WO2018106571A1

WO2018106571A1 - Antifungal compounds and methods

Info

Publication number: WO2018106571A1
Application number: PCT/US2017/064435
Authority: WO
Inventors: Kevin Duane BUNKER; Joseph Robert PINCHMAN
Original assignee: Kalyra Pharmaceuticals, Inc.
Priority date: 2016-12-06
Filing date: 2017-12-04
Publication date: 2018-06-14

Abstract

Compounds of the Formulae (I) and (II) as described herein, or pharmaceutically acceptable salts thereof, are described, along with pharmaceutical compositions comprising such compounds, salts or combinations thereof, as well as methods for using them to make compounds of the Formula (Illa) and/or (Illb), and/or other compounds of the Formulae (I) and (II). Such compounds, salts and compositions are useful for inhibiting fungal growth. For example, in an embodiment, fungal infections can be treated by administering effective amounts of such compounds, salts and/or compositions to a subject in need thereof.

Description

ANTIFUNGAL COMPOUNDS AND METHODS

RELATED APPLICATION INFORMATION

[0001] This application claims priority to U.S. provisional application Serial No. 62/430,534, filed December 6, 2016, which is hereby incorporated herein by reference in its entirety.

Field

[0002] The present application relates to antifungal compounds, processes of making them, and methods of using them to treat fungal infections.

Description

[0003] Amphotericin B (AmB) is a potent anti-fungal compound having the following chemical structure:

[0004] AmB has been used for treating severe fungal infections for over half a century. AmB is an especially valuable treatment for severe fungal infections because it is effective against a wide variety of fungi, and fungal pathogens have been relatively unsuccessful at developing resistance to it. However, despite its potency and ability to evade the development of resistance, the use of AmB is often precluded due to its highly toxic side effects including nephrotoxicity, hepatoxicity, and anemia-related symptoms. There have been many attempts to reduce toxicity while retaining therapeutic effectiveness. See WO 2014165676, WO 2015054148, WO 2015190587, WO 2016168568 and Stephen A Davis et al., "Nontoxic antimicrobials that evade drug resistance," Nature Chemical Biology (June 1 2015). Thus, there remains a need for better tolerated compounds and methods of treatment for fungal infections that are therapeutically effective.

SUMMARY

[0005] An embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Formula (I) has the structure:

Formula (I)

[0006] wherein R¹ is unsubstituted C_1-3 alkyl, R² is hydrogen or a first protecting group, R³ is hydrogen, an unsubstituted C_1-6 alkyl, a substituted C_1-6 alkyl, an optionally substituteCd_3-7 cycloalkyl, an optionally substituted CH2-aryl, an optionally substituted - CFb-heteroaryl, or an optionally substituted monocyclic heterocyclyl, and R⁴ is hydrogen or a second protecting group.

[0007] Another embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Formula (II) has the structure:

[0008] wherein R¹ is unsubstituted C_1-3 alkyl and R³ is hydrogen, an unsubstituted C_1-6 alkyl, a substituted C_1-6 alkyl, an optionally substituted C_3-7 cycloalkyl, an optionally substituted CH₂-aryl, an optionally substituted -CH₂-heteroaryl, or an optionally substituted monocyclic heterocyclyl.

[0009] An embodiment provides a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0010] An embodiment provides a method of inhibiting the growth of a fungus, comprising contacting the fungus with an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof

[0011] An embodiment provides a method of inhibiting the growth of a fungus, comprising contacting the fungus with an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0012] An embodiment provides a method of treating a fungal infection, comprising identifying a subject in need thereof and administering to said subject an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof. [0013] An embodiment provides a method of treating a fungal infection, comprising contacting the fungus with an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0014] An embodiment provides a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, for use in the treatment and/or diagnosis of a fungal infection.

[0015] An embodiment provides a pharmaceutical composition for use in the treatment and/or diagnosis of a fungal infection, wherein the pharmaceutical composition comprises an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0016] Embodiments of compounds of Formula (I) and/or (II) and/or salts thereof are useful as starting materials or intermediates for the preparation of other compounds, such as compounds of Formula (Ilia) and/or (IIIb), and/or pharmaceutically acceptable salts thereof, as described below. An embodiment provides a process of making a compound of Formula (Ilia) and/or (IIIb) using a compound of Formula (I) and/or (II) as a starting material or intermediate. In various embodiments, the process is an acylation process, a reductive animation process or an alkylation process.

[0017] These and other embodiments are described in greater detail below.

DRAWINGS

[0018] FIG. 1A illustrates the chemical structure of Compound 1.

[0019] FIG. IB illustrates a reaction scheme for making Compound 1.

[0020] FIG. 2A illustrates the chemical structure of Compound 2.

[0021] FIG. 2B illustrates a reaction scheme for making Compound 2.

[0022] FIG. 3 A illustrates the chemical structure of Compound 3.

[0023] FIG. 3B illustrates a reaction scheme for making Compound 3.

[0024] FIG. 4 illustrates the chemical structure of Compound 4.

[0025] FIG. 5 illustrates the chemical structure of Compound 5. [0026] FIG. 6 illustrates a reaction scheme for using Compound 3-1 to make other compounds.

[0027] FIG. 7A illustrates an acylation process for making a compound of Formula (Ilia) using a compound of Formula (I).

[0028] FIG. 7B illustrates an acylation reaction scheme using Compound 1-4 as a starting material.

[0029] FIG. 8 illustrates a reductive animation process for making a compound of Formula (IIIb) using a compound of Formula (I).

[0030] FIG. 9 illustrates an alkylation process for making a compound of Formula (IIIb) using a compound of Formula (I).

DETAILED DESCRIPTION

Definitions

[0031] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0032] Whenever a group is described as being "optionally substituted" that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being "unsubstituted or substituted" if substituted, the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated "optionally substituted" or "substituted" group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, an amino, a mono-substituted amino group (e.g., a C_1-6 alkylamino group) and a di-substituted amino group (e.g., a di-C_1-6 alkylamino group).

[0033] As used herein, "Ca to Cb" (or Ca-b) in which "a" and "b" are integers refer to the number of carbon atoms in a group. The indicated group can contain from "a" to "b", inclusive, carbon atoms. Thus, for example, a "C₁ to C₃ alkyl" group (or C_1-3 alkyl group) refers to all alkyl groups (both linear and branched) having from 1 to 3 carbons, that is, CH₃-, CH₃CH_2-, CH₃CH₂CH₂-, and (CH₃)₂CH-. If no "a" and "b" are designated, the broadest range described in these definitions is to be assumed.

[0034] As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of straight chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl. Examples of branched alkyl groups include iso-propyl, s-butyl, iso-butyl, and t-butyl. The alkyl group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as "1 to 6" refers to each integer in the given range; e.g., "1 to 6 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, S carbon atoms or 6 carbon atoms).

[0035] As used herein, "cycloalkyl" refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s), 3 to 7 atoms in the ring(s), 3 to 6 atoms in the ring(s) or 3 to 5 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted.

[0036] As used herein, the term "fused" refers to a connectivity between two rings in which two adjacent atoms sharing at least one bond (saturated or unsaturated) are common to the rings. For example, in the following structure, rings A and B are fused

Examples of fused ring structures include, but are not limited to, decahydronaphthalene, lH-indole, quinolone, chromane, bicyclo[2.1.Ojpentane and 6,7,8,9- tetrahydro-5H-benzo[7]annulene. [0037] As used herein, the term "bridged" refers to a connectivity wherein three

or more atoms are shared between two rings. The following structures

are examples of "bridged" rings because the indicated atoms are shared between at least two rings. Examples of bridged ring structures include, but are not limited to, bicyclo[l.l. l]pentane, 2-oxabicyclo[l.l.l]pentane, 5-azabicyclo[2.1.1]hexane, 6- azabicyclo[3.1.1]heptane, adamantane and norbornane.

[0038] As used herein, the term "spiro" refers to a connectivity between two rings

wherein the rings have only one atom in common. For example, in the structure

rings C and D are joined by a spiro connection. Examples of spiro connected ring structures include, but are not limited to, spiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxa-6- azaspiro[3.3]heptane, spiro[4.5]decane and 2,6-dioxaspiro[3.3]heptane.

[0039] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group, or a C₆ aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.

[0040] As used herein, "heteroaryr refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2, 3, 4 or 5 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term "heteroaryl" includes fused ring systems. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted.

[0041] As used herein, "heterocyclyl" or "heteroalicyclyl" refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic and tricyclic ring systems wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio- systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. Additionally, any nitrogens in a heteroalicyclic may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples of such "heterocyclyl" or "heteroalicyclyl" groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4- oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro- 1 ,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-l,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline and/or 3,4-methylenedioxyphenyl). Examples of bridged heterocyclic compounds include, but are not limited to, l,4-diazabicyclo[2.2.2]octane and 1,4- diazabicyclo[3.1.1]heptane. Examples of spiro-connected heterocyclic compounds include, but are not limited to, 2-azaspiro[3,3]heptane, 2,6-diazaspiro[3,3]heptane, and 2-oxa-6- azaspiro[3 ,3 ]heptane.

[0042] As used herein, "aralkyl" and "aryl(alkyl)" refer to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to CH2- aryl (e.g., benzyl), 2-phenylalkyl, 3-phenylalkyl and naphthylalkyl.

[0043] As used herein, "heteroaralkyl" and "heteroaryl(alkyl)" refer to a heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to -CH₂-heteroaryl, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl and imidazolylalkyl and their benzo-fused analogs.

[0044] The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2,3- dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, trifluoroacetic, benzoic, salicylic, 2- oxopentanedioic, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine. For compounds of Formula (I), those skilled in the art understand that when a salt is formed by protonation of a nitrogen-based group (for example, NH2), the nitrogen-based group can be associated with a positive charge (for example, NH2 can become Ni¾⁺) and the positive charge can be balanced by a negatively charged counterion (such as CI^").

[0045] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition, it is understood that in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.

[0046] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0047] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise. [0048] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0049] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.

[0050] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term 'including' should be read to mean 'including, without limitation,' 'including but not limited to,' or the like; the term 'comprising' as used herein is synonymous with 'including,' 'containing,' or 'characterized by,' and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term 'having' should be interpreted as 'having at least;' the term 'includes' should be interpreted as 'includes but is not limited to;' the term 'example' is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like 'preferably,' 'preferred,' 'desired,' or 'desirable,' and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term "comprising" is to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition or device, the term "comprising" means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. Likewise, except in the claims, a group of items linked with the conjunction 'and' should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as 'and/or' unless the context indicates otherwise. Similarly, except in the claims, a group of items linked with the conjunction 'or' should not be read as requiring mutual exclusivity among that group, but rather should be read as 'and/or' unless the context indicates otherwise.

[0051] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

Compounds

[0052] Some embodiments disclosed herein relate to compounds of the Formulae (I) and/or (II), or pharmaceutically acceptable salts thereof.

[0053] In various embodiments, the compounds of Formulae (I) and (II) are useful for ameliorating, treating and/or diagnosing a fungal infection. Additional details regarding various uses and methods of treatment are described elsewhere herein.

[0054] In various embodiments the variable R¹ in Formulae (I) and (II) is unsubstituted C_1-3 alkyl. In various embodiments the variable R² in Formula (I) is hydrogen or a first protecting group. In various embodiments the variable R³ in Formulae (I) and (II) is hydrogen, an unsubstituted C_1-6 alkyl, a substituted C_1-6 alkyl, an optionally substituted C3-7 cycloalkyl, an optionally substituted -CFfc-aryl, an optionally substituted -CHb-heteroaryl, or an optionally substituted monocyclic heterocyclyl. For example, in various embodiments the variable R³ in Formulae (I) and (II) is hydrogen or unsubstituted C_1-3 alkyl. In an embodiment, R³ in Formulae (I) and (II) is a substituted C_1-6 alkyl that is substituted with a moiety selected from the group consisting of hydroxy, alkoxy, amino,C_3-7 cycloalkyl, halogen, a mono-substituted amine, a di-substituted amine, an optionally substituted N-linked monocyclic heteroaryl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted monocyclic heterocyclyl, an optionally substituted heterocyclyl, and an optionally substituted N-linked monocyclic heterocyclyl. In various embodiments the variable R⁴ in Formula (I) is hydrogen or a second protecting group. Examples of compounds of the Formula (I) thus include compounds 1-22 having the structures summarized in Table 1, and compounds P1-P66 having the general structures summarized in Tables 2-4. Examples of compounds of the Formula (II) include compounds 1-22 having the structures summarized in Table 1.

TABLE 1 : Examples of compounds of the Formulae (T) and (ΤΓ)

[0055] In various embodiments of Formula (I), one or both of R² and R⁴ can be a protecting group. When both of R² and R⁴ are protecting groups, they can be the same or different. For example, in some embodiments one or both of R² and R⁴ can be allyloxycarbonyl (Alloc), fluorenylmethyloxycarbonyl (Fmoc) or carboxybenzyl (Cbz). In an embodiment, R² is not a silyl protecting group. In an embodiment, R⁴ is not a silyl protecting group. Those skilled in the art understand how to make and use a wide variety of protecting groups suitable for R² and R⁴, including selecting suitable protecting groups from among those described in Kocienski, P.J. Protecting Groups (3^rd Ed., Theme, 2004), and/or Wuts, P. G. M. and Greene, T.W., Greene's Protective Groups in Organic Synthesis, (4^th Ed., Wiley, 2006), which are hereby incorporated herein by reference and particularly for the purpose of describing protective groups. Methods of Making

[0056] Compounds of the Formulae (I) and (II), or pharmaceutically acceptable salts thereof, can be made in various ways by those skilled using known techniques as guided by the detailed teachings provided herein. For example, the compounds of Formulae (I) and (II) described herein can be prepared in accordance with the synthetic schemes used to prepare Compounds 1, 2 and 3 as illustrated in FIGS. IB, 2B and 3B, respectively, and the examples below.

[0057] In addition, compounds of Formulae (I) and (II) can be used as starting materials or intermediates to prepare other compounds. In an embodiment, compounds of Formulae (I) and/or (II) can be used to prepare other compounds of the Formulae (Γ) and/or (II).

[0058] For example, Figure IB and Example 1 describe the preparation of Compound 1 (a compound of Formulae (I) and (II) in which R¹ is methyl, R² is hydrogen, R³ is hydrogen, and R⁴ is hydrogen) using Compound 1-4 as a starting material (a compound of Formula (I) in which R¹ is methyl, R² is Alloc, R³ is hydrogen, and R⁴ is Alloc). As another example, Figure 2B and Example 2 describe the preparation of Compound 2 (a compound of Formulae (I) and (II) in which R¹ is methyl, R² is hydrogen, R³ is methyl, and R⁴ is hydrogen) using Compound 1-4 as a starting material, proceeding via intermediate Compound 2-1 (a compound of Formula (I) in which R¹ is methyl, R² is Alloc, R³ is methyl, and R⁴ is Alloc).

[0059] As another example, Figure 3B and Example 3 describe the preparation of Compound 3 (a compound of Formulae (I) and (II) in which R¹ is methyl, R² is hydrogen, R³ is ethyl, and R⁴ is hydrogen) using the Compound 1-4 as a starting material. The preparation of Compound 3 from Compound 1-4 proceeds via intermediate Compound 3-1 (a compound of Formula (J) in which R¹ is methyl, R² is Alloc, R³ is ethyl, and R⁴ is Alloc).

[0060] In addition, compounds of Formula (I) can be used as starting materials or intermediates to prepare other compounds. For example, Figure 6 and Example 6 describe the preparation of Compound 3-3 via intermediate Compound 3-2, by a process in which Compound 3-1 (a compound of Formula (I) in which R¹ is methyl, R² is Alloc, R³ is ethyl, and R⁴ is Alloc) is used as a starting material. [0061] An embodiment provides an acylation process, comprising reacting a compound of Formula (l) with a carboxylic acid of formula R⁵-C02H under acylation conditions selected to form a compound of Formula (Ilia), as illustrated in FIG. 7A.

Formula (IIIa)

[0062] In various embodiments of the acylation process, R¹, R², R³ and R⁴ in Formula (I) are defined as described elsewhere herein for Formula (I). In an embodiment of an acylation process, R¹ is an unsubstituted C_1-3 alkyl, R² is a protecting group, R³ is hydrogen and R⁴ is a protecting group. In various embodiments, R⁵ in Formula (Ilia) and in the formula R⁵-C02H are selected from the group consisting of unsubstituted C_1-6 alkyl, a substituted C_1-6 alkyl, an optionally substituteCd_3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl. In an embodiment, R⁵ in Formula (Ilia) and in the formula R⁵-CChH is a substituted d-6 alkyl that is substituted with a moiety selected from the group consisting of hydroxy, alkoxy, aminoC, _3-7 cycloalkyl, halogen, a mono-substituted amine, a di-substituted amine, an optionally substituted N-linked monocyclic heteroaryl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted monocyclic heterocyclyl, an optionally substituted heterocyclyl, and an optionally substituted N-linked monocyclic heterocyclyl. An example of such an acylation process is described in Example 7 and Fig. 7B.

[0063] In various embodiments, acylation conditions selected to form a compound of Formula (Ilia) include conducting the reaction of the compound of Formula (I) with the carboxylic acid of formula R'-CChH in the presence of an organic solvent suitable for acylation reactions, such as a polar organic solvent or a non-polar organic solvent. Such solvents are known to those skilled in the art, and include, for example, dichloromethane (DCM), tetrahydrofuran (THF), and dimethylformamide (DMF). In various embodiments, acylation conditions selected to form a compound of Formula (Ilia) include conducting the reaction of the compound of Formula (I) with the carboxylic acid of formula R⁵-C02H in the presence of an acylating agent that promotes acylation reactions. Such acylating agents are known to those skilled in the art and include, for example, l-[bis(dimethylamino)methylene]- lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxidhexafluorophosphate) (HATU), diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), N-(3- Dimethylaminopropyl)-N'-ethylcarbodiimide ^. HC1 (EDC · HC1), 1,1'-Carbonyldiimidazole, benzotriazol-l-yloxy-tripyrrolidino-phosphonium hexafluorophosphate (PyBOP^®), 7-Aza- benzotriazol-l-yloxy-tripyrrolidinophosphonium hexafluorophosphate (PyAOP), 2-(lH- Benzotriazol-l-yl)-N,N,N',N'- tetramethylaminium tetrafluoroborate (TBTU), 2-(lH- Benzotriazol-l-yl)-N,N,N',N'- tetramethylaminium hexafluorophosphate (HBTU), 2- Propanephosphonic acid anhydride (T3P), thionyl chloride, and oxalyl chloride. In various embodiments, acylation conditions selected to form a compound of Formula (Ilia) include conducting the reaction of the compound of Formula (I) with the carboxylic acid of formula R⁵-C02H in the presence of a base that promotes acylation reactions. Such bases are known to those skilled in the art. In an embodiment, the base is an inorganic base. Such inorganic bases are known to those skilled in the art and include, for example, Na2C03, K2CO3, L12CO3, CS2CO3, KOtBu, K2HPO4, Na2HP04, Na3P0₄, K3PO4, NaOAc, KOAc, CsOAc, LiOAc, NaHCCb, KHCO3, CsHC03 and L1HCO3. In an embodiment, the base is an organic base. Such organic bases are known to those skilled in the art and include, for example, triethylamine (TEA), pyridine, N,N-diisopropylethylamine (DIPEA), piperidine, morpholine, Proton Sponge™, 4-(Dimethylamino)pyridine, and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).

[0064] An embodiment provides a reductive amination process, comprising reacting a compound of Formula (I) with an aldehyde of formula R⁵-COH under conditions selected to form a compound of Formula (IIIb), as illustrated in FIG. 8.

[0065] In various embodiments of the reductive amination process, R¹, R², R³ and R⁴ in Formula (I) are defined as described elsewhere herein for Formula (I). In an embodiment of the reductive amination process, R¹ is an unsubstituted C_1-3 alkyl, R² is a protecting group, R³ is hydrogen and R⁴ is a protecting group. In various embodiments, R⁵ in Formula (IIIb) and in the formula R⁵-COH are selected from the group consisting of unsubstituted C_1-6 alkyl, a substituted C_1-6 alkyl, an optionally substitute C_3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl. In an embodiment, R⁵ in Formula (IIIb) and in the formula R⁵- COH is a substituted C_1-6 alkyl that is substituted with a moiety selected from the group consisting of hydroxy, alkoxy, amino, C_3-7 cycloalkyl, halogen, a mono-substituted amine, a di-substituted amine, an optionally substituted N-linked monocyclic heteroaryl, an optionally substituted aryl, an optionally substituted monocyclic heterocyclyl, an optionally substituted heterocyclyl, and an optionally substituted N-linked monocyclic heterocyclyl.

[0066] In various embodiments, reductive amination conditions selected to form a compound of Formula (Illb) include conducting the reaction of the compound of Formula (I) with the aldehyde of formula R⁵-COH in the presence of a solvent suitable for reductive amination reactions, such as a polar aprotic solvent. Such solvents are known to those skilled in the art, and include, for example, chloroform, 1,2-dichloroethane (DCE), tetrahydrofuran (THF), N^V-dimethylformamide (DMF), and acetonitrile. In various embodiments, reductive amination conditions selected to form a compound of Formula (IIIb) include conducting the reaction of the compound of Formula (I) with the aldehyde of formula R⁵-COH in the presence of a solvent suitable for reductive amination reactions, such as a polar protic solvent. Such solvents are known to those skilled in the art, and include, for example, methanol (MeOH). In various embodiments, reductive amination conditions selected to form a compound of Formula (Illb) include conducting the reaction of the compound of Formula (I) with the aldehyde of formula R⁵-COH in the presence of an acid that promotes reductive amination reactions. Such acids are known to those skilled in the art and include, for example, acetic acid and hydrochloric acid. In various embodiments, reductive amination conditions selected to form a compound of Formula (Illb) include conducting the reaction of the compound of Formula (I) with the aldehyde of formula R⁵-COH in the presence of a reducing agent that promotes reductive amination reactions. Such reducing agents are known to those skilled in the art and include, for example, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, triethylsilane, and phenyl silane.

[0067] A compound of formula (IIIb) can also be prepared from a compound of Formula (I) via an alkylation process as illustrated in FIG. 9. For example, an embodiment provides an alkylation process, comprising reacting a compound of Formula (I) with a compound of formula R⁵-CH₂-X under conditions selected to form a compound of Formula (IIIb). In various embodiments, R¹, R², R³ and R⁴ in Formula (I) are defined as described elsewhere herein for Formula (I). In an embodiment of the alkylation process, R¹ is an unsubstituted C_1-3 alkyl, R² is a protecting group, R³ is hydrogen and R⁴ is a protecting group. In various embodiments, R⁵ in Formula (Illb) and in the formula R⁵-CH₂-X are selected from the group consisting of unsubstituted C_1-6 alkyl, a substituted C_1-6 alkyl, an optionally substitutedC_3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl. In an embodiment, R⁵ in Formula (IIIb) and in the formula R⁵-CH₂-X is a substituted C_1-6 alkyl that is substituted with a moiety selected from the group consisting of hydroxy, alkoxy, amino,C_3-7 cycloalkyl, halogen, a mono-substituted amine, a di-substituted amine, an optionally substituted N-linked monocyclic heteroaryl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted monocyclic heterocyclyl, an optionally substituted heterocyclyl, and an optionally substituted N-linked monocyclic heterocyclyl. [0068] In various embodiments, X in the formula R⁵-CH₂-X is a halide or pseudohalide. For example, in an embodiment of the alkylation process, X is a halide (such as chloride, bromide or iodide) or a pseudohalide (such as triflate, mesylate, tosylate, nitrophenyl sulfonate, bromophenyl sulfonate, benzene sulfonate or phosphate), R¹ is an unsubstituted C_1-3 alkyl, R² is a protecting group, R³ is hydrogen, R⁴ is a protecting group, and R⁵ is selected from the group consisting of an unsubstituted C_1-6 alkyl, a substituted C_1-6 alkyl, an optionally substituteCd_3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.

[0069] In various embodiments, alkylation conditions selected to form a compound of Formula (IIIb) include conducting the reaction of the compound of Formula (I) with the compound of formula R⁵-CH₂-X in the presence of a solvent suitable for alkylation reactions, such as an organic solvent. Such solvents are known to those skilled in the art, and include, for example, N,N-dimethylformamide (DMF), N-methyl pyrrolidinone, tetrahydrofuran, methylene chloride, and 1,2-dichloroethane. In various embodiments, alkylation conditions selected to form a compound of Formula (IIIb) include conducting the reaction of the compound of Formula (I) with the compound of formula R⁵-CH₂-X in the presence of a base that promotes alkylation reactions. Such bases are known to those skilled in the art. In an embodiment, the base is an inorganic base, for example, Na₂CO₃, K2CO3, L12CO3, CS2CO3, KOtBu, K₂HPO₄, Na₂HPO₄, Na₂HPO₄ K3PO4, NaOAc, KOAc, CsOAc, LiOAc, NaHCO₃ , KHCO3, CsHCO3 and L1HCO3. In an embodiment, the base is an organic base. Such organic bases are known to those skilled in the art and include, for example, triethylamine (TEA), pyridine, N,N-diisopropylethylamine (DIPEA), piperidine, morpholine, Proton Sponge™, 4-(Dimethylamino)pyridine, and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).

Uses and Methods of Treatment

[0070] As described herein, one or more compounds of Formulae (I), (II), (ma) and/or (Illb), or compounds obtained by deprotection of compounds of Formulae (I), (II), (ma) and/or (IIIb), or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as described herein, can be used to inhibit the growth of a fungus. Growth of a fungus can be inhibited by contacting the fungus with an effective amount of at least one of the compounds described herein, or pharmaceutically acceptable salts thereof. Such contacting of the one or more compounds, or pharmaceutically acceptable salts thereof, can take place in various ways and locations, including without limitation away from a living subject (e.g., in a laboratory, diagnostic and/or analytical setting) or in proximity to a living subject (e.g., within or on an exterior portion of an animal, e.g., a human). For example, an embodiment provides a method of treating a fungal infection, comprising identifying a subject in need thereof and administering to said subject an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, as described elsewhere herein.

[0071] As described herein, compounds of Formulae (I), (II), (IIIa) and/or (IIIb), or compounds obtained by deprotection of compounds of Formulae (I), (II), (Ilia) and/or (Illb), or a pharmaceutically acceptable salt thereof, can be administered to such subjects by a variety of methods. In any of the methods described herein, administration can be by various routes known to those skilled in the art, including without limitation oral, intravenous, intramuscular, topical, systemic, and/or intraperitoneal administration to a subject in need thereof.

[0072] As used herein, the terms "treat," "treating," "treatment," "therapeutic," and "therapy" do not necessarily mean total cure or abolition of the fungal infection. Any alleviation of any undesired signs or symptoms of the fungal infection, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject's overall feeling of well-being or appearance.

[0073] The terms "therapeutically effective amount" and "effective amount" are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, a therapeutically effective amount of compound can be the amount needed to prevent, alleviate or ameliorate symptoms of the fungal infection or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the fungal infection being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

[0074] The amount of the compound of Formulae (I), (II), (Ida) and/or (IIIb), or compounds obtained by deprotection of compounds of Formulae (I), (II), (Ilia) and/or (IIIb), or a pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature and/or symptoms of the fungal infection being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges described herein in order to effectively and aggressively treat particularly aggressive fungal infections.

[0075] In general, however, a suitable dose will often be in the range of from about 0.0S mg/kg to about 10 mg/kg. For example, a suitable dose may be in the range from about 0.10 mg/kg to about 7.5 mg/kg of body weight per day, such as about 0.15 mg/kg to about 5.0 mg/kg of body weight of the recipient per day, about 0.2 mg/kg to 4.00 mg/kg of body weight of the recipient per day. The compound may be administered in unit dosage form; for example, containing 1 to 200 mg, 10 to 100 mg or 5 to 50 mg of active ingredient per unit dosage form.

[0076] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.

[0077] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies and in vitro studies. For example, useful dosages of a compound of Formulae (I), (II), (Ma) and/or (Illb), or compounds obtained by deprotection of compounds of Formulae (I), (II), (Ilia) and/or (IIIb), or pharmaceutically acceptable salts thereof, can be determined by comparing their in vitro activity and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as Amphotericin B.

[0078] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vivo and/or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0079] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the fungal infection to be treated and to the route of administration. The severity of the fungal infection may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0080] Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.

Pharmaceutical Compositions

[0081] Some embodiments described herein relate to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (e.g., a compound of Formulae (I), (II), (Ilia) and/or (IIIb), or compounds obtained by deprotection of compounds of Formulae (I), (II), (Ilia) and/or (Mb), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0082] The term "pharmaceutical composition" refers to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.

[0083] The term "physiologically acceptable" defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound nor cause appreciable damage or injury to an animal to which delivery of the composition is intended.

[0084] As used herein, a "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject. [0085] As used herein, a "diluent" refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.

[0086] As used herein, an "excipient" refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A "diluent" is a type of excipient.

[0087] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0088] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0089] Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.

[0090] One may also administer the compound in a local rather than systemic manner, for example, via injection or implantation of the compound directly into the affected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory infection may be desirable.

[0091] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

EXAMPLES

[0092] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.

COMPOUNDS

[0093] The compounds of Formulae (I), (II), (IIIa) and (IIIb) described herein can be prepared in various ways, using techniques known to those skilled in the art as guided by the detailed teachings provided herein. For example, the compounds of Formulae (I) and (II) described herein can be prepared in accordance with the synthetic scheme used to prepared Compounds 1, 2 and 3 as described in Examples 1, 2 and 3 below, respectively, which are exemplary and can be used as a starting point to prepare a large number of additional compounds beyond those specifically described. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise routes based on the disclosures herein; all such modifications and alternate routes are contemplated.

EXAMPLE 1

[0094] Compound 1 (FIGURE 1 A) was prepared as follows (Figure IB): Step 1 : To a stirred solution of Amphotericin B (25.0 g, 27.05 mmol) in DMF: MeOH (2:1, 750 ml) and pyridine (25 ml, 308.4 mmol) was added alloc-succinimide (15.08 g, 75.75 mmol) at room temperature. After 16 h, the reaction mixture was poured into cold Et20. The resulting solid was filtered and dried under reduced pressure to provide a yellow solid. The solid compound was washed with diethyl ether (5 x 100 mL) to afford Compound 1-1 as a yellow solid. Compound 1-1 analysis: LC/MS (ESI) m/z 1006.4 [M-H]-.

[0095] Step 2: To a solution of Compound 1-1 (4.0 g, 3.97 mmol) in a mixture of THF: MeOH (1:1 160 mL) was added camphor sulfonic acid (553.3 mg, 2.38 mmol) at 0 °C. The reaction mixture was stirred for 45 min and then quenched with triethylamine (0.335 ml, 2.38 mmol) at 0 °C. The reaction was filtered and the filtrate was concentrated to roughly half the starting volume and resulting solution was poured into cold diethyl ether to afford a yellow precipitate. The solid was filtered to afford compound 1-2 as a yellow solid. Compound 1-2 analysis: LC/MS (ESI) m/z 1020.7 [M-H]^".

[0096] Step 3 : To a solution of Compound 1-2 (20.0 g, 19.56 mmol) in DMF (220 ml) was added DIPEA (6.9 ml, 39.1 mmol) at room temperature. The reaction mixture was cooled to 0 °C and allyloxycarbonyl chloride (2.36 g, 19.56 mmol) was added slowly drop- wise at 0 °C. The reaction mixture was maintained at an internal temperature below 4 °C and stirred for 3 h at 0 °C. The reaction mixture was then allowed to warm to room temperature and stirring was continued for 16 h. The reaction mixture was poured into cold Et₂O (5 L) and the precipitate was filtered to afford 14 g (64.5%) of crude compound 1-3 as a yellow solid. Compound 1-3 analysis: LC/MS (ESI) m/z 1104.7 [M-H]^".

[0097] Step 4: To a solution of Compound 1-3 (5.0 g, 0.90 mmol) in DMA (92 ml), was added 3 A molecular sieves (500 mg), DIPEA (1.20 ml, 6.89 mmol) followed by DPPA (1.28 ml, 5.97 mmol) at room temperature. The reaction mixture for 2 h and then heated to 50 °C. After 2 h the reaction mixture was cooled to room temperature poured into a solution of Et20:hexanes (7:1, 1.60 L). The reaction mixture was filtered over Celite® 545 and the collected solid was washed with Et20:hexanes (7:1, 200 mL). The crude isocyanate was then dissolved in THF (200 mL) and then concentrated to approximately 60 mL. The crude isocyanate solution was then added dropwise to a rapidly stirring solution of triethylamine (32.0 mL, 230.0 mmol) in THF: H₂O (1:1, 120mL) over 20 min. The reaction was stirred for an additional 30 minutes at rt after which the reaction was concentrated in vacuo using CH3CN to aid in the removal of water from the reaction mixture. The crude product was purified by reverse-phase column chromatography (ISCO RediSepRf Gold C18 275 g, 20:80 to 45:55 0.1% HCO2H (aq): MeCN) to afford compound 1-4 as a yellow solid (730 mg, 15%). LC/MS (ESI) m/z 1099.3 [M+Na]^÷.

[0098] Step 5: To a solution of Compound 1-4 (127 mg, 0.12 mmol) in DMF (3.37 mL) was added acetic acid (20.3 uL, 0.35 mmol) and PdCh(PPh3)2 (16.6 mg, 0.024 mmol) at room temperature. The reaction was cooled to -10°C and treated with wBmSn (159 uL, 0.59 mmol) dropwise over 5 min. After 30 min, additional nBu₃Sn (159 uL, 0.59 mmol) was added dropwise. After 20 min, the reaction mixture was added into EtaO (200 mL) and the reaction mixture was filtered over Celite® 545. The collected solid was washed with Et20 (50 mL). The crude product was then dissolved in THF:MeOH (1:1, 200 mL) and concentrated in vacuo. The crude product was purified by HPLC (PFP, 5μ, 95:5 to 0:100 lOmM NH₄OAC (aq): CH3CN) to afford Compound 1 (29 mg, 27% yield) as a yellow solid. Compound 1 analysis: LC/MS (ESI) m/z 931.3 [M+Na]⁺.

EXAMPLE 2

[0099] Compound 2 (FIGURE 2A) is prepared as follows (FIGURE 2B):

[0100] Step 1 : A solution of Compound 1-4 in DMF is treated with triethylamine followed by methyl iodide (1 eq.). After the reaction is complete, the reaction mixture is concentrated under vacuum and purified by column chromatography to provide Compound 2-1.

[0101] Step 2: To a solution of Compound 2-1 in DMF is added acetic acid (3 eq.) and PdCh(PPh3)2 (0.2 eq.) at room temperature. The reaction is cooled to -10°C and treated with nBmSn (5 eq.) dropwise over 5 min. After 30 min, the reaction mixture is added into EI2O and the reaction mixture is filtered over Celite® 545. The collected solid is washed with EtaO and then dissolved in THF:MeOH and concentrated in vacuo. The crude product is purified by HPLC to afford Compound 2.

EXAMPLE 3

[0102] Compound 3 (FIGURE 3A) can be prepared using either Method 1 described in Example 2 (except that ethyl iodide is used in place of methyl iodide) and/or Method 2.

[0103] Method 2 (FIGURE 3B) Step 1: A solution of acetaldehyde (1.2 eq) and compound 1-4 in DMF:MeOH (1 :1) is stirred at room temperature for 3 hours and then treated with NaBH₃CN (3 eq.). The reaction mixture is stirred overnight and then poured into Et20 and filtered over Celite® 545. The collected solid is then dissolved in THF/MeOH and concentrated in vacuo to provide crude Compound 3-1.

[0104] Step 2: To a solution of Compound 3-1 in DMF is added acetic acid (3 eq.) and PdCh(PPh3)2 (0.2 eq.) at room temperature. The reaction is cooled to -10°C and treated with wBmSn (5 eq.) dropwise over 5 min. After 30 min, the reaction mixture is added into Et₂O and the reaction mixture is filtered over Celite® 545. The collected solid is washed with Et₂O and then dissolved in THF:MeOH and concentrated in vacuo. The crude product is purified by HPLC to afford Compound 3.

EXAMPLE 4

[0105] Compound 4 (FIGURE 4) can be prepared using either Method 1 described in Example 2 (except that propyl iodide is used in place of methyl iodide) and/or Method 2 described in Example 3 using propionaldehyde in place of acetaldehyde.

EXAMPLE 5

[0106] Compound 5 (FIGURE 5) is prepared as described in Example 1 except that ethanol is used in place of methanol in Step 2.

EXAMPLE 6

[0107] Step 1 (FIGURE 6): A solution of compound 3-1 in 2:2:1 CH3CN:THF:H20 is cooled to 0 °C and treated with CSA (1 eq.). The reaction is warmed to 35 °C and stirred for 50 min at which time triethylamine (2.1 eq.) is added. The reaction is concentrated in vacuo and the crude product is purified by RP-HPLC to provide Compound 3-2.

[0108] Step 2 (FIGURE 6): To a solution of compound 3-2 in DMF is treated with Pd(PPh3)4 (0.1 eq.) followed by morpholine (25 eq.). The reaction is stirred for 16 h and then poured into Et₂O and filtered over Celite® 545. The collected solid is washed with Et20, dissolved in THF/MeOH, and concentrated in vacuo to provide crude Compound 3-3. The crude product is purified by RP-HPLC to afford Compound 3-3.

EXAMPLE 7

[0109] Compound 1-4 (a Compound of Formula (I)) was used as a starting material in an acylation process to prepare Compound 7-3 as follows: (Figure 7B) Step 1: To a stirred solution of acetic acid (12.8 uL, 0.22 mmol) in DMF (4 mL) was added N, N- diisopropylethylamine (117 uL, 0.67 mmol), HATU (85.0 mg, 0.22 mmol) at rt. After 90 min, the reaction mixture was cooled to 0 °C and treated with a solution of Compound 1-4 in DMF (1 mL). The reaction was warmed to rt and stirred overnight. The mixture was then poured into Et₂0 (100 mL) and filtered over Celite® 545. The collected solid was washed with Et20 and then dissolved in THF/MeOH and concentrated in vacuo to provide crude Compound 7-1. LC/MS (ESI) m/z 1141.5 [M+Na]⁺.

[0110] Step 2: To a solution of Compound 7-1 (35 mg, 31 umol) in 2:2:1 CH3CN:THF:H20 (1.56 mL) at 0 °C was added CSA (7.7 mg, 31 umol). The reaction was warmed to 35 °C and stirred for 50 min at which time triethylamine (8.8 uL, 63 umol) was added. The reaction was concentrated in vacuo and the crude product was purified by RP- HPLC to provide Compound 7-2 as a yellow solid. LC/MS (ESI) m/z 1127.5 [M+Naf.

[0111] Step 3: To a solution of Compound 7-2 (7.0 mg, 6.6 umol) in DMF (2 mL) was added Pd(PPh3)4 (2.7 mg, 2.3 umol) followed by morpholine (17.3 uL, 0.19 mmol). The reaction was stirred for 16 h and then poured into Et₂O (10 mL) and filtered over Celite® 545. The collected solid was washed with Et₂O, dissolved in THF/MeOH, and concentrated in vacuo to provide crude Compound 7-3. The crude product was purified by RP-HPLC to afford Compound 7-3 as a yellow solid. LC/MS (ESI) m/z 959.5 [M+Na]⁺. IN VITRO MIC ASSAY

[0112] The broth microdilution assay method essentially followed the procedure described by CLSI (1-3) and employed automated liquid handlers to conduct serial dilutions and liquid transfers. Automated liquid handlers included the Multidrop 384 (Labsy stems, Helsinki, Finland) and Biomek 2000 (Beckman Coulter, Fullerton CA). The wells in columns 2-12 in standard 96-well microdilution plates (Costar 3795) were filled with 150 ul of the correct diluent. These would become the 'mother plates' from which 'daughter' or test plates would be prepared. The drugs (300 uL at 40x the desired top concentration in the test plates) were dispensed into the appropriate well in Column 1 of the mother plates. The Biomek 2000 was used to make serial two-fold dilutions through Column 11 in the "mother plate". The wells of Column 12 contained no drug and were the organism growth control wells.

[0113] The daughter plates were loaded with 185 μL, per well of the appropriate test media using the Multidrop 384. The daughter plates were prepared using the Biomek FX which transferred 5 μL of drug solution from each well of a mother plate to the corresponding well of the correct daughter plate in a single step.

[0114] A standardized inoculum of each organism was prepared per CLSI methods (1-3). For yeast isolates, colonies were picked from the primary plate and a suspension was prepared to equal a 0.5 McFarland turbidity standard. Suspensions were then diluted 1:100 in RPMI 1640 medium, resulting in a final inoculum concentration of 0.5-2.5 x 103 CFU/mL per test well. For the fungal isolates, spore suspensions previously prepared in 0.85% saline and enumerated were diluted to achieve a final inoculum concentration of 0.2 - 2.5 x 104 CFU/mL per test well. Standardized inoculum suspensions were transferred to compartments of sterile reservoirs divided by length (Beckman Coulter), and the Biomek 2000 was used to inoculate all plates. Daughter plates were placed on the Biomek 2000 in reverse orientation so that plates were inoculated from low to high drug concentration. The Biomek 2000 delivered 10 uL of standardized inoculum into each well of the appropriate daughter plate for an additional 1:20 dilution. Thus, the wells of the daughter plates ultimately contained 185 of the appropriate media, 5 uL of drug solution, and 10 uL of inoculum. The final concentration of DMSO (if used as a solvent) in the test well was 2.5%.

[0115] Plates were stacked 3 high, covered with a lid on the top plate, placed into plastic bags, and incubated at 35°C for approximately 24-48 hr for all yeast isolates excluding C. neoformans (72 hr), and 48 hr for all fungal isolates excluding R oryzae (24 hr) and T. rubrum (120 hr). Plates were viewed from the bottom using a plate viewer. An un-inoculated solubility control plate was observed for evidence of drug precipitation. MICs were read where visible growth of the organism was inhibited. MECs were read where evident for Aspergillus spp. where the growth shifted to a small, rounded, compact hyphal form as compared to the hyphal growth seen in the growth control well.

TABLE 2. IN VITRO ACTIVITY AGAINST YEAST

¹ MIC reported at 24 hr, 48 hr

2

CLSI QC range shown in parenthesis

3 MIC reported at 48 hr, 72 hr

TABLE 3. IN VITRO ACTIVITY AGAINST FILAMENTOUS FUNGI

RED BLOOD CELL LYSIS ASSAY

[0116] Red blood cell (RBC) preparation: Packed defibrinated human red blood cells (Lampire Biological Laboratories, Pipersville, PA; Cat. No. 7243710; Unit No. LS 23- 80223D) were washed three times with buffer (10 mM Tris-HCl [pH 7.4], 0.9% NaCl) and resuspended to a final concentration of 3% RBCs prior to conducting the assays.

[0117] DMSO Pilot assay: Testing the compounds at high concentrations (up to 100 uM) required a final DMSO concentration of 4% in the RBC lysis assay. A pilot study was conducted to measure hemolysis in the presence of different DMSO concentrations as follows:

[0118] In general, the method described in Stasiuk, M. et al. Biochim. Biophys. Acta. 2004, 1667:215-221 was followed for the RBC lysis assay. DMSO was diluted in water to 75%, 50%, and 25% concentrations. Microfuge tubes were set up in triplicate with the volumes indicated above. Buffer (10 mM Tris-HCl [pH 7.4], 0.9% NaCl) was added to the tubes followed by the DMSO. Tubes were gently inverted 5 times. Ninety microliters of the 3% RBC preparation were added and gently inverted 5 times. The tubes were incubated for 30 min at 37°C, and centrifuged at 1,300 x g for 5 min to pellet the RBCs. Three hundred microliters of the supernatant were removed to a 96-well plate (Corning; Corning, NY; Cat. 3595; Lot No. 04115045) and the released hemoglobin was measured at A540 using a SpectraMax (Molecular Dynamics) plate reader.

[0119] 100% DMSO stock solutions (7680 ug/mL) of amphotericin B and Compound 1 were prepared and each stock solution was diluted to 7.5 mM solution in 100% DMSO. The 7.5 mM stock was used for all subsequent dilutions. For Compound 1 a total of 17 different final compound concentrations were tested in duplicate as follows: 300, 200, 100, 80, 60, 40, 30, 20, 15, 10, 8, 6, 4, 3, 2, and 1 uM. DMSO alone (4% final concentration) served as the negative control to subtract the background, while a reaction with water substituted for buffer serves as a positive control that completely lyses the RBCs. Compounds were added to buffer and inverted gently 5 times. Ninety microliters of 3% RBCs were added to the tubes containing 510 μΐ buffer with various concentrations of the investigational compounds or control reagents. Tubes were inverted gently 5 times to mix. Incubation of buffer, compound, and RBCs was for 30 min at 37°C, followed by centrifugation at 1,300 x g for 5 min to pellet the RBCs. Finally, 300 μΐ of the supernatant was removed to a 96-well plate and the released hemoglobin was measured at A540 using a SpectraMax (Molecular Dynamics) plate reader.

[0120] Incubation of RBCs in the absence of any drug or buffer, using only water as the diluent, provided data representing 100% hemolysis. For each test agent, the amount of hemoglobin released was determined graphically as a per cent of the 100% water hemolysis. Maximum percent hydrolysis values for each of the tested compounds were as follows:

[0121] Amphotericin B produced 83% hemolysis at 15 μΜ and a maximum of 96% hemolysis at the highest concentration of 300 μΜ. Compound 1 produced a maximum of 10% hemolysis at 300 uM.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Formula (I) has the structure:

wherein:

R¹ is unsubstituted C_1-3 alkyl;

R² is hydrogen or a first protecting group;

R³ is selected from the group consisting of hydrogen, an unsubstituted C_1-6 alkyl, a substituted Cw alkyl, an optionally substituted C_3-7 cycloalkyl, an optionally substituted - CH2-aryl, an optionally substituted -CH₂-heteroaryl, and an optionally substituted monocyclic heterocyclyl; and

R⁴ is hydrogen or a second protecting group.

2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl.

3. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is ethyl or propyl.

4. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen.

5. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R² is a first protecting group.

6. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R³ is hydrogen.

7. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R³ is an unsubstituted C_1-6 alkyl or a substituted C_1-6 alkyl.

8. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R³ is an optionally substitutedC_3-7 cycloalkyl.

9. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R³ is an optionally substituted - CH₂-aryl or an optionally substituted - CH₂-heteroaryl.

10. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R³ is an optionally substituted monocyclic heterocyclyl.

11. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R⁴ is hydrogen.

12. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R⁴ is a second protecting group.

13. A compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein Formula (II) has the structure:

wherein:

R¹ is unsubstituted C_1-3 alkyl; and

R³ is selected from the group consisting of hydrogen, an unsubstituted C_1-6 alkyl, a substituted C_1-6 alkyl, an optionally substituted C_3-7 cycloalkyl, an optionally substituted - CEb-aryl, an optionally substituted -CH₂-heteroaryl, and an optionally substituted monocyclic heterocyclyl.

14. The compound of Claim 13, or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl.

15. The compound of Claim 13, or a pharmaceutically acceptable salt thereof, wherein R¹ is ethyl or propyl.

16. The compound of any one of Claims 13 to 15, or a pharmaceutically acceptable salt thereof, wherein R³ is an unsubstituted C_1-6 alkyl or a substituted C_1-6 alkyl.

17. The compound of any one of Claims 13 to 15, or a pharmaceutically acceptable salt thereof, wherein R³ is an optionally substitutedC_3-7 cycloalkyl.

18. The compound of any one of Claims 13 to 15, or a pharmaceutically acceptable salt thereof, wherein R³ is an optionally substituted -CH₂-aryl or an optionally substituted -CH₂-heteroaryl.

19. The compound of any one of Claims 13 to 15, or a pharmaceutically acceptable salt thereof, wherein R³ is an optionally substituted monocyclic heterocyclyl.

20. A compound selected from the group consisting of:

pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising an effective amount of the compound of any one of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

23. A method of inhibiting the growth of a fungus, comprising contacting the fungus with an effective amount of the compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 22.

24. A method of treating a fungal infection, comprising identifying a subject in need thereof and administering to said subject an effective amount of the compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 22.

25. The method of Claim 24, wherein said administering to said subject comprises an intravenous administration.

26. The method of Claim 24, wherein said administering to said subject comprises an oral administration.

27. The method of Claim 24, wherein said administering to said subject comprises an intramuscular administration.

28. The method of Claim 24, wherein said administering to said subject comprises a topical administration.

29. The method of Claim 24, wherein said administering to said subject comprises a systemic administration.

30. The method of any one of Claims 24 to 29, wherein said pharmaceutical composition comprises a pharmaceutically acceptable carrier.

31. The compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 22, for use in the treatment and/or diagnosis of a fungal infection.

32. An acylation process, comprising reacting a compound of Formula (I) with an acylating agent of formula R⁵-CC₂H under conditions selected to form a compound of Formula (ma), as follows:

wherein:

R¹ is an unsubstituted C_1-3 alkyl;

R² is a protecting group; R³ is hydrogen;

R⁴ is a protecting group; and

R⁵ is selected from the group consisting of an unsubstituted C_1-6 alkyl, a substituted C_1-6 alkyl, an optionally substitutedC_3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.

33. The acylation process of Claim 32, wherein the conditions selected to form the compound of Formula (Ilia) comprise reacting the compound of Formula (I) with the carboxylic acid of formula R'-CChH in the presence of an organic solvent.

34. The acylation process of any one of Claims 32 to 33, wherein the conditions selected to form the compound of Formula (Ilia) comprise reacting the compound of Formula (I) with the carboxylic acid of formula R⁵-C02H in the presence of an acylating agent selected from the group consisting of l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxidhexafluorophosphate) (HATU), diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide ^• HC1 (EDC HC1), Ι,Γ-Carbonyldiimidazole, benzotriazol-l-yloxy-tripyrrolidino- phosphonium hexafluorophosphate (PyBOP^®), 7-Aza-benzotriazol-l-yloxy- tripyrrolidinophosphonium hexafluorophosphate (PyAOP), 2-(lH-Benzotriazol-l-yl)- Ν,Ν,Ν',Ν'- tetramethylaminium tetrafluoroborate (TBTU), 2-(lH-Benzotriazol-l-yl> Ν,Ν,Ν',Ν'- tetramethylaminium hexafluorophosphate (HBTU), 2-Propanephosphonic acid anhydride (T3P), thionyl chloride, and oxalyl chloride.

35. The acylation process of any one of Claims 32 to 34, wherein the conditions selected to form the compound of Formula (Ilia) comprise reacting the compound of Formula (I) with the carboxylic acid of formula R⁵-CC«2H in the presence of an organic base.

36. The acylation process of any one of Claims 32 to 34, wherein the conditions selected to form the compound of Formula (Ilia) comprise reacting the compound of Formula (II) with the carboxylic acid of formula R⁵-C02H in the presence of an inorganic base.

37. A reductive animation process, comprising reacting a compound of Formula

[1] with an aldehyde of formula R⁵-COH under conditions selected to form a compound of Formula (Illb), as follows:

wherein:

R¹ is an unsubstituted C_1-3 alkyl;

R² is a protecting group;

R³ is hydrogen;

R⁴ is a protecting group; and

R⁵ is selected from the group consisting of an unsubstituted C_1-6 alkyl, a substituted C_1-6 alkyl, an optionally substituted C_3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.

38. The reductive amination process of Claim 37, wherein the conditions selected to form the compound of Formula (IIIb) comprise reacting the compound of Formula (I) with the aldehyde of formula R⁵-COH in the presence of a reducing agent.

39. The reductive amination process of Claim 38, wherein the reducing agent is selected from the group consisting of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, triethylsilane, and phenyl silane.

40. An alkylation process, comprising reacting a compound of Formula (I) with a compound of formula R⁵-CH₂-X under conditions selected to form a compound of Formula (IIIb), as follows:

wherein:

R¹ is an unsubstituted C_1-3 alkyl;

R² is a protecting group;

R³ is hydrogen;

R⁴ is a protecting group; and

R⁵ is selected from the group consisting of an unsubstituted C_1-6 alkyl, a substituted C_1-6 alkyl, an optionally substituted C_3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl; and

X is a halide or pseudohalide.

41. The alkylation process of Claim 40 wherein the conditions selected to form the compound of Formula (Illb) comprise reacting the compound of Formula (I) with the compound of formula R⁵-CH₂-X in the presence of an organic solvent.

42. The alkyation process of any one of Claims 40 to 41, wherein the conditions selected to form the compound of Formula (Illb) comprise reacting the compound of Formula (I) with the compound of formula R⁵-CH₂-X in the presence of an organic base.

43. The alkyation process of any one of Claims 40 to 41, wherein the conditions selected to form the compound of Formula (Illb) comprise reacting the compound of Formula (I) with a compound of formula R⁵-CH₂-X in the presence of an inorganic base.