WO2009075890A2 - Method for synthesis of triazole compounds that modulate hsp90 activity - Google Patents

Abstract

The present invention provides novel method of synthesis of compounds which inhibit the activity of Hsp90. In one embodiment, the present invention is a method of synthesis of a compound of formula (IA) cyclization of a compound of formula (II): in a base/solvent, thereby producing a compound of formula (IA). The definition of the substituents and the conditions of the reactions are provided herein.

Description

TRIAZOLE COMPOUNDS THAT MODULATE HSP90 ACTIVITY

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No. 61/007,391 , filed on December 12, 2007. The entire teachings of the above application is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Certain triazole-based Hsp90 inhibitors, such as the compounds described in U.S. Pat. App. No. 1 1/282,1 19, incorporated herein by reference in its entirety, show promise in the treatment of proliferative disorders, such as cancer. However, the molecules described in the referenced patent application contain a triazolone ring system, the construction of which is difficult. Synthetic processes currently available for preparing these compounds are unsuitable for commericial scale synthesis. Therefore, the need exists for improved syntheses of these compounds.

SUMMARY OF THE INVENTION

The present invention provides novel method of synthesis of compounds which inhibit the activity of Hsp90.

In one embodiment, the present invention is a method of synthesis of a compound of formula (IA)

comprising cyclization of a compound of formula (II)

(H) in a base/solvent thereby producing a compound of formula (IA). In formulas (IA) and (II): ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R₂₀;

R₅ is an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, a substituted alkyl, a substituted phenyl, an optionally substituted heteroaryl or an optionally substituted aryl;

R₂₀ is -OH, -SH, or -NH₂; R₂, is O, NH or NR₂₆;

R_2U is OH, SH, NH₂ or NHR₂₆; and R₂₆ is a Cl -C6 alkyl.

In another embodiment, the present invention is a method of preparing a compound of formula (II),

comprising: reacting a compound of formula (III):

(III) with ClCH₂C(O)R_x and a compound of formula (IV):

(IV) thereby producing a compound of formula (II), wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R₂₀;

R₅ is an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, a substituted alkyl, a substituted phenyl, an optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl;

R_x is -OH or -ONa; R₂₀ is -OH, -SH, or -NH₂;

R_2I is O, NH or NR₂₆; and

R₂₆ is a Cl -C6 alkyl.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods of total synthesis of certain triazole compounds that are inhibitors of hsp90 activity.

Specifically, the invention relastes to the synthesis of a compound of formula (IA)

(IA) comprising cyclization of a compound of formula (II)

GD in a base/solvent thereby producing a compound of formula (IA). In formulas (IA) and (II): ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R₂o;

R₅ is an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, a substituted alkyl, a substituted phenyl, an optionally substituted heteroaryl or an optionally substituted aryl;

R₂₀ is -OH, -SH, or -NH₂; R₂1 is O, NH or NR₂₆;

R₂₁₃ is OH, SH, NH₂ or NHR₂₆; and

R₂₆ is a Cl -C6 alkyl.

The conditions for the above reactions will be described below.

Terminology

Unless otherwise specified, the below terms used herein are defined as follows:

As used herein, the term "alkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n- heptyl, n-octyl, n-nonyl and n-decyl; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4- methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4- dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2- dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl, 3,3-dimethylhexyl, 4,4- dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4- ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2- diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. The term "(Ci-C₆)alkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms. Representative (Ci-C₆)alkyl groups are those shown above having from 1 to 6 carbon atoms. Alkyl groups included in compounds of this invention may be optionally substituted with one or more substituents.

As used herein, the term "alkenyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and having at least one carbon-carbon double bond. Representative straight chain and branched (C₂-C io)alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2- octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3- decenyl and the like. Alkenyl groups may be optionally substituted with one or more substituents.

As used herein, the term "alkynyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and having at lease one carbon-carbon triple bond. Representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3 -methyl- 1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2- heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8- nonynyl, 1-decynyl, 2-decynyl, 9-decynyl, and the like. Alkynyl groups may be optionally substituted with one or more substituents.

As used herein, the term "cycloalkyl" means a saturated, mono- or polycyclic alkyl radical having from 3 to 20 carbon atoms. Representative cycloalkyls include cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, -cyclodecyl, octahydro-pentalenyl, and the like. Cycloalkyl groups may be optionally substituted with one or more substituents.

As used herein, the term "cycloalkenyl" means a mono- or poly- cyclic non- aromatic alkyl radical having at least one carbon-carbon double bond in the cyclic system and from 3 to 20 carbon atoms. Representative cycloalkenyls include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl, cyclodecadienyl, 1,2, 3,4,5, 8-hexahydronaphthalenyl and the like. Cycloalkenyl groups may be optionally substituted with one or more substituents.

As used herein, the term "haloalkyl" means and alkyl group in which one or more (including all) the hydrogen radicals are replaced by a halo group, wherein each halo group is independently selected from -F, -Cl, -Br, and -I. The term "halomethyl" means a methyl in which one to three hydrogen radical(s) have been replaced by a halo group. Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1 ,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like. As used herein, an "alkoxy" is an alkyl group which is attached to another moiety via an oxygen linker.

As used herein, an "haloalkoxy" is an haloalkyl group which is attached to another moiety via an oxygen linker.

As used herein, the term an "aromatic ring" or "aryl" means a hydrocarbon monocyclic or polycyclic radical in which at least one ring is aromatic. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Aryl groups may be optionally substituted with one or more substituents. In one embodiment, the aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C₆)aryl."

As used herein, the term "aralkyl" means an aryl group that is attached to another group by a (Ci-C₆)alkylene group. Representative aralkyl groups include benzyl, 2-phenyl-ethyl, naphth-3-yl -methyl and the like. Aralkyl groups may be optionally substituted with one or more substituents.

As used herein, the term "alkylene" refers to an alkyl group that has two points of attachment. The term "(Ci-C₆)alkylene" refers to an alkylene group that has from one to six carbon atoms. Straight chain (Cι-C₆)alkylene groups are preferred. Non-limiting examples of alkylene groups include methylene (-CH₂-), ethylene (-CH₂CH₂-), n-propylene (-CH₂CH₂CH₂-), isopropylene (-CH₂CH(CH₃)-), and the like. Alkylene groups may be optionally substituted with one or more substituents. As used herein, the term "heterocyclyl" means a monocyclic (typically having 3- to 10-members) or a polycyclic (typically having 7- to 20-members) heterocyclic ring system which is either a saturated ring or a unsaturated non- aromatic ring. A 3- to 10-membered heterocycle can contain up to 5 heteroatoms; and a 7- to 20-membered heterocycle can contain up to 7 heteroatoms. Typically, a heterocycle has at least on carbon atom ring member. Each heteroatom is independently selected from nitrogen, which can be oxidized (e.g., N(O)) or quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The heterocycle may be attached via any heteroatom or carbon atom. Representative heterocycles include morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. A heteroatom may be substituted with a protecting group known to those of ordinary skill in the art, for example, the hydrogen on a nitrogen may be substituted with a tert-butoxycarbonyl group. Furthermore, the heterocyclyl may be optionally substituted with one or more substituents. Only stable isomers of such substituted heterocyclic groups are contemplated in this definition.

As used herein, the term "heteroaromatic", "heteroaryl" or like terms means a monocyclic or polycyclic heteroaromatic ring comprising carbon atom ring members and one or more heteroatom ring members. Each heteroatom is independently selected from nitrogen, which can be oxidized (e.g., N(O)) or quaternized; oxygen; and sulfur, including sulfoxide and sulfone. Representative heteroaryl groups include pyridyl, 1-oxo-pyridyl, furanyl, benzo[l,3]dioxolyl, benzo[l,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, a isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, a triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, imidazo[l ,2-a]pyridyl, and benzothienyl. In one embodiment, the heteroaromatic ring is selected from 5-8 membered monocyclic heteroaryl rings. The point of attachment of a heteroaromatic or heteroaryl ring to another group may be at either a carbon atom or a heteroatom of the heteroaromatic or heteroaryl rings. Heteroaryl groups may be optionally substituted with one or more substituents.

As used herein, the term "(C₅)heteroaryl" means an aromatic heterocyclic ring of 5 members, wherein at least one carbon atom of the ring is replaced with a heteroatom such as, for example, oxygen, sulfur or nitrogen. Representative (C₅)heteroaryls include furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyrazinyl, triazolyl, thiadiazolyl, and the like. As used herein, the term "(C₆)heteroaryl" means an aromatic heterocyclic ring of 6 members, wherein at least one carbon atom of the ring is replaced with a heteroatom such as, for example, oxygen, nitrogen or sulfur. Representative (C₆)heteroaryls include pyridyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl and the like.

As used herein, the term "heteroaralkyl" means a heteroaryl group that is attached to another group by a (Ci-C₆)alkylene. Representative heteroaralkyls include 2-(pyridin-4-yl)-propyl, 2-(thien-3-yl)-ethyl, imidazol-4-yl-methyl and the like. Heteroaralkyl groups may be optionally substituted with one or more substituents.

As used herein, the term "halogen" or "halo" means -F, -Cl, -Br or -I. Suitable substituents for an alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups include any substituent which will form a stable compound synthetized by the methods of the present invention. Examples of substituents for an alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl include R₂₈, a haloalkyl, -C(O)NR₂₈R₂₉, -C(S)NR₂₈R₂₉,

-C(NR₃₂)NR₂₈R₂₉, -NR₃₀C(O)R₃₁, -NR₃₀C(S)R₃₁, -NR₃₀C(NR₃₂)R₃₁, halo, -OR₃₀, cyano, nitro, haloalkoxy, -C(O)R₃₀, -C(S)R₃₀, -C(NR₃₂)R₃₀, -NR₂₈R₂₉, -C(O)OR₃₀, -C(S)OR₃₀, -C(NR₃₂)OR₃₀, -OC(O)R₃₀, -OC(S)R₃₀, -OC(NR₃₂)R₃₀, -NR₃₀C(O)NR₂₈R₂₉, -NR₃₀C(S)NR₂₈R₂₉, -NR₃₀C(NR₃₂)NR₂₈R₂₉, -OC(O)NR₂₈R₂₉, -OC(S)NR₂₈R₂₉, -OC(NR₃₂)NR₂₈R₂₉, -NR₃₀C(O)OR₃ , , -NR₃₀C(S)OR₃ , ,

-NR₃₀C(NR₃₂)OR₃₁, -S(0)_hR₃o, -OS(O)_pR₃₀, , -NR₃₀S(O)_pR₃₀, -S(O)_PNR₂₈R₂₉, -OS(O)_pNR₂₈R₂₉, or -NR₃oS(0)_pNR₂₈R₂₉, wherein R₂₈ and R₂₉, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R₂₈ and R₂9 taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl. Preferably, R₂₈ and R₂9 are an alkyl, an alkenyl, an alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteraralkyl.

R_3O and R₃₁ for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and R₃₂, for each occurrence is, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, -C(O)R₃₀, -C(O)NR₂₈R₂₉, -S(O)_pR₃₀, or -S(O)_PNR₂₈R₂₉; p, for each occurrence, is independently, 1 or 2; and h is 0, 1 or 2.

In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl, and any saturated portion of a alkenyl, cycloalkenyl, alkynyl, aralkyl, and heteroaralkyl groups, may also be substituted with =O, =S, =N-R₃₂.

When a heterocyclyl, heteroaryl, or heteroaralkyl group contains a nitrogen atom, it may be substituted or unsubstituted. When a nitrogen atom in the aromatic ring of a heteroaryl group has a substituent the nitrogen may be a quaternary nitrogen. As used herein, the term "lower" refers to a group having up to four atoms.

For example, a "lower alkyl" refers to an alkyl radical having from 1 to 4 carbon atoms, "lower alkoxy" refers to "-O-(C|-C₄)alkyl and a "lower alkenyl" or "lower alkynyl" refers to an alkenyl or alkynyl radical having from 2 to 4 carbon atoms, respectively.

Unless indicated otherwise, the compounds of the invention containing reactive functional groups (such as (without limitation) carboxy, hydroxyl (hydroxyl groups of phenols are included), thiol, and amino moieties) also include protected derivatives thereof, as found in T. W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1999 (hereinafter "Greene"), the entire teachings of which are incorporated herein by reference.. "Protected" functional groups are those compounds in which a reactive site or sites are blocked with one or more protecting groups.

Examples of suitable protecting groups for hydroxyl groups include ethers (e.g., methoxymethyl, methylthiomethyl, (phenyldimethylsiyl)methoxymethyl, benzyloxymethyl, p-methoxbenzyloxym ethyl, jo-nitrobenzyloxymethyl, o-nitrobenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, menthoxymethyl, tetrahydropyranyls, 1 -ethoxyethyl, 1 -(2-chloroethoxy)ethyl, 1 -[2-(trimethylsilyl)ethoxy]ethyl, 1 -methyl- 1 -methoxyethy, methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl , 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2,6-difluorobenzyl, p-acylaminobenzyl), silyl ethers (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzyl silyl, tri-p-xylysilyl, triphenylsilyl, diphenylmethylsilyl, di-t-butylmethylsilyl, tris(trimethylsilyl)silyl: sisyl, (2-hydroxystyryl)dimethylsilyl, and

(2-hydroxystyryl)diisopropylsilyl), esters (e.g., benzoylformate, acetates, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, phenyl acetate, /7-P-phenylacetate, and diphenylacetate, nicotinate and the like), and 3-phenylpropionate), carbonates (e.g., methoxylmethyl, 9-fluorenylmethyl, 2,2,2-trichloroethyl, 1 , 1 -dimethyl-2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, /?-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, and p-nitrobenzyl) and other suitable hydroxyl protecting groups recited in Greene.

Examples of suitable protecting groups for phenols groups include ethers (e.g. methyls (e.g. methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methylthiomethyl, phenyl thiomethyl, azidomethyl, cyanomethyl, 2,2-dichloro-l ,l-difluoroethyl, 2-chloroethyl, and 2-bromoethyl) tetrahydropyranyl, and 1-ethoxyethyl), silyl ethers (e.g. trimethylsilyl, J-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl and the like) esters (e.g. formate, acetate, levulinate, pivaloate, benzoate, 9-fluorenecarboxylate, xanthenecarboxylate and the like), carbonates (e.g. methyl, 1-adamantyl, t-butyl, 4-methylsulfinylbenzyl, 2,4-dimethylpent-3-yl, 2,2,2-trichloroethyl, vinyl, benzyl, aryl carbamates and the like) and other phenol protecting groups recited in Greene.

Examples of suitable protecting groups for thiol groups include thioethers (e.g., 5-alkyl, 5-benzyl, S-js-methoxybenzyl, S-o-or/?-hydroxy-or acetoxybenzyl, S-p-nitrobenzyl, 5-2,4,6-trimethylbenzyl, 5'-2,4,6-trimethoxybenzyl, 5-4-picolyl, 5-2-quinolinylmethyl, S-2-picolyl N-oxido, .S-9-anthrylmethyl, 5-phenyl, 5'-2,4-dinitrophenyl, S-t-butyl, 5-methoxymethyl, S-isobutoxymethyl, and S-benzyloxymethyl), thioesters (e.g., 5-acetyl, 5-benzoyl, 5-trifluro acetyl, 5-N-[[(p-biphenylyl)isopropoxy]carbonyl]-n-methyl-γ-aminothiobutyrate, 5-N-(t-butoxycarbonyl)-n-methyl-γ-aminothiobutyrate, and the like), thiocarbonated derivatives (e.g., -S'-2,2,2-trichloroethoxycarbonyl, S-t-butoxycarbonyl, 5-benzyloxycarbonyl, 5-p-methoxybenzyloxycarbonyl and the like), thiocarbamate derivatives (e.g., S-(N-ethyl), 5-(N-methoxymethyl)), and other thiol protecting groups recited in Greene. Examples of suitable protecting groups for amino groups include carbamates

(e.g. methyl, ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fiuorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 17-tetrabenzo[α,c,g, j]fluoernylthmethyl, 2-chloro-3 -indenylmethyl, benz[/] inden-3 -ylmethyl 2,7-dW-butyl-[9-( 10, 10-dioxo- 10,10,10,10-tetrahydrothioxanthyl)]methyl, l,l-dioxobenzo[b]thiophene-2-ylmethyl, 2,2,2-tricholoroethyl, 2-trimethylsilylethyl, 2-phenylethyl, l-(l-adamantyl)-l-methylethyl, 2-chloroethyl, 1 , 1 -dimethyl-2-haloethyl, 1 , 1 -dimethyl-2-dibromethyl, l,l-dimethyl-2,2,2-trichloroethyl, 1 -methyl- l-(4-biphenylyl)ethyl, l-(3,5-di-t-butylphenyl)-l-methylethyl, t-butyl, 1-adamantyl, 2-adamantyl, vinyl, allyl, 1 -isopropylallyl, cinnamyl, 4-nitrocinnamyl, benzyl, /?-methoxybenzyl, /7-nitrobenzyl, /?-bromobenzyl, /7-chlorobenzyl, 2,4-dichlorobenzyl, /n-nitrophenyl, 3,5-dimethoxybenzyl, 1 -methyl- 1 -(3, 5-dimethoxyphenyl)ethyl, α-methylnitropiperonyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o-nitrophenyl)methyl), amides (e.g., n-formyl, «-acetyl, »-chloroacetyl, rc-trichloroacetyl, «-trifluoroacetyl, n-phenylacetyl, and «-3-phenylpropionyl), N- alkyl and N-aryl amines (e.g., n-methyl, n-t-butyl, n-allyl, «-benzyl, rc-4-methoxybenzyl, «-2,4-dimethoxybenzyl, and n-2-hydroxybenzyl) and other amino protecting groups recited in Greene.

The compounds synthetized by the methods of the present invention may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. According to this invention, the chemical structures depicted herein, including the compounds of this invention, encompass all of the corresponding compounds' enantiomers, diastereomers and geometric isomers, that is, both the stereochemically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and isomeric mixtures (e.g., enantiomeric, diastereomeric and geometric isomeric mixtures). In some cases, one enantiomer, diastereomer or geometric isomer will possess superior activity or an improved toxicity or kinetic profile compared to other isomers. In those cases, such enantiomers, diastereomers and geometric isomers of compounds of this invention are preferred.

As used herein, the term "polymorph" means solid crystalline forms of a compound of the present invention or complex thereof. Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to stability (e.g., to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rates (which can affect bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical characteristics (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). Different physical properties of polymorphs can affect their processing. For example, one polymorph might be more likely to form solvates or might be more difficult to filter or wash free of impurities than another due to, for example, the shape or size distribution of particles of it.

As used herein, the term "hydrate" means a compound of the present invention or a salt thereof, that further includes a stoichiometric or non- stoichiometric amount of water bound by non-covalent intermolecular forces. As used herein, he term "clathrate" means a compound of the present invention or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.

Compounds that can be synthesized using the disclosed methods can be obtained in a form of polymorphs, salts, including a pharmaceutically acceptable salt, solvates or clathrates.

As used herein, the term "pharmaceutically acceptable salt," is a salt formed from, for example, an acid and a basic group of one of the compounds of formulas herein or Table 1. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, besylate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound obtained by the synthetic methods of the present invention having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkyl amines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2- hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris- (hydroxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy lower alkyl)- amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2- hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a obtained by the synthetic methods of the present invention having a basic functional group, such as an amine functional group, and a pharmaceutically acceptable inorganic or organic acid.. Suitable acids include, but are not limited to, hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid, lactic acid, salicylic acid, tartaric acid, bitartratic acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

As used herein, the term "pharmaceutically acceptable solvate," is a solvate formed from the association of one or more pharmaceutically acceptable solvent molecules to one of the compounds obtrained by the synthetic method of the present invention. The term solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).

As used herein, a composition that "substantially" comprises a compound means that the composition contains more than about 80% by weight, more preferably more than about 90% by weight, even more preferably more than about 95% by weight, and most preferably more than about 97% by weight of the compound.

As used herein, a reaction that is "substantially complete" means that the reaction contains more than about 80% by weight of the desired product, more preferably more than about 90% by weight of the desired product, even more preferably more than about 95% by weight of the desired product, and most preferably more than about 97% by weight of the desired product.

As used herein, a racemic mixture means about 50% of one enantiomer and about 50% of is corresponding enantiomer relative to a chiral center in the molecule. The invention encompasses all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures of the compounds of the invention.

Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or diastereomers by well known methods, such as chiral- phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods. The compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity. Only those choices and combinations of substituents that result in a stable structure are contemplated. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation. The invention can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non- limiting embodiments of the invention.

The Methods of the Invention

In one embodiment, the present invention is a method of synthesis of a compound of formula (IA):

(IA) The method comprises cyclization of a compound of formula (II)

(H) in a base/solvent, thereby producing a compound of formula (IA). In formulas (IA) and (II), ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R₂₀; R₅ is an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, a substituted alkyl, a substituted phenyl, an optionally substituted heteroaryl or an optionally aryl; R₂₀ is -OH, -SH, or -NH₂; R₂i is O, NH or NR₂₆; R₂i_a is OH, SH, NH₂ or NHR₂₆; and R₂₆ is a C1-C6 alkyl.

In another embodiment, the compound of formula (II) is prepared by reacting a compound of formula (III) :

(III) with ClCH₂C(O)R_x and a compound of formula (IV):

(IV) thereby producing a compound of formula (II), wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R₂o; R₅ is an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, a substituted alkyl, a substituted phenyl, an optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl;

R_x is -OH or -ONa;

R₂₀ is -OH, -SH, or -NH₂;

R_2I is O, NH or NR₂₆; and

R₂₆ is a Cl -C6 alkyl.

In another embodiment, formula (II) is prepared by reacting a compound of formula (III):

(III)

with a compound of formula (XXX):

wherein the variables are defined as above.

In a further embodiment, the compound of formula (XXX) is prepared from a compound of formula (IV):

(IV)

wherein R₂₀ and Ring A are defined above.

In another embodiment, the compound of formula (XXX) is represented by the following:

wherein R₆ is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR₇, -SR₇, -NRi₀Ri i, -OC(O)NR_I0R_I i, -SC(O)NR₁₀Ri i, -NR₇C(O)NR₁₀R_{1 1}, -OC(O)R₇, -SC(O)R₇, -NR₇C(O)R₇, -OC(O)OR₇, -SC(O)OR₇, -NR₇C(O)OR₇, -OCH₂C(O)R₇, -SCH₂C(O)R₇, -NR₇CH₂C(O)R₇, -OCH₂C(O)OR₇, -SCH₂C(O)OR₇, -NR₇CH₂C(O)OR₇, -OCH₂C(O)NR₁₀R₁ I, -SCH₂C(O)NR₁₀RH ,

-NR₇CH₂C(O)NR₁₀R_{1 1}, -OS(O)_PR₇, -SS(O)_PR₇, -NR₇S(O)_PR₇, -OS(O)_pNR₁₀R_n, -SS(O)_PNR₁₀R₁ ,, -NR₇S(O)_PNR₁₀R₁1, -OS(O)_POR₇, -SS(O)_POR₇, -NR₇S(O)_POR₇, -OC(S)R₇, -SC(S)R₇, -NR₇C(S)R₇, -OC(S)OR₇, -SC(S)OR₇, -NR₇C(S)OR₇, -OC(S)NR₁₀R_{1 1}, -SC(S)NR₁₀Rn, -NR₇C(S)NR₁₀R₁₁, -OC(NR₈)R₇, -SC(NR₈)R₇, -NR₇C(NR₈)R₇, -OC(NR₈)OR₇, -SC(NR₈)OR₇, -NR₇C(NR₈)OR₇,

-OC(NR₈)NR₁₀R_{I 1} , -SC(NR₈)NR₁₀R_{1 1}, -NR₇C(NR₈)NR₁₀R_{1 1}, -C(O)R₇, -C(O)OR₇, -C(O)NR₁₀Rn, -C(O)SR₇, -C(S)R₇, -C(S)OR₇, -C(S)NR₁₀R_{1 1}, -C(S)SR₇, -C(NR₈)OR₇, -C(NR₈)R₇, -C(NR₈)NR₁₀RH , -C(NR₈)SR₇, -S(O)_POR₇, -S(O)_pNR₁₀R,,, or -S(O)_PR₇;

R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; and p, for each occurrence, is, independently, 0, 1 or 2.

In another embodiment, the compound of formula (IV) is represented by compound of formula (V):

wherein R₆ is defined above.

In another embodiment, the compound of formula (V) is prepared by reacting a compound of formula (VI):

with potassium ethyl xanthogenate.

In another embodiment, the compound of formula (V) is prepared by reacting a compound of formula (VI):

with carbon disulfide.

In another embodiment the invention is a compound of formula (II)

(") wherein the variables are defined as above.

In another embodiment the invention is a compound of formula (IV):

(IV) wherein the variables are defined as above.

In another embodiment the invention is a compound of formula (XXX):

wherein the variables are defined as above.

In another embodiment the invention is a compound of formula (V):

wherein the variables are defined as above. General conditions for reactions are known in the art and are described, for example, in March, "Advanced Organic Chemistry - Reactions, Mechanisms and Structure", Third Edition, John Wiley & Sons, (1985).

Preferably, in formulas (IA), (II), (III) and (IV), R₂₀ is -OH. In one embodiment, substituent R₅ in formulas (IA), (IB), (II), (III) and (IV) is an optionally substituted naphthalenyl, represented by the following formula:

Other values and preferred values remain as defined with reference to formulas (IA) and (II).

In one embodiment, the substituent R₉, for each occurrence, is independently a substituent selected from an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, or a haloalkyl, halo, cyano, or nitro; -NRi₀Ri ₁, or -OR₇; -O(CH₂)_mNR₇R_p3; -C(O)R₇, -C(O)OR₇; -C(O)NR₁₀R_n; -OC(O)R₇, -OC(O)OR₇, -OC(O)NR₁₀Ri 1; -NR₈C(O)R₇, or -NR₇C(O)NR₁₀RH ; -NR₇C(O)OR₇; -S(O)_pR₇, -OS(O)_PR₇, -OS(O)_POR₇, -OS(O)_pNR₁₀R, ,, -S(O)_POR₇, -S(O)_pNR,₀Rn; -NR₈S(O)_PR₇, -NR₇S(O)_pNR₁₀Ri i, -NR₇S(O)_POR₇. Alterantively, two R₉ groups taken together with the carbon atoms to which they are attached form a fused ring. Substituents R₇ and R₈, for each occurrence, can independently take a value of -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

Rio and Rj ₁, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.

Examples of substituted naphthalenyls include the following substituents:

In the above examples, q is zero or an integer from 1 to 7 and u is zero or an integer from 1 to 8.

In another embodiment, substituent R₅ is represented by the following structural formula:

In one embodiment, R₃₃ is a -H, halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl; R₃₄ is H, a lower alkyl, or a lower alkyl carbonyl; and ring B and ring C are optionally substituted with one or more substituents in addition to R₃₃ and R₃₄. The remainder of the substituents have values and preferred values as defined above with reference to formulas (IA) and (II).

In other embodiments, substituent R₅ is selected from group 1 consisting of:

wherein:

X₆, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(Rj₇), provided that at least three X₆ groups are independently selected from CH and CR₉; X₇, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(Ri₇), provided that at least three X₇ groups are independently selected from CH and CR₉;

Xg, for each occurrence, is independently CH₂, CHR₉, C(Rg)₂, S(O)_P, NR₇, or NR₁₇;

X9, for each occurrence, is independently N or CH; Xio, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(Ri₇), provided that at least one X₁₀ is selected from CH and CR9; and

Ri₇, for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R₇, -C(O)OR₇, or -C(O)NR₁₀R_{1 1}; Values and preferred values for other substituents are as defined above with reference to formulas (IA) and (II).

Examples of R₅ from group 1 include an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3H-indazolyl, an optionally substituted indolizinyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted benzoxazolyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted benzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl, an optionally substituted thiazolo[4,5-c]pyridinyl, an optionally substituted thiazolo[5,4-c]pyridinyl, an optionally substituted thiazolo[4,5-b]pyridinyl, an optionally substituted thiazolo[5,4-b]pyridinyl, an optionally substituted oxazolo[4,5-c]pyridinyl, an optionally substituted oxazolo[5,4-c]pyridinyl, an optionally substituted oxazolo[4,5-b]pyridinyl, an optionally substituted oxazolo[5,4-b]pyridinyl,an optionally substituted imidazopyridinyl, an optionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionally substituted benzotriazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted imidazo[4,5-a]pyridinyl, an optionally substituted imidazo[l,2-a]pyridinyl, an optionally substituted 3H- imidazo[4,5-b]pyridinyl, an optionally substituted lH-imidazo[4,5-b]pyridinyl, an optionally substituted lH-imidazo[4,5-c]pyridinyl, an optionally substituted 3H- imidazo[4,5-c]pyridinyl, an optionally substituted pyridopyrdazinyl, and optionally substituted pyridopyrimidinyl, an optionally substituted pyrrolo[2,3]pyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidyl an optionally substituted cyclopentaimidazolyl, an optionally substituted cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, an optionally substituted pyrrolotriazolyl, or an optionally substituted benzo(b)thienyl. Values and preferred values the remainder of the substituents are as defined above with reference to formulas (IA) and (II).

In another embodiment, R₅ is selected from group 2 consisting of:

In group 2:

Xn, for each occurrence, is independently CH, CR₉, N, N(O), or N⁺(Rn), provided that at least one Xi ₁ is N, N(O), or N⁺(Ri₇) and at least two Xi ₁ groups are independently selected from CH and CR₉;

Xi₂, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(Ri₇), provided that at least one Xi₂ group is independently selected from CH and CR₉; and

Xi ₃, for each occurrence, is independently O, S, S(O)_P, NR₇, or NRi₇. Values and preferred values the remainder of the substituents are as defined above with reference to formulas (IA) and (II).

In another embodiment, substituent R₅ is selected from group 3, consisting of an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or a substituted alkyl. The alkyl group or the cycloalkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, or a haloalkyl; halo, cyano, or nitro; -NRi₀Rn, or -OR₇; -O(CH₂)_mNR₇R_p3; -C(O)R₇, -C(O)OR₇; -C(O)NRi₀Ru; -OC(O)R₇, -OC(O)OR₇, -OC(O)NR_I0R_{I 1}; -NR₈C(O)R₇, or -NR₇C(O)NR₁₀R_{1 1}; -NR₇C(O)OR₇; -S(O)pR₇, -OS(O)_PR₇, -OS(O)_POR₇, -OS(O)_pNR,₀R, ,, -S(O)_POR₇, -S(O)_pNR₁₀Ri i; -NR₈S(O)pR₇, -NR₇S(O)_pNR,₀Rn, -NR₇S(O)_POR₇. Values and preferred values for R₇, R₈, Ri₀, Rn, p and m are as defined above with reference to formulas (IA) and (II). Values and preferred values for the remainder of the substituents are as defined above with reference to formulas (IA) and (II). Preferably, when R₅ is selected from group 3, R₅ is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl. More preferably, R₅ is a substituted alkyl.

In another embodiment, R₅ is a phenyl group substituted with one to five substituents. The substituents on a phenyl group are selected from an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, or a haloalkyl, halo, cyano, or nitro; -NRi₀R_{1 1}, or -OR₇; -O(CH₂)_mNR₇R_p3; -C(O)R₇, -C(O)OR₇; -C(O)NR₁₀Rn; -OC(O)R₇, -OC(O)OR₇, -OC(O)NR₁₀R_{1 1}; -NR₈C(O)R₇, or -NR₇C(O)NRi₀R_{1 1}; -NR₇C(O)OR₇; -S(O)_PR₇, -OS(O)_PR₇, -OS(O)_POR₇, -OS(O)_PNR₁₀R₁ ,, -S(O)_POR₇, -S(O)pNR₁₀Rii; -NR₈S(O)_PR₇, -NR₇S(O)_PNR₁₀R₁ ,, -NR₇S(O)_POR₇. Values and preferred values for R₇, R₈, R₁₀, R_{1 1}, p and m are as defined above with reference to formulas (IA) and (II). Values and preferred values for the remainder of the substituents are as defined above with reference to formulas (IA) and (II).

In one preferred embodiment of a method of the present invention, substituent R₅ in formulas (IA), (II) and (III) is represented as shown and defined above, while ring A in formulas (IA), (II) and (IV) is a substituted phenyl group.

Examples of substituted phenyls include

where the values and preferred values for R₆, R₂₀, and R₂₅ are defined for structural formulas (X), (XI) and (XII) below.

In one embodiment, the compound of formula (II) is represented by structural formula (X):

(^x)

In formula (X), R₆, for each occurrence, is defined as above.

In another embodiment, the compound (X) is represented by structural formula (XI):

(^XI)

In formula (XI), R₂₅ is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, a haloalkyl, halo, cyano, nitro, -NRioRn, -OR₇, -SR₇, -O(CH₂)_mNR₇R_P3, -C(O)R₇, -C(O)OR₇; -C(O)NR₁₀R₁.; -OC(O)R₇, -OC(O)OR₇, -OC(O)NR₁₀RH ; -NR₈C(O)R₇, -NR₇C(O)NR₁₀R_{1 1}, -NR₇C(O)OR₇; -S(O)_PR₇, -OS(O)_PR₇, -OS(O)pOR₇, -OS(O)pNR,₀R_n, -S(O)_POR₇, -S(O)_PNR₁₀R_{1 1}, -NR₈S(O)_PR₇, -NR₇S(O)pNRi₀R| _{l 5} or -NR₇S(O)_POR₇;

R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; p, for each occurrence, is, independently, 0, 1 or 2; m, for each occurrence, is independently, 1, 2, 3, or 4; and r is zero or an integer from 1 to 3.

Preferably, in formula (XI), R₂₅ is a -OR₇ or-NRioRn. Values and preferred values for the remainder of the substituents are as defined above with reference to formulas (IA) and (II).

In another embodiment of formula (XI), R₃₃ is H or C1-C6 alkyl; and R₃₄ is a C1-C6 alkyl. Values and preferred values for the remainder of the substituents are as defined above with reference to formulas (IA) and (II).

In another embodiment, the compound of formula (XI) is represented by structural formula (XII):

(XII)

Preferably, in formula (XII), R₂ , is O; R₆ is a C1-C6 alkyl, a C1 -C6 haloalkyl, a Cl- C6 alkoxy, a C1-C6 haloalkoxy, a C3-C6 cycloalkyl or -NRioRn. In another embodiment of the compound of formula (XII), R₆ is a C1-C6 alkyl and R₃₃ is H. In another embodiment, R₃₃ is -H and ring B is unsubstituted. In yet another embodiment, R₂₀ and R₂₅ are -OH, and R₆ is a C1-C6 alkyl. Values and preferred values for the remainder of the substituents are as defined above with reference to to formulas (IA) and (II).

In another embodiment of the methods of the present invention, the compound of formula (II) is represented by one of the following structural formulas (VIIA) and (VIIB):

(VIIA) (VIIB). In formulas (VIIA) and (VIIB):

X₃ and X₄ are each, independently, N, N(O), N⁺(Ri₇), CH or CR₆;

X₅ is O, S, NR₁₇, CH=CH, CH=CR₆, CR₆=CH, CR₆=CR₆, CH=N, CR₆=N, CH=N(O), CR₆=N(O), N=CH, N=CR₆, N(O)=CH, N(O)=CR₆, N⁺(R,₇)=CH, N⁺(Rn)=CR₆, CH=N⁺(R₁₇), CR₆=N⁺(Ri₇), or N=N; and n is zero or an integer from 1 to 4.

In formulas (VIIA) and (VIIB), values and preferred values for the remainder of the substituents are as defined above with reference to to formulas (IA) and (II).

Preferably, compounds of formuals (VIIA) and (VIIB) are selected from the group consisting of compounds represented by the formulas of group 4:

In group 4, values and preferred values for the remainder of the substituents are as defined above with reference to to formulas (IA) and (II).

In one embodiment of the methods of present invention, the compound of formula (II) is represented by structural formula (XIII):

(XIII).

In formula (XIII): X₄I iS O₅ S₅ Or NR₄₂;

X₄₂ is CR₄₄ or N; Y₄₀ is N or CR₄₃; Y_4I is N or CR₄₅;

Y_42; for each occurrence, is independently N, C or CR₄₆; R_4I is -H, -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy,

-NR₁₀Rn, -OR₇, -C(O)R₇, -C(O)OR₇, -C(S)R₇, -C(O)SR₇, -C(S)SR₇, -C(S)OR₇, -C(S)NR₁₀Rn, -C(NR₈)OR₇, -C(NR₈)R₇, -C(NR₈)NR₁₀Rn, -C(NR₈)SR₇, -OC(O)R₇, -OC(O)OR₇, -OC(S)OR₇, -OC(NR₈)OR₇, -SC(O)R₇, -SC(O)OR₇, -SC(NR₈)OR₇, -OC(S)R₇, -SC(S)R₇, -SC(S)OR₇, -OC(O)NR₁₀R_{1 1}, -OC(S)NR₁₀R_{1 1}, - OC(NR₈)NR₁₀R_I i, -SC(O)NR₁₀R_n, -SC(NR₈)NR₁₀R_{1 1}, -SC(S)NR₁₀R_{1 1}, -OC(NR₈)R₇₅ -SC(NR₈)R₇, -C(O)NR₁₀R₁₁, -NR₈C(O)R₇₅ -NR₇C(S)R₇, -NR₇C(S)OR₇, -NR₇C(NR₈)R₇, -NR₇C(O)OR₇, -NR₇C(NR₈)OR₇, -NR₇C(O)NR₁₀R₁₁, -NR₇C(S)NRi₀R_{1 1}, -NR₇C(NR₈)NR₁₀R_{1 1}, -SR₇, -S(O)_PR₇, -0S(0)_pR₇, -OS(O)_POR₇, -OS(O)_PNR_1OR_{1 15} -S(O)_POR₇, -NR₈S(O)_pR₇, -NR₇S(O)_PNR₁₀R₁1, -NR₇S(O)pOR₇, -S(O)_pNR,₀Ri i, -SS(0)_pR₇, -SS(O)_POR₇, -SS(0)pNR,oRn, -OP(O)(OR₇)₂₎ or -SP(O)(OR₇)₂;

R₄₂ is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, a haloalkyl, halo, cyano, nitro, -NRi₀Rn, -OR₇, -O(CH₂)_mNR₇R_P3, -C(O)R₇, -C(O)OR₇; -C(O)NR₁₀R_{1 1}; -OC(O)R₇, -OC(O)OR₇, -OC(O)NR₁₀Rn; -NR₈C(O)R₇, -NR₇C(O)NR₁₀R₁₁, -NR₇C(O)OR₇; -S(O)_PR₇, -OS(O)_PR₇, -OS(O)_POR₇, -OS(O)pNR₁₀Rn, -S(O)_POR₇, -S(O)_PNR₁₀R₁ ,, -NR₈S(O)_PR₇, -NR₇S(O)_pNR₁₀Rn, or -NR₇S(O)_POR₇;

R₄₃ and R₄₄ are, independently, -H₅ an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, a haloalkyl, halo, cyano, nitro, -NR₁₀R_{1 1}, -OR₇, -O(CH₂)_mNR₇R_p3, -C(O)R₇, -C(O)OR₇; -C(O)NR₁₀R_{1 1}; -OC(O)R₇, -OC(O)OR₇, -OC(O)NR₁₀R_{1 1}; -NR₈C(O)R₇, -NR₇C(O)NR₁₀R_n, -NR₇C(O)OR₇; -S(O)_PR₇, -OS(O)_PR₇, -OS(O)_POR₇, -OS(O)_PNR₁₀R₁ ,, -S(O)_POR₇, -S(O)_pNR₁₀R_π, -NR₈S(O)_PR₇, -NR₇S(O)_pNR₁₀Rn, or -NR₇S(O)_POR₇; or R₄₃ and R₄₄ taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; R₄₅ is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, or a haloalkyl, halo, cyano, nitro, -NRioRn, -OR₇, -O(CH₂)_mNR₇R_P3, -C(O)R₇, -C(O)OR₇; -C(O)NR₁₀Rn; -OC(O)R₇, -OC(O)OR₇, -OC(O)NR₁₀Ri i; -NR₈C(O)R₇, -NR₇C(O)NR₁₀R_H, -NR₇C(O)OR₇; -S(O)_PR₇, -OS(O)_PR₇, -OS(O)_pOR₇, -OS(O)_PNR₁₀R_{1 1}, -S(O)_POR₇, -S(O)_pNR₁₀Ri i, -NR₈S(O)_PR₇, -NR₇S(0)pNRioRn, or -NR₇S(O)_pOR₇;

R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

Ri₀ and R_{1 1}, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R_1O and R₁₁, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R₂₆, for each occurrence is, is independently, a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4. In formula (XIII), the variables can each be independently selected from the following lists of preferred values (values and preferred values for the remainder of the substituents are as defined above with reference to formulas (IA) and (II)):

In one aspect, X₄₁ is NR₄₂ and X₄₂ is CR₄₄. In one aspect, X₄₁ is NR₄₂ and X₄₂ is N. In one aspect, R₄₁ is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. In one aspect, R₄₁ is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. In one aspect, X₄1 is NR₄₂, and R₄₂ is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, and -C(O)N(R₂₇)₂, wherein each R₂₇ is independently -H or a lower alkyl. In one aspect, X₄I is NR₄₂, and R₄₂ is selected from the group consisting of - H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, /ert-butyl, n- pentyl, n-hexyl, -CH₂OCH₃, -CH₂CH₂OCH₃, and -C(O)N(CH₃)₂. In one aspect, R₄₃ and R₄₄ are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. In one aspect, X₄₂ is CR₄₄; Y₄₀ is CR₄₃; and R₄₃ and R₄₄ together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring. In one aspect, R₄₃ and R₄₄ together with the carbon atoms to which they are attached form a C₅-C₈ cycloalkenyl or a C₅-C₈ aryl. In one aspect, R₄₅ is selected from the group consisting of -H, -OH, methoxy and ethoxy. In one aspect, X_4I is O.

In another embodiment of the methods of the present invention, the compound of formula (II) is represented by structural formula (XIV):

Preferably, in formula (XIV) R₂] is O. Values and preferred values for the remainder of the substituents are as defined above with reference to formulas (IA), (II), and (XIII).

In other embodiments of the compound of formula (XIV), the variables can be each be independently selected from the following lists of preferred values:

X₄₂ can be CR₄₄, and R₄₃ and R₄₄ can be, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy; X₄₂ can be CR₄₄, and R₄₃ and R₄₄, taken together with the carbon atoms to which they are attached, can form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring;

R₄₃ and R₄₄, taken together with the carbon atoms to which they are attached, can form a C₅-C₈ cycloalkenyl or a C₅-C₈ aryl;

X₄₂ can be CR₄₄; and

X₄₂ can be N.

In one aspect, X₄₂ is CR₄₄, and R₄₃ and R₄₄ are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.

In one aspect, X₄₂ is CR₄₄, and R₄₃ and R₄₄, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring. In one aspect, R₄₃ and R₄₄, taken together with the carbon atoms to which they are attached, form a C₅-C₈ cycloalkenyl or a C₅-C₈ aryl. In one aspect, X₄₂ is CR₄₄. In one aspect, X₄₂ is N.

In another embodiment of the methods of the present invention, the compound of formula (II) is represented by structural formula (XV):

In formula (XV):

X₄₅ is CR₅₄ or N;

R₅₆ is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl;

R₅₂ is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, and -(CH₂)₂OCH₃;

R₅₃ and R₅₄ are each, independently, -H, methyl, ethyl, or isopropyl; or R₅₃ and R₅₄ taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring; and

R₅₅ is selected from the group consisting of -H, -OH, -OCH3, and -OCH₂CH₃.

Values and preferred values for the remainder of the substituents in formula (XV) are as defined above with reference to formulas (IA), (II), and (XIII)-(XIV).

EXEMPLIFICATION

Synthesis of the Compound of Formula (XXIV)

Formula (XXIV)

STEP-I: To a stirred solution of 1.52g (10 mmols) of 4-isopropylresorcinol 1 in 6mL of anhydrous DMF was added 2.1g (13 mmols) of potassium ethyl xanthogenate. The resultant mixture was then heated at 100 °C overnight, and then cooled. After confirming the completion of the formation of the benzodithioic acid (LC-MS) the mixture was poured into 5OmL of cold water and acidification using 2NHC1 till pH 1-2 and the resultant dark yellow solid was filtered and washed with water and dried. The crude product was recrystallized using EtOH (quantitative yield).

STEP-2: To a stirred suspension of 5Og (220mmols) of 2 and 55.5g (660mmols) of NaHCO₃ in 65OmL of anhydrous DMF was added 21g (220mmols) of chloroacetic acid in 3 portions (for 3mins.) under ice-bath and stirred for Ih at room temperature under N₂ atmosphere. To the resultant mixture was added 45g (220mmols) of aminourea 3 in 3 portions (3mins) at room temperature and stirred at 80 ⁰C for Ih under N₂ atmosphere. Cooled the mixture and poured into 100OmL of ice water with stirring and acidified with 2N HCl till pH 3. The sticky precipitate thus obtained was processed under ultrasound for 25 min. and the precipitate thus obtained was filtered. The solid was dissolved in 1000ml EtOAc and washed with brine 3 times and dried over Na₂SO₄ and concentrated. The crude product was then recrystallized using hexane:ethylacetate mixture to obtain 42g of pale yellow solid. The mother liquor was concentrated and the remaining product was purified by column chromatography to give another 1Og of desired product 4 (yield 59%).

STEP-3: A solution of 10.0g (25.09mmols) of 4 and 7.04g (0.125mols) of potassium hydroxide in 10OmL of water was stirred at 100 °C overnight. The mixture was cooled, poured into lOOg of ice and acidified with 2MHC1 until pH 4-5. The resultant pale yellow precipitate was filtered, washed with water and redissolved in 15OmL of EtOAc:MeOH (95:5) mixture, dried over Na₂SO₄ and concentrated. The crude product was recrystallized using EtOAc to afford 5.47g (60%) of Compound (XXIV) as off white solid.

Alternate Synthesis of 4

quant.

3

STEP-2: Through a stirred solution of 7.Og (30mmols) of 2 in 12OmL of anhydrous

Et₂O at 5 °C was bubbled CO₂ gas for lOmin. To the resultant mixture was added 7.29g (όlmmols) of SOCl₂ drop wise (carefully!), while a strong red precipitate was formed. After the addition, the mixture was stirred at RT for Ih and the precipitates filtered, washed with Et₂O and dried. Yield = 7.Og.

STEP-3: To a stirred suspension of 0.22g (0.59mmols) of 5 in 6mL of anhydrous dimethylformamide was added 0.24g (l . lδmmols) of the amino-urea intermediate 4, portion wise. The mixture was stirred at room temperature for 2h and poured into 2OmL of cold water. The resultant precipitate was filtered, washed with water and dried to obtain quantitative yield of 4. Alternate Synthesis of 2

Synthesis of N-(I -methyl- lH-indol-5-yOhydrazinecarboxamide (aminourea 3)

Step 1: Synthesis of phenyl l-methyl-lH-indol-5-ylcarbamate 7:

To a solution of 5.62g (35.91mmols) of phenylchloroformate 6 in 25mL of dichloromethane at 0 °C was added, a solution of 5.Og (34.20 mmols) of indoleamine 5 in 25mL of dichloromethane drop wise (20 min) at 0 °C. The resultant mixture was then stirred for lOmin at 0 °C and a solution of 6mL (42.75 mmols) of triethylamine in 1OmL of dichloromethane was added drop wise (15min) at 0 °C and stirred for 5min. To the mixture was then added 5OmL of water and organic layer separated. The aqueous layer was then extracted with 2OmL of dichloromethane and organic layers combined and dried over Na2SO4. The solution was then passed through a pad of silica gel, eluted with additional 5OmL of 3:1 hexaneiethylacetate and concentrated. The crude product was then crystallized with 4:1 hexane:ethylacetate to obtain 7.8g (85.7%, 99.5% pure, I crop) and 0.78g (8.5%, 98% pure, II crop) with a combined yield of 94% product.

Step 2: Synthesis of N-(I -methyl- lH-indol-5-yl)hydrazinecarboxamide 8

7 3

To a stirred suspension of 35.Og (0.131mols) of the carbamate 7 in 12OmL of 1,4-dioxane was added 32mL (0.657mols) of hydrazine hydrate and the resultant mixture was refluxed for 3h and concentrated. To the crude mixture was added approx. 25OmL of cold water and the resultant light brown precipitate was filtered and vacuum dried. The crude solid was again treated with 15OmL of ether and stirred for Ih and filtered. Drying in vacuum afforded 21.6g (80%) of 3 as grey solid.

Exemplary Compounds Synthesized by the Methods of the Invention

Exemplary compounds of formula (IA) that can be synthetized by the methods of the present invention are depicted in Table 1 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof .

All publications, patent applications, patents, and other documents cited herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

CLAIMS What is claimed is:

1. A method of preparing of a compound of formula (IA), comprising: cyclization of a compound of formula (II):

(II) in a base/solvent, thereby producing a compound of formula (IA):

(IA) wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to

R₂₀;

R₅ is an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, a substituted alkyl, a substituted phenyl, an optionally substituted heteroaryl or an optionally substituted aryl;

R₂₀ is -OH, -SH, or -NH₂; R_2I is O, NH or NR₂₆; R_2Ia is OH, SH, NH₂ or NHR₂₆; and R₂₆ is a Cl -C6 alkyl.

2. The method of Claim 1 , wherein the base is selected from the group consisting of KOH, NaOH, CsOH, carbonates, organic bases, or alkoxides.

3. The method of Claim 2, wherein the base is KOH.

4. The method of Claim 1, wherein the solvent is selected from the group consisting of water, ethanol, methanol or dioxane.

5. The method of Claim 4, wherein the solvent is water.

6. The method of Claim 1 , wherein the compound of formula (II) is prepared by reacting a compound of formula (III):

OH)

with ClCH₂C(O)R_x and a compound of formula (IV):

wherein R_x is -OH or -ONa.

7. The method of Claim 1, wherein the compound of formula (II) is prepared by reacting a compound of formula (III):

(III) with a compound of formula (XXX):

8. The method of Claim 7, wherein the compound of formula (XXX) is prepared from a compound of formula (IV):

(IV)

9. The method of Claim 7, wherein the compound of formula (XXX) is represented by the following:

wherein R₆ is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR₇, -SR₇, -NRi₀Rn, -OC(O)NRi₀Ri ,, -SC(O)NRi₀Ri i, -NR₇C(O)NR₁₀R_{1 1}, -OC(O)R₇, -SC(O)R₇, -NR₇C(O)R₇, -OC(O)OR₇,

-SC(O)OR₇, -NR₇C(O)OR₇, -OCH₂C(O)R₇, -SCH₂C(O)R₇, -NR₇CH₂C(O)R₇, -OCH₂C(O)OR₇, -SCH₂C(O)OR₇, -NR₇CH₂C(O)OR₇, -OCH₂C(O)NR₁₀R₁I, -SCH₂C(O)NR₁₀Rn, -NR₇CH₂C(O)NR₁₀R_{1 1}, -OS(O)_PR₇, -SS(O)_PR₇, -NR₇S(O)₁₃R₇, -OS(O)_pNR₁₀Rn, -SS(O)_pNR₁₀Rn, -NR₇S(0)_pNRioRn, -OS(O)_POR₇, -SS(O)_POR₇, -NR₇S(O)_POR₇, -OC(S)R₇,

-SC(S)R₇, -NR₇C(S)R₇, -OC(S)OR₇, -SC(S)OR₇, -NR₇C(S)OR₇, -OC(S)NRi₀R₁₁, -SC(S)NR₁₀R_n, -NR₇C(S)NR₁₀Ri,, -OC(NR₈)R₇, -SC(NR₈)R₇, -NR₇C(NR₈)R₇, -OC(NR₈)OR₇, -SC(NR₈)OR₇, -NR₇C(NR₈)OR₇, -OC(NR₈)NR₁₀R_{1 1}, -SC(NR₈)NR₁₀R_{1 1}, -NR₇C(NR₈)NR₁₀R_{1 1}, -C(O)R₇, -C(O)OR₇, -C(O)NR₁₀R_{1 1}, -C(O)SR₇,

-C(S)R₇, -C(S)OR₇, -C(S)NR₁₀R_{1 1}, -C(S)SR₇, -C(NR₈)OR₇, -C(NR₈)R₇, -C(NR₈)NR₁₀R_n, -C(NR₈)SR₇, -S(O)_POR₇, -S(O)_pNR₁₀Rn, or -S(O)_PR₇;

R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R)₀ and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ; and p, for each occurrence, is, independently, O, 1 or 2.

10. The method of Claim 8, wherein the compound of formula (IV) is represented by compound of formula (V):

11. The method of Claim 10, wherein the compound of formula (V) is prepared by reacting a compound of formula (VI):

with potassium ethyl xanthogenate; wherein R₆ is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR₇, -SR₇, -NR|₀Rn, -OC(O)NR,₀Ri ,, -SC(O)NRi₀Ri i, -NR₇C(O)NRi₀Ri i, -OC(O)R₇, -SC(O)R₇, -NR₇C(O)R₇, -OC(O)OR₇, -SC(O)OR₇, -NR₇C(O)OR₇, -OCH₂C(O)R₇, -SCH₂C(O)R₇, -NR₇CH₂C(O)R₇, -OCH₂C(O)OR₇, -SCH₂C(O)OR₇, -NR₇CH₂C(O)OR₇, -OCH₂C(O)NR₁₀R_H, -SCH₂C(O)NR₁₀R_I ,, -NR₇CH₂C(O)NR₁₀R_I ,, -0S(0)pR₇, -SS(0)_pR₇, -NR₇S(O)_PR₇, -OS(O)_PNR₁₀R_{1 15} -SS(O)_PNR_1OR₁ ,, -NR₇S(O)_PNRiOR₁₁, -OS(O)_POR₇, -SS(O)_POR₇, -NR₇S(O)_POR₇, -OC(S)R₇,

-SC(S)R₇, -NR₇C(S)R₇, -OC(S)OR₇, -SC(S)OR₇, -NR₇C(S)OR₇, -OC(S)NR₁₀Ri i, -SC(S)NR₁₀R_n, -NR₇C(S)NR₁₀R₁₁, -OC(NR₈)R₇, -SC(NR₈)R₇, -NR₇C(NR₈)R₇, -OC(NR₈)OR₇, -SC(NR₈)OR₇, -NR₇C(NR₈)OR₇, -OC(NR₈)NR₁₀R₁₁, -SC(NR₈)NR₁₀R_{1 1}, -NR₇C(NR₈)NR₁₀R_{1 1}, -C(O)R₇, -C(O)OR₇, -C(O)NR₁₀Rn, -C(O)SR₇,

-C(S)R₇, -C(S)OR₇, -C(S)NR₁₀R₁₁, -C(S)SR₇, -C(NR₈)OR₇, -C(NR₈)R₇, -C(NR₈)NR₁₀R_{1 1}, -C(NR₈)SR₇, -S(O)_POR₇, -S(O)_pNR₁₀Rπ, or -S(O)_PR₇;

R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R)₀ and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ; and p, for each occurrence, is, independently, O, 1 or 2.

12. The method of Claim 10, wherein the compound of formula (V) is prepared by reacting a compound of formula (VI):

with carbon disulfide; wherein R₆ is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR₇, -SR₇, -NRi₀Ri i, -OC(O)NRi₀Rn, -SC(O)NRi₀Ri i, -NR₇C(O)NR₁₀Ri ,, -OC(O)R₇, -SC(O)R₇, -NR₇C(O)R₇, -OC(O)OR₇, -SC(O)OR₇, -NR₇C(O)OR₇, -OCH₂C(O)R₇, -SCH₂C(O)R₇, -NR₇CH₂C(O)R₇, -OCH₂C(O)OR₇, -SCH₂C(O)OR₇, -NR₇CH₂C(O)OR₇, -OCH₂C(O)NR,₀R,i, -SCH₂C(O)NRi₀Rn, -NR₇CH₂C(O)NRi₀Ri,, -OS(O)_PR₇, -SS(O)_pR₇, -NR₇S(O)_PR₇, -OS(O)_PNR_I0R_{1 15} -SS(O)_PNR₁₀R_{1 1} , -NR₇S(0)_pNRioRu, -OS(O)_POR₇, -SS(O)_POR₇, -NR₇S(O)_POR₇, -OC(S)R₇, -SC(S)R₇, -NR₇C(S)R₇, -OC(S)OR₇, -SC(S)OR₇, -NR₇C(S)OR₇, -OC(S)NR,₀R_U, -SC(S)NR₁₀R₁₁, -NR₇C(S)NR₁₀R_{1 1}, -OC(NR₈)R₇, -SC(NR₈)R₇, -NR₇C(NR₈)R₇, -OC(NR₈)OR₇, -SC(NR₈)OR₇, -NR₇C(NR₈)OR₇, -OC(NR₈)NR₁₀R_{1 1}, -SC(NR₈)NR₁₀R_{1 1}, -NR₇C(NR₈)NR₁₀R_{1 1}, -C(O)R₇, -C(O)OR₇, -C(O)NR₁₀R_{1 1}, -C(O)SR₇, -C(S)R₇, -C(S)OR₇, -C(S)NR₁₀R_n, -C(S)SR₇, -C(NR₈)OR₇, -C(NR₈)R₇, -C(NR₈)NR₁₀Rn, -C(NR₈)SR₇, -S(O)_POR₇, -S(O)_pNR₁₀Rn, or -S(O)_PR₇;

R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ; and p, for each occurrence, is, independently, 0, 1 or 2.

13. The method of Claim 1 , wherein R₂o is -OH.

14. The method of Claim 1 , wherein R₅ is represented by the following formula:

wherein R₉, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10R11, -OR₇, -C(O)R₇,

-C(O)OR₇, -OC(O)R₇, -C(O)NR₁₀Rn, -NR₈C(O)R₇, -SR₇, -S(O)_PR₇, -OS(O)_PR₇, -S(O)_POR₇, -NR₈S(O)₁₅R₇, or -S(O)_pNR,₀Rιi, -S(O)_POR₇, -OP(O)(OR₇)₂, or -SP(O)(OR₇)₂; or two R.₉ groups taken together with the carbon atoms to which they are attached form a fused ring;

R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

RiQ and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; and p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.

15. The method of Claim 14, wherein R₅ is represented by one of the following formulas:

wherein: q is zero or an integer from 1 to 7; and u is zero or an integer from 1 to 8.

16. The method of Claim 1, wherein R₅ is represented by the following structural formula:

wherein:

R₃₃ is a -H, halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;

R₃₄ is H, a lower alkyl, or a lower alkylcarbonyl; and ring B and ring C are optionally substituted with one or more substituents in addition to R₃₃ and R₃₄.

17. The method of Claim 1 , wherein R₅ is selected from the group consisting of:

wherein:

X₆, for each occurrence, is independently CH, CRg, N, N(O), N⁺(Rn), provided that at least three X₆ groups are independently selected from CH and CR₉;

X₇, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(Rj₇), provided that at least three X₇ groups are independently selected from CH and CR₉;

X₈, for each occurrence, is independently CH₂, CHR₉, C(R₉)₂, S(O)_P, NR₇, or NR₁₇;

X₉, for each occurrence, is independently N or CH;

Xio, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(Ri₇), provided that at least one Xi₀ is selected from CH and CR₉;

R₉, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRioRn, -OR₇, -C(O)R₇, -C(O)OR₇, -OC(O)R₇, -C(O)NR₁₀Rn, -NR₈C(O)R₇, -SR₇, -S(O)_PR₇, -OS(O)pR₇, -S(O)pOR₇, -NR₈S(O)pR₇, or -S(O)_pNR₁₀Rn, -S(O)_POR₇, -OP(O)(OR₇)₂, or -SP(O)(OR₇)₂; or two R₉ groups taken together with the carbon atoms to which they are attached form a fused ring; R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; Ri₇, for each occurrence, is independently -H, an alkyl, an aralkyl,

-C(O)R₇, -C(O)OR₇, or -C(O)NRi₀Rn; m, for each occurrence, is independently, 1, 2, 3, or 4; and p, for each occurrence, is, independently, 0, 1 or 2.

18. The method of Claim 17, wherein R₅ is an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3H-indazolyl, an optionally substituted indolizinyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted benzoxazolyl, an optionally substituted benzo[ 1 ,3]dioxolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted benzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl, an optionally substituted thiazolo[4,5-c]pyridinyl, an optionally substituted thiazolo[5,4-c]pyridinyl, an optionally substituted thiazolo[4,5-b]pyridinyl, an optionally substituted thiazolo[5,4-b]pyridinyl, an optionally substituted oxazolo[4,5-c]pyridinyl, an optionally substituted oxazolo[5,4-c]pyridinyl, an optionally substituted oxazolo[4,5-b]pyridinyl, an optionally substituted oxazolo[5,4-b]pyridinyl,an optionally substituted imidazopyridinyl, an optionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionally substituted benzotriazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted imidazo[4,5-a]pyridinyl, an optionally substituted imidazo[l,2-a]pyridinyl, an optionally substituted 3H- imidazo[4,5-b]pyridinyl, an optionally substituted lH-imidazo[4,5- b]pyridinyl, an optionally substituted lH-imidazo[4,5-c]pyridinyl, an optionally substituted 3H-imidazo[4,5-c]pyridinyl, an optionally substituted pyridopyrdazinyl, and optionally substituted pyridopyrimidinyl, an optionally substituted pyrrolo[2,3]pyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidyl an optionally substituted cyclopentaimidazolyl, an optionally substituted cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, an optionally substituted pyrrolotriazolyl, or an optionally substituted benzo(b)thienyl.

19. The method of Claims 1 , wherein R₅ is selected from the group consisting of:

wherein:

Xi i, for each occurrence, is independently CH, CR₉, N, N(O), or N⁺(Ri₇), provided that at least one Xi , is N, N(O), or N⁺(Ri₇) and at least two

Xn groups are independently selected from CH and CR₉;

Xi₂, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R_{J 7}), provided that at least one Xi₂ group is independently selected from CH and CR₉; Xi3, for each occurrence, is independently O, S, S(O)p, NR₇, or NRi₇; R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi₀Ri ₁, -OR₇, -C(O)R₇, -C(O)OR₇, -OC(O)R₇, -C(0)NRioRi i, -NR₈C(O)R₇, -SR₇, -S(O)_PR₇, -OS(O)_PR₇, -S(O)_POR₇,

-NR₈S(O)_PR₇, or -S(O)_pNR,₀Rn, -S(O)_POR₇, -OP(O)(OR₇)₂, or -SP(O)(OR₇)₂; or two R₉ groups taken together with the carbon atoms to which they are attached form a fused ring; R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Ri ₁, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; Ri ₇, for each occurrence, is independently -H, an alkyl, an aralkyl,

-C(O)R₇, -C(O)OR₇, or -C(O)NR₁₀Rn; and p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.

20. The method of Claim 1, wherein R₅ is an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group or the cycloalkyl group is substituted with one or more substituents independently selected from the group consisting of : an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, a haloalkyl, halo, cyano, nitro, -NRioRn, -OR₇, -O(CH₂)_mNR₇R_p3, -C(O)R₇, -C(O)OR₇; -C(O)NR₁₀R₁₁; -OC(O)R₇, -OC(O)OR₇, -OC(O)NR₁₀Ri i; -NR₈C(O)R₇, -NR₇C(O)NR₁₀RH , -NR₇C(O)OR₇; -S(O)pR₇, -OS(O)_PR₇, -OS(O)_POR₇, -OS(O)_pNR₁₀Ri i, -S(O)pOR₇, -S(O)_PNR₁₀R₁1, -NR₈S(O)_PR₇, -NR₇S(0)_pNRioRi i, or

-NR₇S(O)_POR₇;

R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀ and Ri ₁, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.

21. The method of Claim 20, wherein R₅ is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.

22. The method of Claim 21 , wherein R₅ is a substituted alkyl.

23. The method of Claim 1, wherein R₅ is a phenyl group substituted with one to five substiruents selected from: an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, a haloalkyl, halo, cyano, nitro, -NRi₀Ri i, -OR₇, -O(CH₂)_mNR₇R_P3, -C(O)R₇, -C(O)OR₇; -C(O)NR₁₀R_n; -OC(O)R₇,

-OC(O)OR₇, -OC(O)NR₁₀RH ; -NR₈C(O)R₇, -NR₇C(O)NR₁₀RH, -NR₇C(O)OR₇; -S(O)_pR₇, -OS(O)_PR₇, -OS(O)_POR₇, -OS(O)_PNR₁₀R_{1 1}, -S(O)_POR₇, -S(O)_PNR₁₀R_{1 1}, -NR₈S(O)_PR₇, -NR₇S(O)_pNR₁₀R, ,, or -NR₇S(O)_POR₇; R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

Ri₀ and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.

24. The method of Claim 16, wherein the compound of formula (II) is represented by structural formula (X):

(X) wherein R₆ is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR₇, -SR₇, -NRi₀R_n, -OC(O)NRi₀Ri ,, -SC(O)NRi₀Ri i, -NR₇C(O)NR₁₀R_H , -OC(O)R₇, -SC(O)R₇, -NR₇C(O)R₇, -OC(O)OR₇, -SC(O)OR₇, -NR₇C(O)OR₇, -OCH₂C(O)R₇, -SCH₂C(O)R₇, -NR₇CH₂C(O)R₇, -OCH₂C(O)OR₇, -SCH₂C(O)OR₇, -NR₇CH₂C(O)OR₇, -OCH₂C(0)NR,oRi i, -SCH₂C(O)NR,₀R, i, -NR₇CH₂C(O)NR _I0R_n, -OS(O)_PR₇, -SS(O)_pR₇, -NR₇S(O)_pR₇, -OS(O)_pNR,₀Ri i, -SS(O)_pNR,₀R, i, -NR₇S(0)pNR,oRn, -OS(O)_POR₇, -SS(O)_POR₇, -NR₇S(O)_POR₇, -OC(S)R₇, -SC(S)R₇, -NR₇C(S)R₇, -OC(S)OR₇, -SC(S)OR₇, -NR₇C(S)OR₇, -OC(S)NR₁₀Ri i, -SC(S)NR₁₀R_I i, -NR₇C(S)NR₁₀RH, -OC(NR₈)R₇, -SC(NR₈)R₇, -NR₇C(NR₈)R₇, -OC(NR₈)OR₇, -SC(NR₈)OR₇, -NR₇C(NR₈)OR₇, -OC(NR₈)NRi₀Ri ,, -SC(NR₈)NR,₀Rn, -NR₇C(NR₈)NR,oRii, -C(O)R₇, -C(O)OR₇, -C(O)NR₁₀R_n, -C(O)SR₇, -C(S)R₇, -C(S)OR₇, -C(S)NR₁₀R_{1 1}, -C(S)SR₇, -C(NR₈)OR₇, -C(NR₈)R₇, -C(NR₈)NR₁₀R_{1 1}, -C(NR₈)SR₇, -S(O)_POR₇, -S(O)₁₅NR₁OR₁ ,, or -S(O)_PR₇; R₇ and Rg, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl p, for each occurrence, is, independently, 0, 1 or 2; and n is zero of an integer from 1 to 4.

25. The method of Claim 24, wherein compound (X) is represented by structural formula (XI):

(XI) wherein:

R₂₅ is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, a haloalkyl, halo, cyano, nitro, -NRi₀R,,, -OR₇, -SR₇, -O(CH₂)_mNR₇R_p3) -C(O)R₇, -C(O)OR₇;

-C(O)NRI₀RI , ; -OC(O)R₇, -OC(O)OR₇, -OC(O)NR₁₀R, ,; -NR₈C(O)R₇, -NR₇C(O)NR_I0R_I i, -NR₇C(O)OR₇; -S(O)_PR₇, -OS(O)_PR₇, -OS(O)_POR₇,

-OS(O)_PNR₁₀Ri₁, -S(O)_POR₇, -S(0)_pNR,oRn, -NR₈S(O)_PR₇,

-NR₇S(0)pNRioR,i, or -NR₇S(O)_POR₇;

R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R,o and R, ,, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; p, for each occurrence, is, independently, O, 1 or 2; m, for each occurrence, is independently, 1, 2, 3, or 4; and r is zero or an integer from 1 to 3.

26. The method of Claim 25, wherein R₂₅ is a -OR₇ Or-NRi₀R, ,.

27. The method of Claim 26, wherein R₃₃ is H or C1-C6 alkyl; and R₃₄ is a Cl- C6 alkyl.

28. The method of Claim 27, wherein compound (XI) is represented by structural formula (XII):

(XII)

29. The method of Claim 28, wherein R₆ is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C3-C6 cycloalkyl or -NRi₀Ri i-

30. The method of Claim 29, wherein R₆ is a C1-C6 alkyl and R₃₃ is H.

31. The method of Claim 30, wherein R₃₃ is -H and ring B is unsubstituted.

32. The method of Claim 31 , wherein R₂o and R₂₅ are -OH, and R₆ is a C 1 -C6 alkyl.

33. The method of Claim 1 , wherein compound (II) is represented by one of the following structural formulas:

or

wherein: X₃ and X₄ are each, independently, N, N(O), N⁺(Ri₇), CH or CR₆; X₅ is O, S, NR₁₇, CH=CH, CH=CR₆, CR₆=CH, CR₆=CR₆, CH=N, CR₆=N, CH=N(O), CR₆=N(O), N=CH, N=CR₆, N(O)=CH, N(O)=CR₆, N⁺(R₁₇)=CH, N⁺(R₁₇)=CR₆, CH=N⁺(R₁₇), CR₆=N⁺(R₁₇), Or N=N; R₆ for each occurence is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR₇, -SR₇, -NRi₀Ri i, -OC(O)NR₁₀R_n, -SC(O)NR₁₀R_{1 1},

-NR₇C(O)NR₁₀R₁₁, -OC(O)R₇, -SC(O)R₇, -NR₇C(O)R₇, -OC(O)OR₇, -SC(O)OR₇, -NR₇C(O)OR₇, -OCH₂C(O)R₇, -SCH₂C(O)R₇, -NR₇CH₂C(O)R₇, -OCH₂C(O)OR₇, -SCH₂C(O)OR₇, -NR₇CH₂C(O)OR₇, -OCH₂C(O)NR₁₀R_{1 1}, -SCH₂C(O)NRi₀R₁I, -NR₇CH₂C(O)NR₁₀R_{1 1}, -OS(O)_PR₇, -SS(O)_pR₇, -NR₇S(O)_PR₇, -OS(O)_PNR_1OR_{I 15} -SS(O)_PNR₁₀R_{1 1},

-NR₇S(0)pNRioRπ, -OS(O)_POR₇, -SS(O)_POR₇, -NR₇S(O)_POR₇, -OC(S)R₇, -SC(S)R₇, -NR₇C(S)R₇, -OC(S)OR₇, -SC(S)OR₇, -NR₇C(S)OR₇, -OC(S)NR₁₀R_{1 1}, -SC(S)NR₁₀R₁₁, -NR₇C(S)NR₁₀R, ,, -OC(NR₈)R₇, -SC(NR₈)R₇, -NR₇C(NR₈)R₇, -OC(NR₈)OR₇, -SC(NR₈)OR₇, -NR₇C(NR₈)OR₇, -OC(NR₈)NR,oR, i, -SC(NR₈)NR₁₀R₁₁,

-NR₇C(NR₈)NR₁₀R₁₁, -C(O)R₇, -C(O)OR₇, -C(O)NR₁₀R_{1 1}, -C(O)SR₇, -C(S)R₇, -C(S)OR₇, -C(S)NR₁₀R₁₁, -C(S)SR₇, -C(NR₈)OR₇, -C(NR₈)R₇, -C(NR₈)NR₁₀R_{1 1}, -C(NR₈)SR₇, -S(O)_POR₇, -S(O)pNR₁₀R_n, or -S(O)_PR₇; R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and Ri ₁, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; and p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4; and n is zero or an integer from 1 to 4.

34. The method of Claim 33, wherein compound (II) is selected from the group consisting of:

R₆ for each occurence is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR₇, -SR₇, -NRi₀R_n, -OC(O)NR_I0R_{I I}, -SC(O)NR_I0R_H, -NR₇C(O)NR₁₀R_H, -OC(O)R₇, -SC(O)R₇, -NR₇C(O)R₇, -OC(O)OR₇, -SC(O)OR₇, -NR₇C(O)OR₇, -OCH₂C(O)R₇, -SCH₂C(O)R₇,

-NR₇CH₂C(O)R₇, -OCH₂C(O)OR₇, -SCH₂C(O)OR₇, -NR₇CH₂C(O)OR₇, -OCH₂C(O)NR₁₀Rι i, -SCH₂C(O)NR₁₀Ri i, -NR₇CH₂C(O)NR₁₀R_n, -OS(O)_PR₇, -SS(O)_pR₇, -NR₇S(O)_PR₇, -OS(O)_PNR₁₀R_{1 1 5} -SS(O)_PNR_1OR_{1 1}, -NR₇S(O)_PNR₁₀R_{1 1}, -OS(O)pOR₇, -SS(O)_POR₇, -NR₇S(O)₁₅OR₇, -OC(S)R₇, -SC(S)R₇, -NR₇C(S)R₇, -OC(S)OR₇, -SC(S)OR₇, -NR₇C(S)OR₇,

-OC(S)NR₁₀R₁₁, -SC(S)NR₁₀R₁₁, -NR₇C(S)NR₁₀R_{1 1}, -OC(NR₈)R₇, -SC(NR₈)R₇, -NR₇C(NR₈)R₇, -OC(NR₈)OR₇, -SC(NR₈)OR₇, -NR₇C(NR₈)OR₇, -OC(NR₈)NR₁₀R_{1 1}, -SC(NR₈)NR₁₀Rn, -NR₇C(NR₈)NR₁₀R_I ,, -C(O)R₇, -C(O)OR₇, -C(O)NR₁₀R₁₁, -C(O)SR₇, -C(S)R₇, -C(S)OR₇, -C(S)NR₁₀R_{1 1}, -C(S)SR₇, -C(NR₈)OR₇, -C(NR₈)R₇,

-C(NR₈)NR₁₀R₁₁, -C(NR₈)SR₇, -S(O)_POR₇, -S(O)_PNR₁₀R₁₁₁ Or -S(O)_PR₇;

R₂₅ for each occurence is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, a haloalkyl, halo, cyano, nitro, -NR₁₀R_{1 1}, -OR₇, -SR₇, -O(CH₂)_mNR₇R_P3, -C(O)R₇, -C(O)OR₇; -C(O)NR₁₀R₁₁; -OC(O)R₇, -OC(O)OR₇, -OC(O)NR₁₀Ri i; -NR₈C(O)R₇, -NR₇C(O)NRi₀R_n, -NR₇C(O)OR₇; -S(O)pR₇, -0S(0)_pR₇, -OS(O)_POR₇, -OS(O)pNR₁₀Rπ, -S(0)p0R₇, -S(O)_PNR₁₀R_n, -NR₈S(O)_PR₇, -NR₇S(O)_pNR₁₀R_n, or -NR₇S(O)_POR₇.

35. The method of Claim 1 , wherein the compound of formula (II) is represented by the following structural formula:

wherein:

X₄I is O, S, or NR₄₂;

X₄₂ is CR₄₄ or N;

Y₄₀ is N or CR₄₃;

Y₄₁ is N or CR₄₅;

Y_42, for each occurrence, is independently N, C or CR₄₆;

R_4I is -H, -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, -NRi₀R_n, -OR₇, -C(O)R₇, -C(O)OR₇, -C(S)R₇, -C(O)SR₇, -C(S)SR₇, -C(S)OR₇, -C(S)NRi₀R_n, -C(NR₈)OR₇, -C(NR₈)R₇, -C(NR₈)NR₁₀R_H, -C(NR₈)SR₇, -OC(O)R₇, -OC(O)OR₇, -OC(S)OR₇, -OC(NR₈)OR₇, -SC(O)R₇, -SC(O)OR₇, -SC(NR₈)OR₇, -OC(S)R₇, -SC(S)R₇, -SC(S)OR₇, -OC(O)NR₁₀R_{1 1}, -OC(S)NR₁₀R_n, -OC(NR₈)NR₁₀RI 1, -SC(O)NR₁₀R_n, -SC(NR₈)NR₁₀R_{1 1}, -SC(S)NR₁₀R_{1 1}, -OC(NR₈)R₇, -SC(NR₈)R₇, -C(O)NR₁₀R_n, -NR₈C(O)R₇, -NR₇C(S)R₇, -NR₇C(S)OR₇, -NR₇C(NR₈)R₇, -NR₇C(O)OR₇, -NR₇C(NR₈)OR₇, -NR₇C(O)NR₁₀RH, -NR₇C(S)NR₁₀Rn, - NR₇C(NR₈)NR₁₀R₁₁₅ -SR₇, -S(O)_PR₇, -OS(O)_PR₇₎ -OS(O)_POR₇, -OS(O)pNR₁₀R_n, -S(O)_POR₇, -NR₈S(O)_PR₇, -NR₇S(O)_PNR₁₀R₁₁, -NR₇S(O)₁₃OR₇, -S(O)_pNR₁₀R, ,, -SS(O)_PR₇, -SS(O)_POR₇, -SS(O)_pNR₁₀R, .,

-OP(O)(OR₇)₂, or -SP(O)(OR₇)₂;

R₄₂ is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, a haloalkyl, halo, cyano, nitro, -NR₁₀R_{1 1}, -OR₇, -O(CH₂)_mNR₇R_p3, -C(O)R₇, -C(O)OR₇; -C(O)NR₁₀R_{1 1}; -OC(O)R₇, -OC(O)OR₇, -OC(O)NR₁₀R_{1 1}; -NR₈C(O)R₇, -NR₇C(O)NR₁₀R₁ , , -NR₇C(O)OR₇; -S(O)_PR₇, -OS(O)_PR₇, -OS(O)_POR₇,

-OS(O)_pNR₁₀Ru, -S(O)_POR₇, -S(O)_pNR₁₀Rπ, -NR₈S(O)_PR₇, -NR₇S(O)_PNR₁₀R₁1, or -NR₇S(O)_POR₇;

R₄₃ and R₄₄ are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, a haloalkyl, halo, cyano, nitro, -NR₁₀R₁₁, -OR₇, -O(CH₂)_mNR₇R_P3, -C(O)R₇, -C(O)OR₇; -C(O)NR₁₀R₁ , ; -OC(O)R₇,

-OC(O)OR₇, -OC(O)NRi₀Rn; -NR₈C(O)R₇, -NR₇C(O)NR₁₀R_{1 1}, -NR₇C(O)OR₇; -S(O)_PR₇, -OS(O)_PR₇, -OS(O)_POR₇, -OS(O)_pNR₁₀R_n, -S(O)_POR₇, -S(0)_pNR,oRπ, -NR₈S(O)_PR₇, -NR₇S(O)pNR,₀Ri ι, or -NR₇S(O)_POR₇; or R₄₃ and R₄₄ taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; R45 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, or a haloalkyl, halo, cyano, nitro, -NRi₀Ri 1, -OR₇, -O(CH₂)_mNR₇R_p3, -C(O)R₇, -C(O)OR₇; -C(O)NRi₀R_n; -OC(O)R₇, -OC(O)OR₇, -OC(O)NR_I0R_{I 1}; -NR₈C(O)R₇, -NR₇C(O)NR₁₀RH, -NR₇C(O)OR₇; -S(O)_PR₇, -OS(O)_PR₇, -OS(O)_POR₇, -OS(O)pNR₁₀Rii, -S(O)_POR₇, -S(O)_pNR₁₀Rπ, -NR₈S(O)_PR₇,

-NR₇S(O)_PNR₁₀RI _I , or -NR₇S(O)_POR₇;

R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and R_{1 1}, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

R₂₆, for each occurrence is, is independently, a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.

36. The method of Claim 35, wherein X₄₁ is NR₄₂ and X₄₂ is CR₄₄.

37. The method of Claim 35, wherein X₄₁ is NR₄₂ and X₄₂ is N.

38. The method of Claim 35, wherein R₄I is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.

39. The method of Claim 35, wherein R₄) is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.

40. The method of Claim 35, wherein X₄₁ is NR₄₂, and R₄₂ is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, and -C(O)N(R₂₇)₂, wherein each R₂₇ is independently -H or a lower alkyl.

41. The compound of Claim 35, wherein X_4I is NR₄₂, and R₄₂ is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, /erf-butyl, n-pentyl, n-hexyl, -CH₂OCH₃, -CH₂CH₂OCH₃, and -C(O)N(CH₃)₂.

42. The method of Claim 35, wherein R₄₃ and R₄₄ are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.

43. The method of Claim 35, wherein X₄₂ is CR₄₄; Y₄₀ is CR₄₃; and R₄₃ and R₄₄ together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.

44. The method of Claim 43, wherein R₄₃ and R₄₄ together with the carbon atoms to which they are attached form a C₅-C₈ cycloalkenyl or a C₅-C₈ aryl.

45. The method of Claim 44, wherein R₄₅ is selected from the group consisting of -H, -OH, methoxy and ethoxy.

46. The method of Claim 43, wherein X₄] is O.

47. The method of Claim 35, wherein the compound of formula (II) is represented by the following structural formula:

48. The method of Claim 47, wherein X₄₂ is CR₄₄, and R₄₃ and R₄₄ are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.

49. The method of Claim 48, wherein X₄₂ is CR₄₄, and R₄₃ and R₄₄, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring.

50. The method of Claim 47, wherein R₄₃ and R₄₄, taken together with the carbon atoms to which they are attached, form a C₅-C₈ cycloalkenyl or a C₅-

C₈ aryl. - _ _ . .

51. The method of Claim 47, wherein X₄₂ is CR₄₄.

52. The method of Claim 47, wherein X₄₂ is N.

53. The method of Claim 35, wherein the compound of formula (II) is represented by the following structural formula:

wherein:

X₄₅ is CR₅₄ or N;

R₅₆ is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl;

R₅₂ is selected from the group consisting of -H, methyl, ethyl, n- propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, and -(CH₂)₂OCH₃;

R₅₃ and R₅₄ are each, independently, -H, methyl, ethyl, or isopropyl; or R₅₃ and R₅₄ taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring; and

R₅₅ is selected from the group consisting of -H, -OH, -OCH₃, and -OCH₂CH₃.

54. A method of preparing a compound of formula (II),

(H) comprising: reacting a compound of formula (III):

(III) with ClCH₂C(O)R_x and a compound of formula (IV):

(IV) thereby producing a compound of formula (II), wherein: ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to

R20;

R₅ is an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, a substituted alkyl, a substituted phenyl, an optionally substituted heteroaryl or an optionally substituted aryl;

R_x is -OH or -ONa;

R₂₀ is -OH, -SH, or -NH₂;

R₂₁ is O, NH or NR₂₆; and _

R₂₆ is a Cl -C6 alkyl.

55. The method of Claim 54, wherein R₅ is represented by the following formula:

wherein R₉, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR₁₀R_{1 1}, -OR7, -C(O)R₇, -C(O)OR₇, -OC(O)R₇, -C(O)NR₁₀R_{1 1}, -NR₈C(O)R₇, -SR₇, -S(O)_PR₇, -OS(O)_PR₇, -S(O)pOR₇, -NR₈S(O)pR₇, or -S(O)_pNR₁₀Rn, -S(O)_POR₇,

-OP(O)(OR₇)₂, or -SP(O)(OR₇)₂; or two R₉ groups taken together with the carbon atoms to which they are attached form a fused ring;

R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and R₁₁, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; and p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.

56. The method of Claim 55, wherein R₅ is represented by one of the following formulas:

wherein: q is zero or an integer from 1 to 7; and u is zero or an integer from 1 to 8.

57. The method of Claim 54, wherein R₅ is represented by the following structural formula:

wherein:

R₃₃ is a -H, halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;

R₃₄ is H, a lower alkyl, or a lower alkyl carbonyl; and ring B and ring C are optionally substituted with one or more substituents in addition to R₃₃ and R₃₄.

58. The method of Claim 54, wherein R₅ is selected from the group consisting of:

wherein:

X₆, for each occurrence, is independently CH, CRg, N, N(O), N⁺(Rj₇), provided that at least three X₆ groups are independently selected from CH and CR₉;

X₇, for each occurrence, is independently CH, CRg, N, N(O), N⁺(Rj₇), provided that at least three X₇ groups are independently selected from CH and CR₉;

X₈, for each occurrence, is independently CH₂, CHR₉, C(R₉)₂, S(O)_P, NR₇, or NR_n;

X₉, for each occurrence, is independently N or CH; Xio, for each occurrence, is independently CH, CR9, N, N(O), N⁺(R]₇), provided that at least one Xio is selected from CH and CR9;

R₉, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi₀Ri ₁, -OR₇, -C(O)R₇,

-C(O)OR₇, -OC(O)R₇, -C(O)NR₁₀R₁₁, -NR₈C(O)R₇, -SR₇, -S(O)_PR₇, -OS(O)_PR₇, -S(O)_POR₇, -NR₈S(O)pR₇, or -S(O)_pNR₁₀Rπ, -S(O)_POR₇, -OP(O)(OR₇)₂, or -SP(O)(OR₇)₂; or two R₉ groups taken together with the carbon atoms to which they are attached form a fused ring;

R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

R₁₀ and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R_1O and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

R₁₇, for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R₇, -C(O)OR₇, or -C(O)NR₁₀R_{1 1}; m, for each occurrence, is independently, 1, 2, 3, or 4; and p, for each occurrence, is, independently, 0, 1 or 2.

59. The method of Claim 58, wherein R₅ is an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3H-indazolyl, an optionally substituted indolizinyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted benzoxazolyl, an optionally substituted benzo[l,3]dioxolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted benzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl, an optionally substituted thiazolo[4,5-c]pyridinyl, an optionally substituted thiazolo[5,4-c]pyridinyl, an optionally substituted thiazolo[4,5-b]pyridinyl, an optionally substituted thiazolo[5,4-b]pyridinyl, an optionally substituted oxazolo[4,5-c]pyridinyl, an optionally substituted oxazolo[5,4-c]pyridinyl, an optionally substituted oxazolo[4,5-b]pyridinyl, an optionally substituted oxazolo[5,4-b]pyridinyl,an optionally substituted imidazopyridinyl, an optionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionally substituted benzotriazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted imidazo[4,5-a]pyridinyl, an optionally substituted imidazo[l,2-a]pyridinyl, an optionally substituted 3H- imidazo[4,5-b]pyridinyl, an optionally substituted lH-imidazo[4,5- b]pyridinyl, an optionally substituted l//-imidazo[4,5-c]pyridinyl, an optionally substituted 3H-imidazo[4,5-c]pyridinyl, an optionally substituted pyridopyrdazinyl, and optionally substituted pyridopyrimidinyl, an optionally substituted pyrrolo[2,3]pyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidyl an optionally substituted cyclopentaimidazolyl, an optionally substituted cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, an optionally substituted pyrrolotriazolyl, or an optionally substituted benzo(b)thienyl.

60. The method of Claims 54, wherein R₅ is selected from the group consisting of:

wherein:

X) i, for each occurrence, is independently CH, CR₉, N, N(O), or N⁺(R)₇), provided that at least one X) ₁ is N, N(O), or N⁺(R)₇) and at least two X) ) groups are independently selected from CH and CR₉;

X)₂, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R)₇), provided that at least one X)₂ group is independently selected from CH and CR₉;

Xi₃, for each occurrence, is independently O, S, S(O)p, NR₇, or NR)₇; R₉, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR)₀R,,, -OR₇, -C(O)R₇, -C(O)OR₇, -OC(O)R₇, -C(O)NR₁₀Ri ,, -NR₈C(O)R₇, -SR₇, -S(O)_PR₇, -OS(O)_PR₇, -S(O)_POR₇, -NR₈S(O)pR₇, or -S(O)_pNR₁₀Rii, -S(O)_POR₇, -OP(O)(OR₇)₂, or -SP(O)(OR₇)₂; or two R₉ groups taken together with the carbon atoms to which they are attached form a fused ring;

R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

Ri₀ and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

Ri₇, for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R₇, -C(O)OR₇, or -C(O)NR₁₀Rn; and p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.

61. The method of Claim 54, wherein R₅ is an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group or the cycloalkyl group is substituted with one or more substiruents independently selected from the group consisting of : an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, a haloalkyl, halo, cyano, nitro, -NRi₀Ri i, -OR₇, -O(CH₂)_mNR₇R_p3, -C(O)R₇, -C(O)OR₇; -C(O)NR₁₀R₁₁; -OC(O)R₇, -OC(O)OR₇, -OC(O)NR₁₀R₁₁; -NR₈C(O)R₇, -NR₇C(O)NR₁₀R_n, -NR₇C(O)OR₇; -S(O)pR₇, -OS(O)_PR₇, -OS(O)_POR₇, -OS(O)_pNR,₀Rii,

-S(O)_POR₇, -S(O)_PNR₁₀R₁ ,, -NR₈S(O)pR₇, -NR₇S(O)_PNR₁₀R_{1 1}, or -NR₇S(O)₁₅OR₇;

R₇ and Rg, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.

62. The method of Claim 61 , wherein R₅ is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.

63. The method of Claim 62, wherein R₅ is a substituted alkyl.

64. The method of Claim 54, wherein R₅ is a phenyl group substituted with one to five substituents selected from: an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, a haloalkyl, halo, cyano, nitro, -NRioRn,

-OR₇, -O(CH₂)_mNR₇R_P3, -C(O)R₇, -C(O)OR₇; -C(O)NR₁₀R, ,; -OC(O)R₇, -OC(O)OR₇, -OC(0)NR,oRii; -NR₈C(O)R₇, -NR₇C(O)NR₁₀Rn, -NR₇C(O)OR₇; -S(O)_PR₇, -OS(O)_PR₇, -OS(O)_POR₇, -OS(O)_pNR₁₀Rn, -S(O)_POR₇, -S(O)pNR₁₀Rn, -NR₈S(O)_PR₇, -NR₇S(O)_pNR₁₀Rn, or -NR₇S(O)_POR₇;

R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.

65. The method of Claim 54, wherein the compound of formula (IV) is represented by the following structural formula:

wherein R₆ is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR₇, -SR₇, -NRi₀Ri 1, -OC(O)NR_I0R_I 1, -SC(O)NRi₀Ri ,, -NR₇C(O)NR₁₀R_{1 1}, -OC(O)R₇, -SC(O)R₇, -NR₇C(O)R₇, -OC(O)OR₇,

-SC(O)OR₇, -NR₇C(O)OR₇, -OCH₂C(O)R₇, -SCH₂C(O)R₇, -NR₇CH₂C(O)R₇, -OCH₂C(O)OR₇, -SCH₂C(O)OR₇, -NR₇CH₂C(O)OR₇, -OCH₂C(O)NRioRi 1, -SCH₂C(O)NR,oRi i, -NR₇CH₂C(O)NR₁₀R_{1 1}, -OS(O)_PR₇, -SS(O)pR₇, -NR₇S(COpR₇, -OS(O)_PNR₁ORIb -SS(O)_PNR₁₀R₁,, -NR₇S(0)pNRioRn, -OS(O)_POR₇, -SS(O)_POR₇, -NR₇S(O)_pOR₇, -OC(S)R₇, -SC(S)R₇, -NR₇C(S)R₇, -OC(S)OR₇, -SC(S)OR₇, -NR₇C(S)OR₇, -OC(S)NRI₀RI i, -SC(S)NRi₀Ri i, -NR₇C(S)NR₁₀RH , -OC(NR₈)R₇, -SC(NR₈)R₇, -NR₇C(NR₈)R₇, -OC(NR₈)OR₇, -SC(NR₈)OR₇,

-NR₇C(NR₈)OR₇, -OC(NR₈)NR₁₀Ri ₁, -SC(NR₈)NR₁₀R_{1 1}, -NR₇C(NR₈)NR₁₀R_{1 1}, -C(O)R₇, -C(O)OR₇, -C(O)NR₁₀R₁ I, -C(O)SR₇, -C(S)R₇, -C(S)OR₇, -C(S)NR₁₀Rn, -C(S)SR₇, -C(NR₈)OR₇, -C(NR₈)R₇, -C(NR₈)NR₁₀R_n, -C(NR₈)SR₇, -S(O)_POR₇, -S(O)_pNR₁₀Rn, or -S(O)_PR₇; R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

R₁₀ and Ru, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl p, for each occurrence, is, independently, O, 1 or 2; and n is zero of an integer from 1 to 4.

66. The method of Claim 54, wherein the compound of formula (III) is represented by the following structural formula:

wherein:

R₃₃ is a -H, halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl; R₃₄ is H, a lower alkyl, or a lower alkylcarbonyl; and ring B and ring C are optionally substituted with one or more substituents in addition to R₃₃ and R₃₄.

67. The method of Claim 65, wherein the compound of formula (IV) is represented by the following structural formula:

wherein:

R₂₅ is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, a haloalkyl, halo, cyano, nitro, -NRi₀Ri ι, -OR₇, -SR₇, -O(CH₂)_mNR₇R_p3, -C(O)R₇, -C(O)OR₇; -C(O)NR_{I 0}R_I i; -OC(O)R₇, -OC(O)OR₇, -OC(O)NR₁₀Ri ■; -NR₈C(O)R₇, -NR₇C(O)NR₁₀R_H , -NR₇C(O)OR₇; -S(O)_PR₇, -OS(O)_PR₇, -OS(O)_POR₇, -OS(O)pNR₁₀Rii, -S(O)_POR₇, -S(O)_pNR,₀Ri i, -NR₈S(O)_PR₇, -NR₇S(O)pNR₁₀Rn, or -NR₇S(O)_POR₇.

68. The method of Claim 67, wherein the compound of formula (III) is represented by the following structural formula:

wherein:

R₃₃ is a -H, halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;

R₃₄ is H, a lower alkyl, or a lower alkyl carbonyl; and ring B and ring C are optionally substituted with one or more substituents in addition to R₃₃ and R₃₄.

69. The method of Claim 68, wherein wherein R₂₅ is a -OR₇ or-NRioRi i .

70. The method of Claim 69, wherein R₃₃ is H or C1-C6 alkyl; and R₃₄ is a Cl- C6 alkyl.

71. The method of Claim 70, wherein the compound of formula (IV) is represented by the following structural formula:

72. The method of Claim 71 , wherein

R_2I is O;

R₆ is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C3-C6 cycloalkyl or -NRioRn.

73. The method of Claim 72, wherein R₆ is a C1-C6 alkyl and R₃₃ is H.

74. The method of Claim 73, wherein R₃₃ is -H and ring B is unsubstituted.

75. The method of Claim 74, wherein R₂₀ and R₂₅ are -OH, and R₆ is a C1-C6 alkyl.

76. The method of Claim 54, wherein the copmpound of formula (IV) is represented by the following structural formulas:

wherein:

R₂₅ is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, a haloalkyl, halo, cyano, nitro, -NRi₀Rn, -OR₇, -SR₇, -O(CH₂)_mNR₇R_p3, -C(O)R₇, -C(O)OR₇; -C(O)NR₁₀Rn; -OC(O)R₇, -OC(O)OR₇, -OC(O)NR₁₀Ri i; -NR₈C(O)R₇, -NR₇C(O)NR₁₀R_H, -NR₇C(O)OR₇; -S(O)_PR₇, -OS(O)_PR₇, -OS(O)_POR₇, -OS(0)_pNR,oRii, -S(O)_POR₇, -S(O)_pNRi₀Rii, -NR₈S(O)₁₅R₇, -NR₇S(O)_pNR₁₀Ri i, or -NR₇S(O)_POR₇.

77. The method of Claim 54, wherein the compound of formula (III) is represented by the following structural formula:

wherein: X_4I is O, S₅ Or NR₄₂;

X4₂ is CR4₄ or N;

Y_4O is N or CR₄₃;

Y₄ι is N or CR₄₅; Y₄₂, for each occurrence, is independently N, C or CR₄₆;

R₄₂ is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, a haloalkyl, halo, cyano, nitro, -NRi₀Ri ₁, -OR₇, -O(CH₂)_mNR₇Rp₃, -C(O)R₇, -C(O)OR₇; -C(O)NR₁₀Rn; -OC(O)R₇, -OC(O)OR₇, -OC(O)NR₁₀R_H ; -NR₈C(O)R₇, -NR₇C(O)NR₁₀R₁₁, -NR₇C(O)OR₇; -S(O)_PR₇, -OS(O)_PR₇, -OS(O)_POR₇, -OS(O)_pNR₁₀Rπ, -S(O)_POR₇, -S(O)_pNR₁₀Rπ, -NR₈S(O)_PR₇,

-NR₇S(O)_PNR₁₀R_{1 1}, or -NR₇S(O)_POR₇;

R₄₃ and R₄₄ are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, a haloalkyl, halo, cyano, nitro, -NRi₀R_{1 1}, -OR₇, -O(CH₂)_mNR₇R_P3, -C(O)R₇, -C(O)OR₇; -C(O)NR₁₀R₁₁; -OC(O)R₇, -OC(O)OR₇, -OC(O)NRi₀R₁ , ; -NR₈C(O)R₇, -NR₇C(O)NR₁₀R₁ , ,

-NR₇C(O)OR₇; -S(O)_PR₇, -OS(O)_PR₇, -OS(O)_POR₇, -OS(O)_pNR₁₀Rπ, -S(O)_POR₇, -S(O)_PNR₁₀R_{1 1}, -NR₈S(O)_PR₇, -NR₇S(O)_PNR₁₀R_{1 1}, or -NR₇S(O)₁₃OR₇; or R₄₃ and R₄₄ taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; R₄₅ is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, alkoxyalkyl, haloalkoxyalkyl, a heteroalkyl, or a haloalkyl, halo, cyano, nitro, -NR₁₀Rn, -OR₇, -O(CH₂)_mNR₇R_p3, -C(O)R₇, -C(O)OR₇; -C(O)NR₁₀R_{1 1}; -OC(O)R₇, -OC(O)OR₇, -OC(O)NR₁₀R_{1 1}; -NR₈C(O)R₇, -NR₇C(O)NR₁₀R_n, -NR₇C(O)OR₇; -S(O)_PR₇, -OS(O)_PR₇, -OS(O)_POR₇, -OS(O)₁₃NR₁OR₁ ,, -S(O)_POR₇, -S(O)_pNR₁₀R, ,, -NR₈S(O)_PR₇,

-NR₇S(O)_PNR₁₀R₁ ,, or -NR₇S(O)_POR₇;

R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;

Ri₀ and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R₁₀ and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

R₂₆, for each occurrence is, is independently, a lower alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.

78. The method of Claim 77, wherein the compound of formula (IV) is represenented by a compound of formula (VI):

wherein R₆ is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR₇, -SR₇, -NRi₀Ri i, -OC(O)NR_I0R_{I I} , -SC(O)NR_{I 0}R_H , -NR₇C(O)NR_{I 0}R_I i, -OC(O)R₇, -SC(O)R₇, -NR₇C(O)R₇, -OC(O)OR₇, -SC(O)OR₇, -NR₇C(O)OR₇, -OCH₂C(O)R₇, -SCH₂C(O)R₇, -NR₇CH₂C(O)R₇, -OCH₂C(O)OR₇, -SCH₂C(O)OR₇, -NR₇CH₂C(O)OR₇, -OCH₂C(0)NR,oRii, -SCH₂C(O)NR₁₀R_{1 1}, -NR₇CH₂C(O)NR₁₀R₁₁, -OS(O)_PR₇, -SS(O)pR₇, -NR₇S(O)_PR₇, -OS(O)_PNR₁₀R_{1 I 5} -SS(O)_PNR₁₀R, ,, -NR₇S(0)_pNR,oR, i, -OS(O)_POR₇, -SS(O)_POR₇, -NR₇S(O)_POR₇, -OC(S)R₇, -SC(S)R₇, -NR₇C(S)R₇, -OC(S)OR₇, -SC(S)OR₇, -NR₇C(S)OR₇, -OC(S)NR₁₀R, ,, -SC(S)NR₁₀R_{1 1}, -NR₇C(S)NR₁₀R_{1 1}, -OC(NR₈)R₇, -SC(NR₈)R₇, -NR₇C(NR₈)R₇, -OC(NR₈)OR₇, -SC(NR₈)OR₇, /

-NR₇C(NR₈)OR₇, -OC(NR₈)NR₁₀R_{I 1}, -SC(NR₈)NR₁₀R₁₁, -NR₇C(NR₈)NR₁₀R₁₁, -C(O)R₇, -C(O)OR₇, -C(O)NR₁₀R_{1 1}, -C(O)SR₇, -C(S)R₇, -C(S)OR₇, -C(S)NR₁₀R₁₁, -C(S)SR₇, -C(NR₈)OR₇, -C(NR₈)R₇, -C(NR₈)NR₁₀R₁₁, -C(NR₈)SR₇, -S(O)_POR₇, -S(O)_PNR₁₀R₁₁₅ Or -S(O)_PR₇;

R₇ and R₈, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl ; and p, for each occurrence, is, independently, 0, 1 or 2.

79. The method of Claim 78, wherein X₄] is NR₄₂ and X₄₂ is CR₄₄.

80. The method of Claim 78, wherein X₄I is NR₄₂ and X₄₂ is N.

81. The method of Claim 78, wherein R₄] is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.

82. The method of Claim 78, wherein R_4I is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.

83. The method of Claim 78, wherein X₄) is NR₄₂, and R₄₂ is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, and -C(O)N(R₂₇)₂, wherein each R₂₇ is independently -H or a lower alkyl.

84. The compound of Claim 78, wherein X₄₁ is NR₄₂, and R₄₂ is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, -CH₂OCH₃, -CH₂CH₂OCH₃, and -C(O)N(CH₃)₂.

85. The method of Claim 78, wherein R₄₃ and R₄₄ are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.

86. The method of Claim 78, wherein X₄₂ is CR₄₄; Y₄o is CR₄₃; and R₄₃ and R₄₄ together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.

87. The method of Claim 86, wherein R₄₃ and R₄₄ together with the carbon atoms to which they are attached form a C₅-C₈ cycloalkenyl or a C₅-C₈ aryl.

88. The method of Claim 86, wherein R₄₅ is selected from the group consisting of -H, -OH, methoxy and ethoxy.

89. The method of Claim 86, wherein X_4I is O.

90. The method of Claim 78, wherein the compound of formula (III) is represented by the following structural formula:

wherein R₂₁ is O.

91. The method of Claim 90, wherein X₄₂ is CR₄₄, and R₄₃ and R₄₄ are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.

92. The method of Claim 91 , wherein X₄₂ is CR₄₄, and R₄₃ and R₄₄, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring.

93. The method of Claim 92, wherein R₄₃ and R₄₄, taken together with the carbon atoms to which they are attached, form a C₅-C₈ cycloalkenyl or a C₅- C₈ aryl.

94. The method of Claim 92, wherein X₄₂ is CR₄₄.

95. The method of Claim 92, wherein X₄₂ is N.

96. The method of Claim 78, wherein the compound of formula (III) is represented by the following structural formula:

wherein:

X₄₅ is CR₅₄ or N;

R₂₁ is O;

R₅₆ is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl;

R₅₂ is selected from the group consisting of -H, methyl, ethyl, n- propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, and -(CH₂)₂OCH₃;

R₅₃ and R₅₄ are each, independently, -H, methyl, ethyl, or isopropyl; or R₅₃ and R₅₄ taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring; and

R₅₅ is selected from the group consisting of -H, -OH, -OCH₃, and -OCH₂CH₃.