinyl optionally substituted from 1 to 3 times with a substituent selected independently from OH, C1- C6alkyl, -OP(O)(ORa)2, and -C1-C6alkylene-OP(O)(ORa)2. . The compound according to claim 1, wherein.

14. The compound according to claim 1, wherein R2and R3combine with the nitrogen atom to which they are attached to form, whereinis a pyridine optionally substituted from 1 to 3 times with a substituent selected independently from OH, C1- C6alkyl, and -CH2-OP(O)(ORa)2. 310888514v1- 76 - 15. The compound according to claim 1, wherein R2and R3combine with the nitrogen atom to which they are attached to form.

16. The compound according to claim 1, wherein k is 0.

17. The compound according to claim 1, wherein k is 1.

18. The compound according to claim 1, wherein R4is selected from the group consisting of H, cycloalkyl, and C1-C16 alkyl.

19. The compound according to claim 1, wherein the compound of Formula (I) is selected from the group consisting of: ,, 310888514v1- 77 -.

20. The compound according to claim 1, wherein the compound of Formula (I) is selected from the group consisting of:310888514v1- 78 - ,310888514v1- 79 -21. The compound according to claim 1 having a Formula (IA):a pharmaceutically acceptable salt or solvate thereof, wherein310888514v1- 80 - A2is optional, and if present iR1is selected from the group consisting of OH, i-Pr, C1-C6alkyl substituted with OH, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, substituted aryl, and optionally substituted heteroaryl; R2is selected from the group consisting of H, -C(O)O-t-Bu (Boc), optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R1and R2can combine with the atoms to which they are attached to form an optionally substituted heterocyclyl; R3is selected from the group consisting of H, -C(O)O-t-Bu (Boc), optionally substituted alkyl, optionally substituted aryl, and optionally substituted heteroaryl; R4is selected from the group consisting of H, cycloalkyl, optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; W is C or S; W1is optional, and if present is O or NH; n is 0, 1, or 2; m is 0 or 1; X is optional, and if present is selected from the group consisting of O, N(OR5), N(OCH2COZR6), N(NHR7), N(NHCOR8), N(NHSO2NHR9), and N(NHSO2R10); Y is optional, and if present is selected from the group consisting of O, N(OR5), N(OCH2COZR6), N(NHR7), N(NHCOR8), N(NHSO2NHR9), and N(NHSO2R10); R5is H or optionally substituted C1-C6alkyl; R6is H; R7is H or optionally substituted C1-C6 alkyl; R8is H or optionally substituted C1-C6alkyl; R9is H or optionally substituted C1-C6alkyl; R10is H or optionally substituted C1-C6 alkyl; Z is O or NH; and is an optionally present double bond, 310888514v1- 81 - with the proviso that i) when R1is CH2OH, A is, W1is absent, and R4is H, C1-C12alkyl, or C1-C12alkyl substituted with OH, then X is not O, N(OH), or N(OMe); ii) when m is 0, then R1is not OH; and iii) the compound is not.

22. The compound according to claim 1 having a Formula (IB):A2is optional, and if present iR1is CH2OH or CH(CH3)OH; R2is H; or R1and R2can combine to formR3is H; R4is selected from the group consisting of H, cycloalkyl, and C1-C12 alkyl; W is C; W1is optional, and if present is O or NH; n is 0, 1; X is optional, and if present is O, =N-OH, =N-NH2; and is an optionally present double bond, 310888514v1- 82 - with the proviso that i) when R1is CH2OH, W1is absent, and R4is H or C1-C12alkyl, then X is not O and ii) the compound is not.

23. The compound according to claim 22, wherein the compound of Formula ,.

24. A compound of Formula (II): 310888514v1- 83 -a pharmaceutically acceptable salt or solvate thereof, wherein Z1is O, NH, or CH2; and R´is C1-C30alkyl.

25. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1-24 and a pharmaceutically acceptable carrier.

26. A method of treating a fungal infection in a subject, said method comprising: administering to the subject in need thereof the compound according to any one of claims 1-24.

27. A method of treating a fungal infection in a subject, said method comprising: administering to the subject in need thereof a combination therapeutic comprising: (i) the compound according to any one of claims 1-24; and (ii) an antifungal agent.

28. The method according to claim 27, wherein the fungal infection is resistant to treatment using the antifungal agent alone.

29. The method according to claim 27, wherein the antifungal agent is administered in an amount that is less than a therapeutically effective amount needed to treat the fungal infection.

30. A method of inhibiting the growth of yeast types of fungi or filamentous types of fungi, said method comprising: contacting yeast types of fungi or filamentous types of fungi with the compound according to any one of claims 1-24 under conditions effective to inhibit the growth of yeast types of fungi or filamentous types of fungi. 310888514v1- 84 - 31. A method of inhibiting the growth of yeast types of fungi or filamentous types of fungi, said method comprising: contacting yeast types of fungi or filamentous types of fungi with a combination therapeutic comprising: (i) the compound according to any one of claims 1-24; and (ii) an antifungal agent.

32. The method according to claim 30 or 31, wherein the yeast types of fungi are selected from a species of Candida, Cryptococcus, and combinations thereof.

33. The method according to claim 30 or 31, wherein the filamentous types of fungi are selected from a species Aspergillus.

34. The method according to any one of claims 25-33, wherein the antifungal agent is selected from an azole, polyene, echinocandin, orotomide, or combinations thereof.

35. The method according to claim 34, wherein the antifungal agent is an azole selected form the group consisting of allylamines, polyenes, echinocandins, azoles, and orotomides.

36. The method according to any one of claims 26-29, wherein said administering is carried out intramuscularly, intravenously, subcutaneously, orally, pulmonary, intrathecally, topically, or intranasally.

37. The method according to any one of claims 26-29, wherein the subject is a mammal.

38. The method according to claim 37, wherein the subject is a human.

39. The method according to any one of claims 26-29, wherein the fungal infection is caused by Cryptococcus neoformans, Candida auris (C.au), Aspergillus fumigatus, Candida albicans, Nakaseomyces glabrata (Candida glabrata), Histoplasma spp., eumycetoma causative agents, Mucorales, Fusarium spp., Candida tropicalis, Candida Parapsilosis (C.Para), Candida Albicans (C.Albi), Scedosporium spp., Lomentospora prolificans, Coccidioides spp., 310888514v1- 85 - Pichia kudriavzeveii (Candida krusei), Cryptococcus gattii, Cryptococcus Neoformans (C. Neo), Talaromyces marneffei, Pneumocystis jirovecii, or Paracoccidioides spp.

40. The method according to any one of claims 26-29, wherein the fungal infection is selected from the group consisting of head ringworm, body ringworm, foot ringworm, onychomycosis, perionychomycosis, pityriasis versicolor, phlegm, vaginal candidiasis, airway candidiasis, biliary tract Candidiasis, esophageal candidiasis, urinary tract candidiasis, systemic candidiasis, mucocutaneous candidiasis, aspergillosis, mucormycosis, paracoccidioidomycosis, North American blastosis, histoplasmosis, coccidioidomycosis, sporotrichosis, and fungal sinusitis.

41. A combination therapeutic comprising: (i) a compound according to any one of claims 1-24; and (ii) an antifungal agent.

42. The combination therapeutic according to claim 41, wherein the antifungal agent is an azole, polyene, echinocandin, or orotomide.

43. The combination therapeutic according to claim 42, wherein the azole antifungal agent is selected form the group consisting of allylamines, polyenes, echinocandins, azoles, and orotomides. 310888514v1

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