WO2007139952A2 - Method for the preparation of triazole compounds with hsp90 modulating activity - Google Patents

Method for the preparation of triazole compounds with hsp90 modulating activity Download PDF

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WO2007139952A2
WO2007139952A2 PCT/US2007/012520 US2007012520W WO2007139952A2 WO 2007139952 A2 WO2007139952 A2 WO 2007139952A2 US 2007012520 W US2007012520 W US 2007012520W WO 2007139952 A2 WO2007139952 A2 WO 2007139952A2
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optionally substituted
independently
group
alkyl
occurrence
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PCT/US2007/012520
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WO2007139952A3 (en
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Chi-Wan Lee
David James
Shijie Zhang
Weiwen Ying
Dinesh U. Chimmanamada
Junghyun Chae
Teresa Przewloka
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Synta Pharmaceuticals Corp.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • triazole-based hsp90 inhibitors such as the compounds described in U.S. Publication No. 20060167070, incorporated herein by reference in its entirety, show promise in the treatment of proliferative disorders, such as cancer.
  • 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 commercial scale synthesis. Therefore, the need exists for improved synthese of these compounds.
  • the present invention is directed to novel synthetic methods for preparing certain [1 ,2,4]-trizole compounds, which are suitable for industrial-scale synthesis with minimal purification required.
  • One embodiment of the invention is directed to a method (method I) of preparing a triazole compound represented by Structural Formula (I):
  • the method of preparing a [l,2,4]triazole compound comprises the steps of: a) reacting an amide represented by Structural Formula (II):
  • ring A is an aryl or a heteroaryl optionally further substituted with one or more substituents in addition to Ry
  • R 3 is -OR 26 , -SR 26 , -O(CH 2 ) m OR A , -O(CH 2 ) m SR B , -O(CH 2 ) m NR 7 Rc,
  • R 5 is an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted cycloaliphatic, or an optionally substituted alkyl;
  • R 7 and R 8 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 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 Ri 0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
  • R 26 is a C1-C6 alkyl; p, for each occurrence, is, independently, 0, 1 or 2; m, for each occurrence, is independently, 1, 2, 3, or 4; in Structural Formula (I), Ri is -OH, -SH or -NHR 7 ; and X is a leaving group.
  • the present invention is directed to a method of preparing a triazole compound represented by the Structural Formula (V):
  • the method of preparing the [l,2,4]triazole compound comprises the steps of: a) reacting an amide represented by Structural Formula (VI):
  • step c) reacting the hydrazonamide of step b) with a carbonylation reagent to form a • protected triazole compound; and d) deprotecting the protected triazole compound formed in step c) to form the triazole compound; wherein R A is a hydroxyl protecting group.
  • Another embodiment of the invention is directed to a method of preparing the thioamide represented by Structural Formula (III) by reacting the amide represented by Structural Formula (II) with thionation reagent.
  • the present invention is also directed to a method of preparing the hydrazonamide represented by Structural Formula (FV) by reacting the thioamide of Structural Formula (III) with hydrazine.
  • Another embodiment of the invention is directed to a method of preparing the [l,2,4]triazole compound by reacting the hydrazonamide of Structural Formula (IV) with a carbonylation reagent, a thiocarbonylation reagent or an isocyanide.
  • inventions of the present invention are synthetic intermediates in the preparation of the [ 1 ,2,4]triazole compound represented by Structural Formula (III) and Structural Formula (IV) by the methods disclosed herein.
  • the present invention is a method (method II) of synthesis of a compound of Structural Formula (IA)
  • 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 R 20 ;
  • Rs 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;
  • R2 0 is -OR p i, -NHRp 3 or -N(Rp3) 2 , wherein R p i, for each occurrence, is independently selected from groups suitable for protecting hydroxyl, and R p3 , for each occurrence, is independently selected from groups suitable for protecting an amino group; R21 is O, NH, or NR 26 , and R 2)a is OH, NH 2 or NHR 26 ; and R 26 is a C 1-C6 alkyl- In another embodiment, the present invention is a method of synthesis of a compound of Structural Formula (IIA),
  • the present invention is a method of synthesis of a compound of Structural Formula (XXXIA)
  • Substituents R 30 ] and R 302 are each independently -H, an alkyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, each optionally substituted by one or more of an alkyl, alkoxy, haloalkyl, halogen nitro, cyano or alkyl alkanoate groups.
  • the present invention is a method of synthesis of the compound of Structural Formula (XXA)
  • the present invention is a compound of Structural Formula (UA):
  • Another embodiment of the present invention is directed to a method (method III) of preparing a compound thereof represented by the following Structural Formula:
  • the method comprises the step of reacting a first starting compound represented by the following Structural Formula:
  • Ri b is -OH, -SH or -NHR 60 ; preferably, R Ib is -OH or -SH.
  • R 60 is H, an optionally substituted alkyl group, or an optionally substituted cycloalkyl group.
  • Ring A is an aryl or a heteroaryl, wherein the aryl group and the heteroaryl group represented by ring A is optionally further substituted with one or more substituents in addition to R 3b .
  • R 3b is -OR 100 , -SRioi, -N(R,02) 2 , -NR 7 Ri 025 -OR 26 , -SR 2 6, -NR 26 Ri 02 , -O(CH 2 ) m OR 100 , -O(CH 2 ) m SR 101 , -O(CH 2 ) m NR 7 R, 02 , -S(CH 2 ) m OR, 00 , -S(CH 2 ) m SR, O i, -S(CH 2 )H 1 NR 7 R 1 O 25 -OC(O)NR 10 Rn, -SC(O)NR 10 Rn, -NR 7 C(O)NR 10 R 11 , -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -NR 7 C(O)OR 7 , -OC
  • R 3b is -ORi 00 , -SR 10I5 -N(R, 02 ) 2 , -NR 7 R 102 , -OR 26 , -SR 26 , -NR 26 R, 02 , -0(CHz) 1n OR 100 , -O(CH 2 ) m SR 10 i, -O(CH 2 ) m NR 7 Ri 02 , -S(CH 2 ) m OR 100 , -S(CH 2 ) m SR 101 , and -S(CH 2 ) m NR 7 R 102 .
  • Each Rioo is a hydroxy 1 protecting group.
  • Each Rioi independently, is a thiol protecting group.
  • Each R- 102 is -H or an amino protecting group, provided that at least one group represented by R 1 0 2 is a protecting group.
  • R 5 is an optionally substituted aryl group, an optionally substituted heteroarylgroup, an optionally substituted cycloalkyl group, an optionally substituted cycloakenyl group, or a substituted alkyl group, wherein each of the aryl group, heteroaryl group, cycloaryl group, cycloalkyl group, cycloalkenyl group, and alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkyl group, an optionally substituted alkynyl, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted heteroaryl group, an optionally substituted aralyalkyl group, or an optionally substituted heteraralkyl group.
  • R 7 and Rs 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, or R 7 , taken together with the oxygen atom to which it is bonded, forms an optionally substituted heterocyclyl or an optionally substituted heteroaryl.
  • Rio and R n are, independently, amine protecting group, 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 Ri 0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.
  • R 2 6 is a lower alkyl group.
  • R 50 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, or an optionally substituted heteraralky.
  • p for each occurrence, is, independently, 0, 1 or 2.
  • m for each occurrence, is, independently, 1, 2, 3, or 4.
  • the present invention is directed to a method of preparing a compound thereof represented by the following Structural Formula:
  • the method comprises the step of reacting a first starting compound represented by the following Structural Formula:
  • each Rioo independently, is a hydroxyl protecting group; and R 50 is an alkyl.
  • the present invention is directed to a method of preparing a compound thereof represented by the following Structural Formula: (VIIB) or a tautomer, a pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. The method comprises the steps of:
  • R 3b is -ORi 00 , -SRioi, -N(R, 02 )2 , -NR 7 Ri 02 , -OR 26 , -SR 26 , -NR 26 R 102 ,
  • the methods of the present invention described above overcomes the problem of poor selectivity and eliminates the need of high temperature heating in the prior methods. Instead, the methods provides compounds in high yield and with clean crystallization that is obtained under moderate temperature.
  • FIG. 1 shows a synthetic scheme for preparing [1 ,2,4]triazole compound represented by Structural Formula (I).
  • the present invention is directed to novel synthetic methods for synthesizing certain [l,2,4]-triazole compounds, which inhibit the activity of Hsp90 and are useful in the treatment of proliferative disorders, such as cancer.
  • the terms used herein are defined as follows:
  • 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, /erf-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, 2-methyIhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3- dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpent
  • (C r C fi )alkyP' means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms.
  • Representative (Ci-C 6 )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.
  • 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 (C 2 -Ci 0 )alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-l-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.
  • 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-l-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
  • 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.
  • 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 substituent
  • 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.
  • 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, A- iodobutyl, 2-fluoropentyl, and the like.
  • an "alkoxy” is an alkyl group which is attached to another moiety via an oxygen linker.
  • an “haloalkoxy” is an haloalkyl group which is attached to another moiety via an oxygen linker.
  • an "aromatic ring” or “aryl” means a hydrocarbon monocyclic or polycyclic radical in which at least one ring is aromatic.
  • 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.
  • the aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(Ce)aryl.”
  • aralkyl means an aryl group that is attached to another group by a (Ci-Ce)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.
  • alkylene refers to an alkyl group that has two points of attachment.
  • (Ci-C 6 )alkylene refers to an alkylene group that has from one to six carbon atoms.
  • Straight chain (Ci -C 6 )alkylene groups are preferred.
  • Non-limiting examples of alkylene groups include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), n-propylene (-CH 2 CH 2 CH 2 -), isopropylene (-CHaCH(CHa)-), and the like.
  • Alkylene groups may be optionally substituted with one or more substituents.
  • 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.
  • 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 morpholi ⁇ yl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • 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.
  • the heterocyclyl may be optionally substituted with one or more substituents. Only stable isomers of such substituted heterocyclic groups are contemplated in this definition.
  • 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 quatemized; 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, imidazopyridy
  • 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.
  • (C 5 )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 (Cs)heteroaryls include fiiranyl, thienyU pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyrazinyl, triazolyl, thiadiazolyl, and the like.
  • (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 (C 6 )heteroaryls include pyridyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl and the like.
  • heterooaralkyl means a heteroaryl group that is attached to another group by a (Ci-C 6 )alkylene.
  • 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.
  • 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 of the invention.
  • substituents for an alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl include R 28 a haloalkyl, -C(O)NR 28 R 29 , -C(S)NR 28 R 29 , -C(NR 32 )NR 28 R 29 , -NR 30 C(O)R 3 ], -NR 30 C(S)R 3I , -NR 30 C(NR 32 )R 31 , halo, -OR 30 , cyano, nitro, haloalkoxy, -C(O)R 30 , -C(S)R 30 , -C(NR 32 )R 30 , -NR 28 R 29 , -C(O)OR 30 , -C(S)OR 30 , -C(NR 32 )OR 30 , -OC
  • R 28 and R 29 for each occurrence are, independently, H, alkyl, alkenyl, alkynyl, an cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteraralkyl; or R 28 and R 29 taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl.
  • the substituents are HOt -C(O)NR 28 R 29 , -NR 30 C(O)R 3I , -C(O)OR 30 , -NR 30 C(O)NR 28 R 29 , -OC(O)NR 28 R 29 , -NR 30 C(O)OR 3 I.
  • R 30 and R 3] 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
  • R 32 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)R 30 , -C(O)NR 28 R 29 , -S(O) p R 30 , or - S(O) P NR 28 R 29 ; p, for each occurrence, is independently, 1 or 2; and h is 0, 1 or 2.
  • a heterocyclyl, heteroaryl, or heteroaralkyl group contains a nitrogen atom, it may be substituted or unsubstituted.
  • the nitrogen may be a quaternary nitrogen.
  • lower refers to a group having up to four atoms.
  • a “lower alkyl” refers to an alkyl radical having from 1 to 4 carbon atoms
  • “lower alkoxy” refers to "-O-(Ci-C 4 )alkyl
  • a “lower alkenyl” or “lower alkynyl” refers to an alkenyl or alkynyl radical having from 2 to 4 carbon atoms, respectively.
  • the compounds of the invention containing reactive functional groups also include protected derivatives thereof, such as those found in T.W. Greene, Protecting Group in Organic Synthesis, Wiley & Sons, Inc. 1999 (hereinafter "Greene”), the entire teachings of which are incorporated by reference.
  • Greene Protecting Group in Organic Synthesis, Wiley & Sons, Inc. 1999
  • Protected derivatives are those compounds in which a reactive site or sites are blocked with one ore more protecting groups.
  • suitable protecting groups for hydroxy 1 groups include ethers ⁇ e.g., methoxymethyl, methylthiomethyl, (phenyldimethylsiyl)methoxymethyl, benzyloxymethyl, p-methoxben2yloxymethyl 5 j!?-nitrobenzyloxymethyl, o-nitrobenzyloxymethyl, (4-methoxyphenoxy)methyI, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methy 1, 2-(trimethy Isi Iy l)ethoxy methyl, menthoxymethy 1, tetrahydropyranyls, 1-ethoxyethyl, l-(2-chloroethoxy)ethyl, l-[2-(trimethylsilyl)ethoxy]ethyl, 1
  • suitable protecting groups for phenols groups include ethers (e.g. methyls (e.g. methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyI, methylthiomethyl, phenylthiomethyl, azidomethyl, cyanomethyl, 2,2-dichloro-l,l-difluoroethyl, 2-chloroethyl, and 2-bromoethyl) tetrahydropyranyl, and 1-ethoxyethyl), silyl ethers (e.g.
  • 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).
  • Suitable protecting groups for thiol groups include thioethers (e.g., iS-alkyl, S-benzyl, S-p-methoxybenzyl, S-o-or /?-hydroxy-or acetoxybenzyl, S-p-nitrobenzyl, 5-2,4,6-trimethylbenzyl, 5-2,4,6-trimethoxybenzyl, 5-4-picolyI, 5'-2-quinolinylmethyl, 5-2-picolyl N-oxido, 5-9-anthrylmethyl, S-phenyl, >S'-2,4-dinitrophenyl 3 ⁇ -/-butyl, 5-methoxymethyl, 5-isobutoxymethyl, and S'-benzyloxymethyl), thioesters (e.g., ⁇ -acetyl, iS-benzoyl, iS-trifluro acetyl,
  • suitable protecting groups for amino groups include carbamates (e.g, methyl, ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylrnethyl, 9-(2,7-dibromo)fluorenylmethyl, 17-tetrabenzo[ ⁇ f,c,#, /]fluoernylthmethyl, 2-chloro-3-indenylmethyl, benz[/]inden-3-ylmethyl- 2, ' 7-di-/-butyl-[9-(l 0,10-dioxo-l 0, 10, 10, 10-tetrahydrothioxanthyl)]methyl,
  • the compounds synthesized 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.
  • stereoisomers such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers.
  • 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).
  • 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.
  • the compounds synthesized by the methods of the present invention can be obtained in a form of polymorphs, salts, including a pharmaceutically acceptable salt, solvates or clathrates.
  • 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.
  • 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.
  • 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.
  • prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may become active upon such reaction under biological conditions, or they may have activity in their unreacted forms.
  • prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of Structural Formulas (I), (V) 5 (IA), (IA'), (XXA), (EB), (IVB), (VIIB), (XIB) 3 or Tables 1 and 2 that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • Other examples of prodrugs include derivatives of compounds of
  • biohydrolyzable ester means an amide, ester, carbamate, carbonate, ureide, or phosphate analogue, respectively, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as improved water solubility, improved circulating half-life in the blood (e.g., because of reduced metabolism of the prodrug), improved uptake, improved duration of action, or improved onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound.
  • biohydrolyzable amides include, but are not limited to, lower alkyl amides, ⁇ -amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.
  • biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.
  • biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
  • the term "pharmaceutically acceptable salt,” is a salt formed from, for example, an acid and a basic group of one of the compounds of Structural Formulas (I), (V), (IA), (IA'), (XXA), (IB), (IVB), (VIIB), (XIB), or Tables 1 and 2.
  • 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,/?-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
  • pamoate i.e., l,
  • pharmaceutically acceptable salt also refers to a salt prepared from a compound of Structural Formulas (I), (V), (IA), (IA'), (XXA), (IB), (IVB), (VIIB), (XIB), or Tables 1 and 2 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 trialkylamines; dicyclohexylamine; triburyl 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-hydroxyethy
  • pharmaceutically acceptable salt also refers to a salt prepared from a compound of Structural Formulas (I), (V), (IA), (IA'), (XXA), (IB), (IVB), (VIIB), (XIB), or Tables 1 and 2 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) 5 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.
  • solvate is a solvate formed from the association of one or more pharmaceutically acceptable solvent molecules to one of the compounds of Structural Formulas (I), (V), (IA), (IA'), (XXA), (IB), (IVB), (VIIB), (XIB), or Tables 1 and 2.
  • solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).
  • a pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compounds.
  • the pharmaceutically acceptable carriers should be biocompatible, i.e., non-toxic, non-inflammatory, non-immunogenic and devoid of other undesired reactions upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, ibid.
  • Suitable pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg/ml benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer's-lactate and the like.
  • compositions such as in a coating of hard gelatin or cyclodextran
  • Methods for encapsulating compositions are known in the art (Baker, et al., "Controlled Release of Biological Active Agents", John Wiley and Sons, 1986).
  • the compounds synthesized by the methods of the present 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.
  • 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.
  • 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.
  • 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.
  • tautomeric forms of the compounds disclosed herein exist, such as the tautomeric structures shown below:
  • the present invention provides novel synthetic methods (methods I, II and III) suitable for manufacturing [l,2,4]-triazole compounds on an industrial scale.
  • the synthesis begins with an amidation reaction of the starting carboxylic acid represented by the following structural formula: with an amine R 5 NH 2 to form an amide represented by Structural Formula (II).
  • the amide is then thionated to form a thioamide represented by Structural Formula (III).
  • the thioamide is reacted with hydrazine to form a hydrazonamide compound represented by Structural Formula (IV), which is cyclized with a carbonylation reagent, thoicarbonylation reagent or an isocyanide to form the [l,2,4]trizole compound represented by Structural Formula (I).
  • This synthesis is shown schematically in Figure 1. A detailed description of each reaction in the synthesis is provided below.
  • the starting carboxylic acid is first converted to the amide intermediate represented by Structural Formula (II) by reacting the starting carboxylic acid of Structural Formula
  • the carboxylic acid is first converted into a more reactive derivative with a leaving group that is more readily displaced by an amine group than -OH.
  • a "leaving group” is a group which can readily be displaced by a nucleophile.
  • a carboxylic acid can be converted to a more reactive acyl halide, typically acyl chloride.
  • Suitable reagents and conditions for converting a carboxylic acid to an acyl halide are well known in the art and are described, for example, in March, "Advanced organic Chemistry — Reactions, Mechanisms and Structure", 5th Edition, John Wiley & Sons, 2001, pages 523 — 524, and references cited therein.
  • Suitable reagents include thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorous pentachloride.
  • each carboxylic acid group is reacted with about one equivalent or a slight excess of thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorous pentachloride in an inert solvent such as an ethereal solvent (e.g., diethyl ether, tetrahydrofuran or 1,4-dioxane), a halogenated solvent (e.g.
  • an ethereal solvent e.g., diethyl ether, tetrahydrofuran or 1,4-dioxane
  • a halogenated solvent e.g.
  • methylene chloride or 1 ,2-dichloroethane or aromatic solvent (e.g., benzene or toluene).
  • aromatic solvent e.g., benzene or toluene.
  • carboxylic acid is amidated following an initial conversion of carboxylic acid to acyl halide
  • stoichiometric amount of the carboxylic acid and amine can be used.
  • excess of either the carboxylic acid or amine can be used.
  • oxalyl chloride a tertiary amine is often added to accelerate the reaction in quantities ranging from a catalytic amount to about one equivalent relative to oxalyl chloride.
  • tertiary amine can be used is triethylamine.
  • reaction temperature generally range from between about 0 0 C to 100 0 C, preferably between about 0 0 C to about ambient temperature.
  • the carboxylic acid is first converted into an "activated ester".
  • An ester -COOR is said to be “activated” when -OR is readily displaced by an amine or hydrazine. -OR is more easily displaced as R becomes more electron withdrawing.
  • Some activated esters are sufficiently stable that they can be isolated, e.g., esters wherein R is phenyl or substituted phenyl.
  • diphenylmalonate can be prepared from malonyl chloride and phenol, both commercially available from Aldrich Chemical Co., Milwaukee, WL, by procedures described above
  • Other activated esters are more reactive and are generally prepared and used in situ.
  • Coupled ester Formation of an activated ester in situ requires a "coupling agent”, also referred to as a “carboxylic acid activating agent”, which is a reagent that replaces the hydroxyl group of a carboxyl acid with a group which is susceptible to nucleophilic displacement.
  • a “coupling agent” also referred to as a “carboxylic acid activating agent”
  • Examples of coupling agents include l,l'-carbonyldiimidazole (CDI), isobutyl chloroformate, dimethylaminopropylethyl-carbodiimide (EDC), dicyclohexyl carbodiimide (DCC).
  • CDI l,l'-carbonyldiimidazole
  • EDC dimethylaminopropylethyl-carbodiimide
  • DCC dicyclohexyl carbodiimide
  • reaction is generally carried in inert, aprotic solvents, for example, halogenated solvents such as methylene chloride, dichloroethane and dimethylformamide.
  • aprotic solvents for example, halogenated solvents such as methylene chloride, dichloroethane and dimethylformamide.
  • thionation reagent is a reagent which, under suitable conditions, can convert a ketone, ester, or amide into a thioketone, thioester or thioamide, respectively.
  • thionation reagents There are many thionation reagents known to one of ordinary skill in the art.
  • Examples include Lawesson's Reagent, tetraphosphorous pentasulfide, Scheeren's reagent (P 4 S 1 0- Na 2 S), P 4 Sio-N(ethyl) 3 , Davy's Reagent and Heimgarner's reagent. Also known are conditions suitable for carrying out these conversions with thionation reagents. . For example, such conditions are disclosed in Fieser and Fieser, "Reagents for Organic Synthesis", Volume 1, John Wiley & Sons (1975) page 870-871, Fieser and Fieser, “Reagents for Organic Synthesis", Volume 5, John Wiley & Sons, (1975) page 653 and publication cited therein.
  • the amide of Structural Formula (II) it may be desirable to use a slight excess of the amide, for example up to about 5 equivalents, preferably no more than about 1.5 equivalents. It may also be desirable to use excess thionation reagent. In some cases, it may be desirable to use equal equivalents of the amide and the thionation reagent.
  • Suitable inert solvents include ethereal solvents (e.g., diethyl ether, tetrhydrofuran, glyme and 1,4- dioxane), aromatic solvents (e.g., benzene and toluene) or chlorinated solvents (e.g., methylene chloride and 1,2-dichloroethane).
  • ethereal solvents e.g., diethyl ether, tetrhydrofuran, glyme and 1,4- dioxane
  • aromatic solvents e.g., benzene and toluene
  • chlorinated solvents e.g., methylene chloride and 1,2-dichloroethane.
  • the reaction is carried out at temperatures ranging from about room temperature to about 150 0 C, preferably from about 75° C to about 125° C.
  • the thionation reagent is Lawesson's reagent. Representative conditions for carrying
  • the reaction mixture of the amide and thionation reagent is treated with a water soluble amine after completion of the reaction.
  • a "water soluble amine” may include any amines (e.g., methylammine), ammonium hydroxide, and hydrazines.
  • the water soluble amine is aqueous ammonium hydroxide.
  • the water soluble amine is hydrazine.
  • excess ammonium hydroxide solution is used, for example up to 10 equivalents, preferably up to 5 equivalents, even more preferably up to 2 equivalents.
  • Example 1 The thioamide of Structural Formula (II) is then converted to hydrazonamide of
  • Structural Formula (III) by reacting the thioamide with hydrazine in an inert solvent.
  • excess of hydrazine is used, for example up to 100 equivalents, up to 50 equivalents, up to 10 equivalents. In some cases, it may be desirable to use excess of thioamide or equal equivalents of thioamide and hydrazine.
  • Suitable inert solvents include ethereal solvents (e.g., diethyl ether, tetrhydrofuran, glyme and 1 ,4-dioxane), aromatic solvents (e.g., benzene and toluene) or chlorinated solvents (e.g., methylene chloride and 1,2-dichloroethane).
  • ethereal solvents e.g., diethyl ether, tetrhydrofuran, glyme and 1 ,4-dioxane
  • aromatic solvents e.g., benzene and toluene
  • chlorinated solvents e.g., methylene chloride and 1,2-dichloroethane
  • a "leaving group” is a group that can be displaced by a nucleophile.
  • X can be a imidazoly group, a halide, more specifically, a chloride.
  • carbonylation reagent examples include phosgene, carbonyldiimidazole, diphenyl carbonate, bis(4-nitrophenyl) carbonate, bis(pentafluorophenyl) carbonate, bis(trichloromethyl) carbonate, 4-nitrophenyl chloroformate, phenyl chloroformate, trichloromethyl chloroformate.
  • the carbonylation reagent is carbonyldiimidazole.
  • the hydrazonamide of Structural Formula (IV) is converted to the triazole compound of Structural Formula (I) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, by reacting the hydrazonamide with a carbonylation reagent in an inert solvent.
  • Suitable inert solvents include ethereal solvents (e.g., diethyl ether, tetrhydrofuran, glyme and 1,4- dioxane), aromatic solvents (e.g., benzene and toluene), chlorinated solvents (e.g., methylene chloride and 1 ,2-dichloroethane) or ethyl acetate.
  • ethereal solvents e.g., diethyl ether, tetrhydrofuran, glyme and 1,4- dioxane
  • aromatic solvents e.g., benzene and toluene
  • chlorinated solvents e.g., methylene chloride and 1 ,2-dichloroethane
  • ethyl acetate ethyl acetate.
  • the reaction is carried out at temperatures ranging from about room temperature to about 15O 0 C 3 preferably from about room temperature to
  • excess of the carbonylation reagent is used, for example, up to 10 equivalent, more preferably, up to 5 equivalent, even more preferably, up to 1.5 equivalent. In some case, it may be desirable to use excess of the hydrazonamide, or equal equivalents of the hydrazonamide and the carbonylation reagent.
  • X can be a imidazoly group, a halide, more specifically, a chloride.
  • Examples of thiocarbonylation reagent may be used include thiocarbonyldiimidazole and thiophosgene.
  • the thiocarbonylation reagent is thiocarbonyldiimidazole.
  • the hydrazonamide of Structural Formula (IV) is converted to the triazole compound of Structural Formula (T) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, by reacting the hydrazonamide with a thiocarbonylation reagent in an inert solvent.
  • Suitable inert solvents include ethereal solvents (e.g., diethyl ether, tetrhydrofuran, glyme and 1,4-dioxane), aromatic solvents (e.g., benzene and toluene), chlorinated solvents (e.g., methylene chloride and 1 ,2-dichIoroethane) or ethyl acetate.
  • the reaction is carried out at temperatures ranging from about room temperature to about 15O 0 C, preferably from about room temperature to about 100° C, more preferably from about room temperature to about 40 0 C.
  • excess of the carbonylation reagent is used, for example, up to 10 equivalent, more preferably, up to 5 equivalent, even more preferably, up to 1.5 equivalent. In some case, it may be desirable to use excess of the hydrazonamide, or equal equivalents of the hydrazonamide and the thiocarbonylation reagent.
  • X can be a imidazolyl group, a halide, more specifically a chloride.
  • X is -Cl.
  • Suitable inert solvents include ethereal solvents (e.g., diethyl ether, tetrhydrofuran, glyme and 1,4-dioxane), aromatic solvents (e.g., benzene and toluene), chlorinated solvents (e.g., methylene chloride and 1,2-dichloroethane) or ethyl acetate .
  • the reaction is carried out at temperatures ranging from about room temperature to about 150° C, preferably from about room temperature to about 100° C, more preferably from about room temperature to about 40 0 C, even more preferably, the reaction is carried out at room temperature.
  • excess of the carbonylation reagent is used, for example, up to 5 equivalent, more preferably, up to 5 equivalent, even more preferably, up to 1.5 equivalent. In some case, it may be desirable to use excess of the hydrazonamide, or equal equivalents of the hydrazonamide and the thiocarbonylation reagent.
  • the compound of Structural Formula (V) is prepared by the disclosed methods.
  • the synthesis of the compound of Structural Formula (V) comprises an inital step of thionating the amide of Structural Formula (VI) with a thionation reagent to form a thioaminde of Structural Formula (VII).
  • the thioamide is then reacted with hydrazine to form a hydrazonamide of Structural Formula (VIII).
  • the hydrazonamide is reacted with a carbonylation reagent to form the compound of Structural Formal (V).
  • the thionation reagent is Lawesson's reagent and the thionation reagent is carbonyldiimidazole. Any remaining protecting groups can be removed by standard methods following formation of the hydrazonamide.
  • Method II of the present invention provides a method of synthesizing a compound of Structural Formula (IA):
  • the method comprises reacting a compound of Structural Formula (IIA)
  • the oxidizing agent is K 3 Fe(CN)6, Mn ⁇ 2 , Br 2 , N-bromosuccinimide or N-chlorosuccinimide. More preferably, the oxidizing agent is K 3 Fe(CN) 6 .
  • K 3 Fe(CN) 6 is K 3 Fe(CN) 6 .
  • some oxidizing agents e.g., K 3 Fe(CN) 6 , MnO 2 ) are commonly used in combination with a base.
  • any organic or inorganic base can be used, such as a hydroxide base (e.g., NaOH, KOH, LiOH), amine bases (e.g., ammonia, allylamide, dialkylamine) or 1,1,1,3,3,3-hexamethyl-disilazane (HMDS).
  • the base is non-nucleophilic.
  • the molar ratio of the base to the oxidizing agent can be about 5:1, 4;1, 3: 1, 2: 1; 1:1, 1 :2, 1:3, 1:4 or 1 :5.
  • equimolar ratio of the oxidizing agent and the base is used.
  • the oxidizing cyclization is generally carried out in polar solvent.
  • the polar solvent can be a polar protic solvent, such as water or an alcohol; a polar aprotic aromatic solvent such as nitrobenzene; or a polar aprotic solvent such as nitromethane, dimethyl acetamide (DMA), N,N-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), hexamethyl phosphoramide (HMPA), or N-methyl pyrrolidone (NMP).
  • DMA dimethyl acetamide
  • DMF N,N-dimethyl formamide
  • DMSO dimethyl sulfoxide
  • HMPA hexamethyl phosphoramide
  • NMP N-methyl pyrrolidone
  • the molar ratio of the compound of Structural Formula (IIA) to the oxidizing agent can vary greatly. Although equimolar amount can be used, the compound of formula (II) is typically used in excess.
  • the molar ratio of the compound of formula (II) to an oxidizing agent can be 1000:1, 900:1, 800:1, 700:1, 600:1, 500:1, 400:1, 300:1, 200:1, 100: 1, 50:1 , 20:1, 10:1
  • the molar ratio of the compound (IIA) to KFe(CN) 6 is from about 500:1 to about 200:1, preferably from 350:1 to 300:1
  • the molar ration of the compound (IIA) to NaOH is from about 600:1 to 400:1, preferably from 550:1 to 450:1.
  • the reaction temperature can be from about 50 0 C to about 150 0 C, preferably, from about 70 0 C to about 120 0 C, more preferably, from about 90 0 C to about 1 10 0 C.
  • the compound of Structural Formula (IIA) is prepared by reacting a compound of Structural Formula (HIA)
  • catalytic amount typically means a molar ratio from about 0.1 to about 0.001 of the acid catalyst to the reagents. In one embodiment, catalytic amount is 0.01 equivalents.
  • Any acid catalyst can be used, such as organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid), sulfonic acids (e.g., methanesulfonic acid, benzenesulfonic acid and the like), and mineral acids (sulfuric acid, hydrochloric acid, and the like).
  • Any suitable solvent in which reagents are soluble and with which reagents do not react can be used.
  • the reaction is most commonly carried out in an alcoholic solvent such as methanol or ethanol with water as co-solvent (e.g., between 0% and about 50% volume/volume (v/v), preferably between about 5% and about 15% v/v).
  • the reaction is allowed to proceed at a temperature from about 30 0 C to about 150 0 C, preferably from about 40 0 C to about 130 0 C, more preferably, from about 50 0 C to about 120 0 C, even more preferably, from about 60 0 C to about 100 0 C.
  • the compound of Structural Formula (IA) can further be deprotected, thereby producing a compound of Structural Formula (IA')
  • R 22 is -OH, or -NH 2 .
  • the present invention is a method of synthesis of a compound of Structural Formula (HA),
  • OVA OVA R 2° 5 in the presence of acid catalyst. The conditions for this reaction are described above.
  • R 2 o is -OR p i
  • R p i is a benzyl group
  • the step of deprotecting the compound of formula (IA) comprises reacting a compound of formula (IA) with hydrogen in the presence of palladium-on- charcoal catalyst.
  • formulas (IA), (IIA), (IIIA) and (IVA) 5 R 2 o is -OR p i, R p i is a benzyl group and the step of deprotecting the compound of formula (IA) comprises reacting a compound of formula (IA) with ammonium formate in the presence of a hydrogen catalyst.
  • Method III of the present invention begins with an amidation reaction of the starting carboxylic acid represented by the following Structural Formula:
  • the starting carboxylic acid is first converted to the amide intermediate represented by Structural Formula (XIIB) by reacting the starting carboxylic acid with the amine R 5 NH 2 .
  • the amide of Structural Formula (XIIB) is then reacted with a thionation reagents to form a thioamide.
  • Thionation reagent is as described above for method I.
  • the amide of Structural Formula (XIIB) it may be desirable to use a slight excess of the amide, for example up to about 5 equivalents, preferably no more than about 1.5 equivalents. It may also be desirable to use excess thionation reagent. In some cases, it may be desirable to use equal equivalents of the amide and the thionation reagent.
  • Suitable inert solvents include ethereal solvents (e.g., diethyl ether, tetrhydrofuran, glyme and 1,4-dioxane), aromatic solvents (e.g., benzene and toluene) or chlorinated solvents (e.g., methylene chloride and 1 ,2-dichloroethane).
  • ethereal solvents e.g., diethyl ether, tetrhydrofuran, glyme and 1,4-dioxane
  • aromatic solvents e.g., benzene and toluene
  • chlorinated solvents e.g., methylene chloride and 1 ,2-dichloroethane
  • the thionation reagent is Lawesson's reagent.
  • thioamide is then reacted with a hydrazino carboxylate in the presence of a mercuric salt.
  • a mercuric salt typically, an excess amount of the hydrazino carboxylate and mercuric salt (e.g., from 1-10 equivalents, 1-5 equivalents or 1-2.5 equivalents) relative to the thioamide is employed for this synthesis. More typically, at least about two molar equivalents of the hydrazino carboxylate and mercuric salt relative to the thioamide, or preferably from 2.0 to about 2.5 equivalents.
  • an excess of the thioamide can be used.
  • Suitable solvent can be any inert organic solvent which is able to dissolve the hydrazino carboxylate, the thioamide and the mercuric salt when mixed.
  • the organic solvent can generally be selected from a C1-C4 aliphatic alcohol (e.g., methanol, ethanol,
  • the organic solvent can be selected from tetrahydrofuran or dioxane, and more preferably, dioxane.
  • Suitable reaction temperature ranges between about 50 0 C and about 150 0 C, preferably between about 90 0 C and about 120 0 C.
  • Suitable mercuric salts include mercuric halides (HgF 2 , HgCb and HgBr 2 ), mercury acetate and HgO, preferably, mercuric halides, and more preferably, HgCl 2 .
  • a base such as an amine base (e.g.
  • ammonia alkyl amines, dialkyl amines, trialkyl amines, optionally substituted amines, optionally substituted cycloalkylamines, N-alkylphthalimide, pyridine, aminopyridines, pyrrolidine, /7-toluidine, aniline, /?-nitroaniline, azetidine, morpholine, piperidine or the like) can be added to the mixture of the hydrazino carboxylate, thioamide and mercuric salt.
  • concentration of the reagents is between 0.005 M and 1.0 M, or preferably, between 0.010 M and 0.500 M.
  • the synthesis of the triazole compound further includes the step of deprotecting the compound represented by Structural Formula (IB).
  • the products of this deprotecting reaction are triazole-based hsp90 inhibitors.
  • Variables in Structural Formulas (I)-(IV), (IA)-(IVA), (EB)-(IIIB) are as described above.
  • R 5 in Structural Formulas (I)-(IV), (IA), (IA*), (ILA), (IIIA), (IB), (HIB), (VIIB), (VIIIB), (KB) and (XIB) is optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl.
  • the remainder of the variables are as described in Structural Formulas (I)-(IV), (IA), (IA'), (HA), (IHA), (IB), (IHB), (VIIB), (VIIIB), (DCB) and (XtB).
  • R 5 in Structural Formulas (I)-(IV), (IA), (IA'), (HA), (IIIA), (IB), (lire), (Vile), (VI ⁇ B), (IXB) and (XlB) is a substituted phenyl.
  • the remainder of the variables are as described in Structural Formulas (I)-(IV), (IA), (IA'), (HA), (IIIA), (IB), (IIIB), (VIIB), (VIIIB), (DCB) and (XIB).
  • R 5 in Structural Formulas (I)-(rV), (IA), (IA'), (HA), (IIIA), (EB), (HIB), (VIIB), (VIIEB), (IXB) and (XIB) is an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, or a substituted alkyl.
  • R 5 in Structural Formulas (I)-(EV), (IA), (IA'), (HA), (IIIA), (EB), (HEB), (VIEB) 5 (VIIIB), (DCB) and (XEB) is an optionally substituted naphthyl.
  • the remainder of the variables are as described in Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB), (VIIB), (VIIIB), (DCB) and (XIB).
  • R 5 in Structural Formulas (I)-(IV), (IA), (IA'), (IIA), ( ⁇ iA), (IB), (IIIB), (VIIB), (VIBB), (KB) and (XIB) is represented by the following Structural Formula:
  • R 9 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, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR 10 Rn (provided Rj 0 and Rn are not -H), -OR 7 (provided R 7 is not -H), -SR 7 (provided R 7 is not H), -S(O) P R 7 , -OS(O) P
  • R 7 and Rg 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 10 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; for Structural Formulas (IB), (IIIB), (VIEB), (VIIIB), (IXB) and (XIB) 5 R 9 , for each occurrence, is independently a substituent selected from the group
  • R 5 in Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB), (VIIB), (VIIB), (IXB) and (XIB) is represented by the following Structural Formula: wherein q is zero or an integer from 1 to 7; and u is zero or an integer from 1 to 8. The remainder of the variables are as described in the fifth specific embodiment.
  • R 5 in Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB), (VIIB), (VIIB), (IXB) and (XIB) is an optionally substituted indolyl.
  • R 5 is an indolyl represented by the following Structural Formula:
  • R 33 is a halo, a lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, or a lower alkyl sulfanyl;
  • R 34 is H. or a lower alkyl;
  • Ring B and Ring C are optionally substituted with one or more substituents in addition to R 33 and R 34 .
  • the remainder of the variables are as described in Structural Formulas (I)-(IV); for Structural Formulas (IA) 5 (IA'), (IIA), and (IIIA), R 33 is H; -ORpi, -NHRp 3 or -N(Rp 3 ) 2 , a halo, a lower alkyl, a lower alkoxy, a lower haloalkyl, or a lower haloalkoxy; R 34 is H, -OR p i, -NHR p3 or -N(R p3 ) 2 , a C1-C6 alkyl, or a lower alkylcarbonyl; and ring B and ring C are optionally substituted with one or more substituents in addition to R 33 and R 34 .
  • R 33 is a halo, a lower alkyl, a lower alkoxy, a lower haloalkyl, and a lower haloalkoxy, and a lower alkyl sulfanyl
  • R 34 is -H, a lower alkyl, or a lower acyl
  • Rings B and Ring C are optionally substituted with one or more substituents in addition to R 33 and R 34 ; and the remainder of the variables are as described in Structural Formulas (IB) 3 (IIIB), (VIIB) 5 (VIIIB), (IXB) and (XIB).
  • R 5 in Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB), (VIIB), (VIIB), (IXB) and (XB) is a substituted phenyl.
  • the phenyl group is optionally substituted with: i) one substituent selected from nitro, cyano, a haloalkoxy, 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, guanadino, -NRi 0 Ri i (provided Rio and Rn are not -H) -0-R 20 , -SR 7 (provided R 7 is not H), -S(O) P R 7 , -OS(O) n R 7 , -NRgS(O) p R 7 , -S(O) p NR I0 R
  • the substituents for the phenyl group is selected from the group consisting of -OR p i, -NHR p3 , -N(R p3 ) 2 , -O(CH 2 ) m OR p i, or -(CH 2 ) m ORpi, 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
  • R 1 ,,, Rp 3 , R 7 , R 8 , Rio, Rn, p and m are as defined above with reference to formulas (IA), (IA'), (IIA), and (IIIA)
  • the phenyl group is substituted with: i) the one substituent selected from nitro, cyano, a haloalkoxy, 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, protected hydroxylalkyl, alkoxyalkyl, guanadin
  • R 5 is represented by the following structural formula:
  • R 5 in Structural Formulas (I)-(EV), (IA), (IA'), (HA), (IHA), (EB), (IIIB), (VIEB), (VIIB), (EXB) and (XEB) is selected from the group
  • X 6 for each occurrence, is independently CH, CR 9 , N, N(O), N + (Rn), provided that at least three X 6 groups are independently selected from CH and CR 9 ;
  • X 7 for each occurrence, is independently CH, CR 9 , N, N(O), N + (Rn), provided that at least three X 7 groups are independently selected from CH and CRg;
  • X 8 for each occurrence, is independently CH 2 , CHR 9 , C(Rg) 2 , S, S(O)p, NR7, or NR 17 ;
  • X 9 for each occurrence, is independently N or CH;
  • Rn for each occurrence, is independently -H 5 an alkyl, an aralkyl.
  • R n can also be -C(O)R 7 , - C(O)OR 7 Or -C(O)NR 10 Rn.
  • R 17 can also be -C(O)R 7 .
  • R 5 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
  • Rs in Structural Formulas (I)-(IV) 5 (IA), (IA'), (IIA), (IIIA), (E3), (IIIB), (VIIB) 5 (VIIIB) 5 (IXB) and (XIB) is selected from the group consisting of:
  • Xn for each occurrence, is independently CH 5 CRg 5 N 5 N(O) 5 or N + (Rn), provided that at least one Xn is N 5 N(O) 5 or N + (R ⁇ ) and at least two Xi i groups are independently selected from CH and CR 9 ;
  • Xi2 for each occurrence, is independently CH, CRg 5 N 5 N(O) 5 N + (Ri 7 ), provided that at least one Xi 2 group is independently selected from CH and CRg;
  • Xi3 for each occurrence, is independently O 5 S, S(O)p, NR 7 , or NR n . Values and specific values for the remainder of the variables are as described in the ninth specific embodiment.
  • R 5 in Structural Formulas (I)-(TV) 5 (IA), (LV) 5 (IIA), (IIIA), (ffi), (IIIB), (VIIB), (VIIB), (EXB) and (XIB) is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the following groups: for Structural Formulas (I)-(FV), the one or more substituents for the alkyl group are independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino,
  • R A> R B> R C5 and p are as described for the Structural Formulas (I)-(FV); for Structural Formulas (IA), (IA'), (FIA), and (FIIA), the one or more substituents for the alkyl or the cycloalkyl group are independently selected from the group consisting of -ORp 1 , -NHRp 3 , -N(Rp 3 ) 2 , -O(CH 2 ) m OR pI , or -(CH 2 ) m OR p r, 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, al
  • R p i, R p3 , R 7 , R 8 , R] 0 , Rn, p and m are as defined above with reference to Structural Formulas (IA), (IA'), (1IA) 5 and (IIIA).
  • the one or more substituents for the alkyl group are independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR 10 Rn, -OR 10 O, and -C(O)R 7 .
  • R 5 in Structural Formulas (F)-(FV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB), (VIFB), (VIIIB), (FXB) and (XFB) is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl. The remainder of the variables are as described above in the eleventh specific embodiment.
  • R 5 in Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB), (VIIB), (VIIIB), (EKB) and (XIB), is a substituted alkyl. The remainder of the variables are as described above in the eleventh specific embodiment.
  • ring A in Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IVA), (IB), (IIIB), (VIIB), (VIIIB), (DCB), and (XEB) is presented by Structural Formula (DC):
  • R f i is independently 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 heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR 10 Ru (provided Rio and R n are not -H), -OR 7 (provided R 7 is not H), -C(NR 8 )OR 7 , -C(NR 8 )NR 1 OR H , -C(NRg)SR 7 , -OC(S)OR 7 , -OC(NR 8 )OR 7
  • R 30 O is R 2 oas described in Structural Formulas (IA), (IA'), (IIA) and (FVA).
  • R 6 for each occurrence, is independently a substituent selected from: -OR p i, -NHR p3 , -N(R p3 ) 2 , -O(CH 2 ) m OR p i, or -(CH 2 ) H1 OR p1 ; 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, alkoxyalky
  • R 300 is R 3b as described above in Structural Formulas (IB), (HIB) 5 (VIIB) 5 (VIIIB) 5 (IXB) 5 and (XIB).
  • R 4 for each occurrence, is independently 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 heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, a protected hydroxyalkyl, haloalkoxy, -NR 10 R M , -OR IOO , -C(O)R 7 , or -SRio ⁇ or two R 5 groups, taken together with the carbon atoms to which they are attached, form a fused ring,
  • n is zero or an integer from 1 to 4.
  • the remainder of the variables are as described above in Structural Formulas (I)-(IV), (IA) 5 (IA'), (HA), (IVA) 5 (IVA) 5 (DB) 5 (HIB), (VIIB) 5 (VIIIB), (DCB), and (XlB).
  • R 5 in compounds of Structural Formulas (I)-(IV) 5 is an optionally substituted phenyl, wherein the phenyl group is substituted with substituents as described in the eighth specific embodiment. Values and specific values for the remainder of the variables are as described in the twelfth specific embodiment.
  • Structural Formulas (I)-(IV) is an optionally substituted phenyl, wherein the phenyl group is substituted with substituents as described in the eighth specific embodiment. Values and specific values for the remainder of the variables are as described in the twelfth specific embodiment.
  • Rs in compounds of Structural Formulas (I)- (IV), (IA) 5 (IA'), (HA), (IB), (HIB) 5 (VIIB), (VIIIB), (DCB), and (XIB) 5 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group described above in the eleventh specific embodiment. Values and specific values for the remainder of the variables are as described in the twelfth specific embodiment.
  • R5 is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.
  • Rs is an optionally substituted alkyl.
  • R 5 in the compounds of Structural Formulas (I)-(IV) 5 (IA) 5 (IA'), (HA), (IB), (HIB), (VIIB) 5 (VIIIB) 5 (DCB) 5 and (XIB) is represented by the following structural formula: wherein Rg and m are as described in the fifth specific embodiment. Values and specific values for the remainder of the variables are as described the twelfth specific embodiment.
  • R 5 in compounds of Structural Formulas (I)- (IV) 5 is selected from the group consisting of the following structural formulas:
  • Rs 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
  • R 5 in the compounds of Structural Formulas (I)-(IV), (IA), (IA 5 ), (HA), (IB), (HIB) 5 (VIIB), (VIIIB), (DCB), and (XDB), is selected from the group consisting of the following structural formulas:
  • R5 is an indolyl represented by the following Structural Formula:
  • R 33 , R 34 , ring B and ring C are as described above in the seventh specific embodiment. Values and specific values for the remainder of the variables are as described above in the twelfth specific embodiment.
  • ring A in compounds represented by Structural Formulas (I)-(IV), (IA) 9 (IA'), (IIA), (IVA), (IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB) is represented by the Structural Formula (X):
  • R 25 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 heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, or -NR 1 0R 1 1 (provided Rio and Rn are not H); for Structural Formulas (IA), (IA'), (IIA), and (IVA), R 25 is -OR pl , -NHR p3 , -N(Rp 3 ) 2 , -O(
  • R 25 in Structural Formulas (I)-(FV) is -OR A . -SR B , - N(Rc) 2 , -OC(S)OR 7 , -OC(NR 8 )OR 7 , -SC(NR 8 )OR 7 , -SC(S)OR 7 , -OC(S)NR 10 Rn, -SC(S)NR 10 Rn, -OC(NR 8 )R 7 , -SC(NR 8 )R 7 , -OS(O) P R 7 , -S(O) P OR 7 , -SS(O) P OR 7 , -SS(O)pR 7 , -OP(O)(ORv) 2 , or -SP(O)(OR 7 ) 2 , wherein p is 0, 1 , or 2; Values and specific values for the remainder of the variables are as described in the thirteenth specific embodiment.
  • R 2 5 in Structural Formulas (IA), (IA'), (IIA), and (FVA) is a -OR,,,, -NHR p3 , -N(R ⁇ ) 2 , -0(CHa) 1n OR p1 , or -(CHa) 1n ORp 1 .
  • R 33 is H, -ORpi, -NHR p3 , -N(R p3 ) 2 ,
  • R 34 is a C1-C6 alkyl.
  • R 3b and R25 in Structural Formulas (IB), (IIIB), (VIIB), (VIIIB), (JXB), and (XEB) are -ORi 00 , -SRi ⁇ i, or -N(Ri O2 ) 2 .
  • R ⁇ is -SH or -OH
  • R 3b and R 2 s are -OR 100
  • R 5 in Structural Formulas (I)-(FV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (EXB), and (XEB) is an optionally substituted phenyl, wherein the phenyl group is substituted with substituents as described in the eighth specific embodiment. Values and specific values for the remainder of the variables are as described in the thirteenth specific embodiment.
  • R 3 is -OR A , SR B , N(R C ) 2 .
  • R 5 in compounds of Structural Formulas (I)- (TV), (IA), (IA'), (IIA), (IB), (IIIB), (VIEB), (VIIIB), (EXB), and (XEB), is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group as described above in the eleventh specific embodiment. The remainder of the variables are as described in the thirteenth specific embodiment.
  • R 5 is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.
  • R 5 is an optionally substituted alkyl.
  • R 5 in the compounds of Structural Formulas (I)-(IV), (IA) 5 (IA'), (IIA), (IB), (Urn), (Vim), (V ⁇ iB), (KB), and (XEB) is represented by the following structural formula:
  • R 9 and m are as described in the fifth specific embodiment. Values and specific values for the remainder of the variables are as described the thirteenth specific embodiment.
  • R 5 in compounds of Structural Formulas (I)- (IV), (IA), (IA'), (IIA), (IB), (IHB), (VIIB), (VIIIB), (DCB), and (XlB), is selected from the group consisting of the following structural formulas:
  • R 5 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
  • R 5 in Structural Formulas (I)-(FV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB) 5 (VIIIB), (EXB), and (XIB) is an optionally substituted indolyl.
  • R 5 is an indolyl represented by the following Structural Formula:
  • R 33 , R 34 , ring B and ring C are as described above in the seventh specific embodiment. Values and specific values for the remainder of the variables are as described above in the thirteenth specific embodiment. In a even more specific embodiment, for
  • R 25 is a -OR P ,, -N ⁇ R p3 , -N(R p3 ) 2 , -O(CH 2 ) m OR p i, or -(CH 2 ) H iOP pI .
  • R 33 is H, -OR p1 , -NHRp 3 , -N(Rp 3 ) 2 , -O ⁇ H ⁇ OR p :, or -(CH 2 ) m OP pl and R 34 is a C1-C6 alkyl.
  • R 25 is a -OR pl , -NHR p3 , -N(R p3 ) 2 , -O(CH 2 ) m ORp,, or -(CH 2 ) m OP pI ;
  • R 33 is H, -ORp 1 , -NHR p3 , -N(R p3 ) 2 , -O(CH 2 ) m OR pl , or -(CH 2 ) m OP p i and R 34 is a C1-C6 alkyl.
  • R 2 i is O;
  • Re is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C3-C6 cycloalkyl or -NRj oR ⁇ .
  • R 6 is a C1-C6 alkyl and R 33 is H.
  • R 33 is -H and ring B is unsubstituted.
  • R 2 o and R 2 s are -OH, and Re is a C1-C6 alkyl.
  • R 2 i is O; R 6 is a C1-C6 alkyl and R 33 is H.
  • R 2 i is O; R 6 is a Cl -C6 alkyl; R 33 is H and ring B is unsubstituted.
  • R 2J is O; R 6 is a C1-C6 alkyl; R 33 is H; ring B is unsubstituted; R 2 o and R 25 are -OH, and R 6 is a Cl- C6 alkyl.
  • Rs in the compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (DCB), and (XIB), is selected from the group consisting of the following structural formulas:
  • Xn, X) 2 , Xi 3 , Rg and R n are defined as described in the tenth specific embodiment. Values and specific values for the remainder of the variables are as described in the thirteenth specific embodiment.
  • ring A of the compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IVA), (IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XEB), is represented by Structural Formula (XI):
  • R 25 in Structural Formulas (I)-(W) is -OR A , -SR B , -N(Rc) 2 , -OC(S)OR 7 , -OC(NR 8 )OR 7 , -SC(NR 8 )OR 7 , -SC(S)OR 7 , -OC(S)NRi 0 R ⁇ , -SC(S)NR 10 Rm -OC(NR 8 )R 7 , -SC(NR 8 )R 7 , -OS(O) P R 7 , -S(O) P OR 7 , -SS(O) P OR 7 , -SS(O) P R 7 , -OP(O)(OR 7 ) 2 , or -SP(O)(OR 7 ) 2 , wherein p is O, 1, or 2.
  • R 3 and R 2 s are -OR A -
  • R 6 is a lower alkyl, C3-C6 cycloalkyl, lower alkoxy, a lower alkyl sulfanyl, or -NRi 0 Ri 1 .
  • R 2 i is O;
  • R 6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C3-C6 cycloalkyl or -NRi 0 R] 1 .
  • R 6 is a C1-C6 alkyl and R 33 is H.
  • R 33 is -H and ring B is unsubstituted.
  • R 20 and R 25 are -OH, and R 5 is a C1-C6 alkyl.
  • R 3b and R 25 are -OR 10 O, -SR101, or -N(R, 02 ) 2 .
  • R 3 and R 25 are -OR A ;
  • Rs is a lower alkyl, C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl, or -NRi 0 Rn.
  • Rs in the compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIEB), (VIIIB), (DCB), and (XIB) is represented by the following structural formula:
  • Rio and Rn are each independently a hydrogen, a C1-C6 straight or branched alky I, optionally substituted by -OR A , -CN, -SR A , N(Rc). : . a C1-C6 alkoxy, alkylsulfanyl, dialkylamino or a cycloalkyl; or R ]0 and R n taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl. More preferably, Ri 0 and Rn are each independently a hydrogen, methyl, ethyl, propyl, isopropyl, or taken together with the nitrogen to which they are attached, are:
  • (IV), (IA), (IA'), (UA), (IB), (IIIB), (VIIB), (VIIIB), (IXB) 5 and (XEB), is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group desribed above in the eleventh specific embodiment. Values and specific values for the remainder of the variables are as described in the fourteenth specific embodiment.
  • R 5 is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.
  • R 5 is an optionally substituted alkyl.
  • R 5 in the compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (EKB), and (XIB) is represented by the following structural formula: wherein R 9 and m are as described in the fifth specific embodiment. Values and specific values for the remainder of the variables are as described the fourteenth specific . embodiment.
  • R 3 and R 2 5 are -OR A
  • R 6 is a lower alkyl, a C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl, or — NRjoRii
  • R 9 for each occurrence is independently selected from the group consisting of-OR A , -SR B , halo, a lower haloalkyl, cyano, a lower alkyl, a lower alkoxy, and a lower alkyl sulfanyl.
  • R 5 in compounds of Structural Formulas (I)- (IV), (IA) 5 (IA'), (IIA), (IB) 5 (HIB) 5 (VIIB) 5 (VIIIB) 5 (IXB), and (XIB), is selected from the group consisting of the following structural formulas:
  • R 5 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
  • R 6 is a lower alkyl, a C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl, or — NRioR ⁇ -
  • Rg is a lower alkyl, a C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl, or -NRioRn; and R 3 and R 2S are -OR A .
  • R5 is represented by the following Structural Formula:
  • R 6 is selected from the group consisting of - ⁇ , a lower alkyl, a lower alkoxy, a lower cycloalkyl. and a lower cycloalkoxy.
  • R 5 in the compounds of Structural Formulas (I)-(IV) 5 is selected from the group consisting of the following structural formulas: wherein Xn, X 12 , X B , R 9 and Rn are defined as described in the tenth specific embodiment. The remainder of the variables are as described in the fourteenth specific embodiment.
  • Re is a lower alkyl, a C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl, or —NR 1 0R11.
  • R 6 is a lower alkyl, a C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl, or -NR10R11; and R 3 and R 25 are -OR A .
  • R 5 in Structural Formulas (I)-(TV), (IA), (IA'), (IIA), (IB), (HIB), (VIIB), (VIIIB), (IXB), and (XIB) is an optionally substituted indolyl.
  • R 5 is an indolyl represented by the following Structural Formula:
  • R 25 is a-OR pb -NHR p3 , -N(R p3 ) 2 , -O(CH 2 ) m ORpi, Or -(CHz) 1n OR p
  • R 33 is H, -OR p1 , -NHR p3 , -N(R p3 ) 2 , -O(CH 2 ) m OR p i, Or -(CHz) 1n OR p1
  • R 34 is a C1-C6 alkyl.
  • R 21 is O;
  • R 5 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C3-C6 cycloalkyl or -NR] 0 Ri I .
  • R 6 is a C1-C6 alkyl and R 33 is H.
  • R 33 is -H and ring B is unsubstituted.
  • R 5 is a C1-C6 alkyl; R 33 is H; and ring B is unsubstituted.
  • R 20 and R 25 are -OH, and R 6 is a Cl -C6 alkyl.
  • ring A in compounds of Structural Formulas (I)- (IV), (IA), (IA'), (IIA), (IVA) 5 (IB), (DIB), (VIIB), (VIIIB), (DCB) 5 and (XIB), is represented by one of Structural Formulas (XII):
  • R 5 in the compounds of Structural Formulas (I)- (IV), (IA) 5 (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), is an optionally substituted phenyl, wherein the phenyl group is substituted with substituents as described in the eighth specific embodiment. The remainder of the variables are as described in the fifteenth specific embodiment.
  • R 3 and R 25 are -OR A - Even more specifically, R 6 is a lower alkyl, C3-C6 cycloalkyl, lower alkoxy, a lower alkyl sulfanyl, or -NRi 0 Rn.
  • R 5 in compounds of Structural Formulas (I)- (IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIBB), (VIIIB), (IXB), and (XIB), is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group described above in the eleventh specific embodiment. The remainder of the variables are as described in the fifteenth specific embodiment.
  • R 5 is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.
  • R 5 is an optionally substituted alkyl.
  • R 5 in the compounds of Structural Formulas (I)-(IV), (IA) 5 (IA'), (IIA), (IB) 5 (HIB) 5 (VIIB) 5 (VIIIB) 5 (DCB) 5 and (XIB) is represented by the following structural formula: wherein R9 and m are as described in the fifth specific embodiment. Values and specific values for the remainder of the variables are as described the fifteenth specific embodiment.
  • R 5 in compounds of Structural Formulas (I)- (IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), is selected from the group consisting of the following structural formulas:
  • R 5 is an optionally substituted indolyl, an optionally substituted benzoimidazoly!, an optionally substituted indazolyl, an optionally substituted 3H-indazoIyl, 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]
  • Rs in the compounds of Structural Formulas (I)-(IV) 3 is selected from the group consisting of the following structural formulas:
  • R 33 , R 34 , ring B and ring C are as described above in the seventh specific embodiment. Values and specific values for the remainder of the variables are as described above in the thirteenth specific embodiment.
  • R 2 i is O;
  • R 6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C3-C6 cycloalkyl or -NRioRu.
  • Re is a C1-C6 alky I and R 33 is H.
  • R 33 is -H and ring B is unsubstituted.
  • R 2 o and R 25 are -OH, and R 5 is a C1-C6 alkyl.
  • ring A in compounds represented by Structural Formulas (D-(IV), (IA), (IA'), (IIA), (IVA), (IB), (IIIB), (VIIB), (VIIIB), (DCB), and (XIB), is selected from Structural Formula (XIII):
  • R 2 5 is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, -OR 1 00, -SR 1 0 1 , -N(RiCo) 2 , -NR 7 R 102 , -OR 26 , -SR 26 , -NR 26 R 102 , -O(CH 2 ) m OH, -O(CH 2 ) m SH, -O(CH 2 ) m NR 7 H, -S(CH 2 ) m OH, -S(CH 2 ) m SH, -S(CH 2 ) m NR 7 H, -OCH 2 C(O)R 7 , -
  • R5 in the compounds of Structural Formulas (I)- (IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (EXB), and (XIB), is an optionally substituted phenyl, wherein the phenyl group is substituted with substituents as described in the eighth specific embodiment. Values and specific values for the remainder of the variables are as described in the sixteenth specific embodiment.
  • R 3 and R 25 are -OR A - Even more specifically, R 6 is a lower alkyl, C3-C6 cycloalkyl, lower alkoxy, a lower alkyl sulfanyl, or -NRioRu.
  • R5 in compounds of Structural Formulas (I)- (IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIEB), (VIIIB), (IXB), and (XIB), is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group described above in the eleventh specific embodiment. Values and specific values for the remainder of the variables are as described in the sixteenth specific embodiment.
  • R 5 is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.
  • R 5 is an optionally substituted alkyl.
  • R 5 in the compounds of Structural Formulas (I)-(IV) 3 is represented by the following structural formula:
  • R 9 and m are as described in the fifth specific embodiment.
  • the remainder of the variables are as described the sixteenth specific embodiment.
  • R 5 in compounds of Structural Formulas (I)- (IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (EXB), and (XEB), is selected from the group consisting of the following structural formulas:
  • R 5 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]
  • R 5 in the compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB) 5 (HIB) 3 (VIIB) 5 (VIIIB) 5 (DCB) 5 and (XIB), is selected from the group consisting of the following structural formulas:
  • R 5 is an indolyl represented by the following Structural Formula:
  • R 33 , R 34 , ring B and ring C are as described above in the seventh specific embodiment. Values and specific values for the remainder of the variables are as described above in the thirteenth specific embodiment.
  • R 21 is O;
  • R 6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C3-C6 cycloalkyl or -NRioR ⁇ .
  • Re is a C1-C6 alkyl and R 33 is H.
  • R 33 is -H and ring B is unsubstituted.
  • R 2 o and R 25 are -OH, and R 6 is a C1-C6 alkyl.
  • compounds of Structural Formulas (I)-(IY), (IA), (IA'), (IIA), (IB), (HIB) 5 (VIIB), (VIIIB), (IXB), and (XIB) are defined as the following:
  • Rs 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, or an optionally substituted heteraralkyl;
  • ring A is represented by Structural Formulas(XIV):
  • X 14 is O, S, or NR 7 ; for Structural Formulas (I)-(IV): R 22 , for each occurrence, is independently an -H or is 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, or an optionally substituted heteraralkyl, a haloalkyl, -S(O) P R.7, or ⁇ S(0) p NRioRn; and
  • R 23 and R 24 are independently -H or are 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, or an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR 1 0R 11 (provided Rio and Rn are not H), -OR7 (provided R 7 is not H), -SR7(provided R7 is not H), -S(O) P R 7 , -OS(O) p R 7 , -NR 8 S(O p R 7 , or -S(O)
  • R 22 is independently an -H or is 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, or an optionally substituted heteraralkyl, a haloalkyl, -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 Rn, - NR 8 C(O)R 7 , -S(O) P R 7 , -S(O) P OR7 or -S(O) p NR, 0 Rii; and
  • R 2 3 and R 2 4 are independently -H or are 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, or an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi 0 Ri 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR, 0 R,, s -NR 8 C(O)R 7 , -SR 7 , -S(O) P R
  • R 23 and R 24 are independently -H or are 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, or an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRioRn, -OR 7 , or -C(O)R 7 ; Values and specific values for the remainder of the variables are as described in
  • R 5 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl.
  • the remainder of the variables are as described in the seventeenth specific embodiment.
  • R 22 is — H, or an alkyl, an aralkyl. The remainder of the variables are as described in the seventeenth specific embodiment.
  • X 14 is O.
  • the remainder of the variables are as described in the seventeenth specific embodiment.
  • Ring A is represented by the following Structural Formula:
  • R 5 is represented by the following Structural Formula:
  • X 4 J is O 5 S, or NR 42 ;
  • X 42 is CR 44 or N;
  • Y 40 is N or CR 43 ;
  • Y 4 ] is N or CR 45 ;
  • R 4 I, R 42 , Rt3, Rt 4 , R 4 S, R46, and R 40 O are defined as the following: for Structural Formulas (I)-(IV), R 4I is -H, -OR A , -SR B , 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, -NRi 0
  • R 42 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, a haloalkyl, a heteroalkyl, -S(O) P R 7 , or -S(O) P NR 1O Ri I ;
  • R 43 and R 44 are, independently, -H, -OR A , 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, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -SR 7 (provided R 7 is not H), -S(O) P R 7 , -OS(O) P R 7 , -NR 8 S(O) 15 R 7 , -S(O)pNR
  • R 46 for each occurrence, is independently, selected from the group consisting 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, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRioRn (provided R 10 and R 11 are not H), -OR 7 (provided R 7 is not H), -SR 7 (provided R 7 is not H), -S(O) P R 7 , -OS(O) P R 7 , -NR 8 S(O) P R 75 or -S ⁇ NR ⁇ R, , ;
  • R 40 O is R A as described for Structural Formulas (I)-(IV).
  • R 41 is -H, -OR pl , -NHR p3> -N(R p3 ) 2 , -O(CH 2 ) m OR p i, or -(CH 2 ) U1 OR p1 ; 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, cyan
  • R 42 is -H, -ORp 1 , -NHRp 3 , -N(R p3 ) 2 , -O(CH 2 ) m ORp,, or -(OHb) 1n OR p1 ; 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; -NRioRn, or -OR 7 ;-O(CH 2 ) m NR 7 Rp 3 ;-C(O)
  • R 43 and R 44 are, independently, -H, -OR p i, -NHR p3 , -N(R p3 ) 2 , -O(CH 2 ) m OR pl , or -(CH 2 ) m OR p i; 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; -NR 10 Rn, or -OR 7 ; -O(CH 2 ) m NR 7 R
  • R 45 is -H, -ORpi, -NHR p3 , -N(R p3 ) 2 , -O(CH 2 ) m OR pU or -(CHz) 1n ORp,; 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; -NR 10 Rn, or -OR 7 ; -O(CH 2 ) m NR 7 R p3 ; -C(O)
  • R) 6 for each occurrence, is independently, a lower alkyl;
  • R 400 is Rp 1 as described in Structural Formulas (IA), (IA') and (IIA); for Structural Formulas (IB), (HIB), (VIIB), (VIIIB), (KB), and (XIB),
  • R 42 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, protected hydroxyalkyl that is optionally substituted, an optionally substituted alkoxyalkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, and -C(O)
  • R 4 3 and R 44 are, independently, -H, -OR100, — N(R 1O2 ) 2> 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, protected hydroxy alkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -C(O)R 7 , or -SR 101 .
  • R 43 and R 44 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;
  • R 45 is -H, -OR 10 O, -SR 1 Oi, -N(R 102 ) 2, -0(CH 2 ) m OR ]0 o, -O(CH 2 ) m SR 101 ,
  • R 4S for each occurrence, is independently, selected from the group consisting 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, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi 0 R 11 , -OR 1 00, -C(O)R 7 , and-SR 101 . Or two R)6 groups taken together with the carbon atoms to which they are attached form a fused ring;
  • R 41 is -H, -OR A , -SR B , 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, -NRi 0 Ri 1 or -C(O)R 7 . More specifically, R n is selected from the group consisting of -H, a lower alkyl, a lower alkoxy, a lower cycloalkyl and a lower cycloalkoxy.
  • R400 is R 100 as described in Structural Formulas (IB), (IIIB), (VIIB), (VIIlB), (DCB), and (XIB).
  • X 41 is NR 42 and X 42 is N. Values and specific values for the remainder of the variables are as described in the eighteenth specific embodiment.
  • R 4 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. More specifically, R 4I is selected from the group consisting of H, methyl, ⁇ thyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. Values and specific values for the remainder of the variables are as described in the eighteenth specific embodiment.
  • X 41 is NR 42
  • R 42 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, wherein each R 2 7 is independently -H or a lower alkyl. More specifically, R 42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, /erf-butyl, n-pentyl, n-hexyl, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 .
  • R 43 and R 44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. Values and specific values for the remainder of the variables are as described in the eighteenth specific embodiment.
  • X 42 is CR 44 ;
  • Y 4 o is CR 43 ; and R 43 and R 44 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.
  • X 4 i is O.
  • R 43 and R 44 together with the carbon atoms to which they are attached form a C 5 -C 8 cycloalkenyl or a C 5 -Cg aryl.
  • R 45 or CR 4 S is selected from the group consisting of -H, -OR A , -SR B , -N(Rc) 2 , a lower alkoxy, and a lower dialkyl amino.
  • R 45 is selected from the group consisting of -H, -OR A , methoxy and ethoxy. Values and specific values for the remainder of the variables are as described in the eighteenth specific embodiment.
  • the variables can each be independently selected from the following lists of preferred values (values and specific values for the remainder of the substituents are as defined above in the eighteenth specific embodiment):
  • X 4I can be NR 42 and X 42 can be CR 44 ;
  • X 41 can be NR « and X 42 can be N;
  • R 41 can be selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy;
  • R 41 can be selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cycloprppyl, methoxy, ethoxy, propoxy, and cyclopropoxy;
  • X 41 can be NR 42 , and R 42 can be selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, -C(O)N(R 2 7) 2 , and -R 0 , wherein R 0 is a protected carboxyl group as defined above, and each R 2 7 is independently -H or a lower alkyl;
  • X 41 can be NR 42 , and R 42 can be selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, -R-, -(CH 2 )H 1 R 5 , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , and -C(O)N(CH 3 ) 2 , wherein R 0 is a protected carboxyl group and m is 1 or 2;
  • R 43 and R 44 can be, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy;
  • X 42 can be CR 44 ;
  • Y 40 can be CR 43 ; and
  • R 43 and R 44 together with the carbon atoms to which they are attached can form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring;
  • R 43 and R 44 together with the carbon atoms to which they are attached can form a
  • R 45 or CR 45 can be selected from the group consisting of -H, -OR p i, -SR p2 , -NHR p3 , -N(Rp3) 2 , a lower alkoxy, -(CH 2 ) m -NHR p3> and -(CH 2 ) m -N(Rp 3 ) 2 , wherein m is an integer from 1 to 6; R 45 can be selected from the group consisting of -H 5 -OR p i, methoxy and ethoxy;
  • X 41 can be O.
  • R, b is -SH or -OH; R 3b and R 25 are
  • X 41 is NR 42 and X 42 is CR 44 or N; and values and specific values of the remaining variables are as described above in the eighteenth specific embodiment. More preferrably, X 41 is NR 42 ; and Rj 2 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, and an optionally substituted alkyl; and the values and specific values of the remaining variables are as described above in the eighteenth specific embodiment.
  • X 4 1 is NR 42 ;
  • X 42 is CR 44 ;
  • Y 40 is CR 43 ; and
  • R 43 and R 44 together with the carbon atoms to which they are attached, form a cycloalkenyl, an aryl, heterocyclyl, heteroaryl ring.
  • the values and specific values of the remaining variables are as described above in the eighteenth specific embodiment.
  • the compounds of Structural Formulas (I)- (IV), (IA), (IA'), (HA), (IB), (IHB) 5 (VIIB), (VIIIB), (IXB) and (XIB) are defined as the following or a tautomer, a pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof:
  • ring A is represented by the following Structural Formula:
  • R 5 is represented by the following Structural Formula:
  • X 42 is CR 44 .
  • R 43 and R 44 are, independently, selected from the group consisting of — H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methooxy, ethoxy, propoxy, and cyclopropoxy.
  • R 4 3 and R 44 taken together with the carbon atoms to which they are attached, form a Cs-Cg cycloalkyenyl or a C 5 -Cs aryl. Values and specific values for the remainder of the variables are as described in the nineteenth specific embodiment.
  • X 42 is N. Values and specific values for the remainder of the variables are as described in the nineteenth specific embodiment.
  • X 42 is CR 44 or N;
  • R 4I is selected from the group consisting of — H, methyl, ethyl, isopropyl, and cyclopropyl;
  • R 42 is selected selected from the group consisting of -H, methyl, ethyl, n- propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CH 2 ) 2 OCH 3 ;
  • R 43 and R 44 are each, independently, -H, methyl, ethyl, or isopropyl; or R 53 and R 54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring; and
  • R 4 S is selected from the group consisting of -H, -OCH 3 ,-OCH 2 CH 3 and -OR 40 O. Values and specific values for the remainder of the variables are as described in the nineteenth specific embodiment. In a more specific embodiment, for Structural Formula (IIA), R 2J is O. Values and specific values for the remainder of the variables are as described in the nineteenth specific embodiment.
  • X 42 can be CR ⁇ , and R 43 and R 44 can be, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy;
  • X 42 can be CR 44 , and R 43 and R 44 , taken together with the carbon atoms to which they are attached, can form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring;
  • R 43 and R 44 taken together with the carbon atoms to which they are attached, can form a Cs-C 8 cycloalkenyl or a C 5 -C 8 aryl;
  • X 42 can be CR 44 ; and
  • X 42 can be N.
  • X 42 is CR 44
  • R 43 and R 44 are, independently, -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, cyclopropoxy, or, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring. Values and specific values for the remainder of the variables are as described above in the nineteenth specific embodiment.
  • X 42 is CR 44 ;
  • R 43 and R 44 are are, independently, -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, cyclopropoxy, or, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring; and R ⁇ are selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl. Values and specific values for the remainder of the variables are as described above in the nineteenth specific embodiment.
  • the compounds of Structural Formulas (I)-(FV), (IA), (IA'), (HA), (IB), (IIIB), (VIIB), (VlIlB), (IXB) and (XIB) are defined as the following or a tautomer, a pharmaceutically acceptable salt, solvate, clarthrate, or a prodrug thereof:
  • ring A is represented by the following Structural Formula:
  • R 5 is represented by the following Structural Formula:
  • X 45 is CR 54 or N;
  • R 52 for Structural Formulas (I)-(IV) 5 (IB), (IIIB), (VIIB), (VIIIB), (DCB) and (XIB) is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CH 2 ) 2 OCH 3 , -CH 2 C(O)OH, and -C(O)N(CH 3 ) 2 ;
  • R 52 for Structural Formulas (IA), (IA') and ( ⁇ IA) is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, - (CH 2 ) 2 OCH 3 , ⁇ (CH 2 ) m R c , wherein R
  • R 53 and R 54 are each, independently, -H, methyl, ethyl, or isopropyl; or R 53 and R 54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring;
  • R 55 is selected from the group consisting of -H, -OH, -OCH 3 , and -OCH 2 CH 3 ; and R 56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl; and the remainder of the variables are as described in the nineteenth specific embodiment.
  • R 53 is H or a lower alkyl. Values and specific values for the remainder of the variables are as described in the twentieth specific embodiment.
  • X 45 is CR 54 .
  • R 54 is H or a lower alkyl. Values and specific values for the remainder of the variables are as described in the twentieth specific embodiment.
  • X 45 is N. Values and specific values for the remainder of the variables are as described in the twentieth specific embodiment.
  • ring A is represented by the following Structural Formula:
  • R 5 is represented by the following Structural Formula:
  • X 44 for each occurrence, is independently, O, NR 42 or C(R)O) 2 ;
  • Y- U5 Y 42J Z, R 41 , RJ) 2 , and R 4 6 are as described in the eighteenth specific embodiment.
  • R 4I is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. Values and specific values for the remainder of the variables are as described in the twenty-first specific embodiment.
  • R 4J is selected from the group consisting of - H 5 methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. Values and specific values for the remainder of the variables are as described in the twenty-first specific embodiment.
  • R 42 is selected from the group consisting of - H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, .sec-butyl, tert-buty ⁇ , n-pentyl, n- hexyl, -C(O)OH, -(CH 2 ) m C(O)OH, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , and -C(O)N(CH 3 ) 2 .
  • Values and specific values for the remainder of the variables are as described in the twenty-first specific embodiment.
  • Y 41 is CR 45 .
  • R 45 is H, a lower alkoxy, or -OH.
  • Values and specific values for the remainder of the variables are as described in the twenty-first specific embodiment.
  • Y 42 is CH. Values and specific values for the remainder of the variables are as described in the twenty-first specific embodiment.
  • Y 43 is CH 2 .
  • Values and specific values for the remainder of the variables are as described in the twenty-first specific embodiment.
  • Y 43 is NR 42 , wherein R 42 is H or a lower alkyl. Values and specific values for the remainder of the variables are as described in the twenty-first specific embodiment.
  • one of X 44 is NR 42 and the other is CH 2 or C(Re) 2 .
  • one of X 44 is NR 42 and the other is CH 2.
  • Values and specific values for the remainder of the variables are as described in the twenty-first specific embodiment.
  • the compounds of of Structural Formulas are as described in the twenty-first specific embodiment.
  • R 4 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. Values and specific values for the remainder of the variables are as described in the twenty-second specific embodiment.
  • R4 1 is selected from the group consisting of - H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. The remainder of the variables are as described in the twenty-second specific embodiment.
  • X41 is NR 42 .
  • R 4 2 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec- butyl, tert-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH 2 ) m C(O)OH, -CH 2 OCH 3 ,
  • R 42 is H or a lower alkyl. Values and specific values for the remainder of the variables are as described in the twenty-second specific embodiment.
  • X41 is O. Values and specific values for the remainder of the variables are as described in the twenty-second specific embodiment.
  • X 4 1 is S. Values and specific values for the remainder of the variables are as described in the twenty-second specific embodiment.
  • Y 4] is CR 45 .
  • R 45 is H, a lower alkoxy, or -OH.
  • Values and specific values for the remainder of the variables are as described in the twenty-second specific embodiment.
  • Y 42 is CH. Values and specific values for the remainder of the variables are as described in the twenty-second specific embodiment.
  • R 46 is H or a lower alkyl. Values and specific values for the remainder of the variables are as described in the twenty-second specific embodiment.
  • ring A is represented by the following Structural Formula:
  • X n for each occurrence, is independently CH, CR 9 , N, N(O), or N + (R] 7 ), provided that at least one Xn is N, N(O), or N + (Ri 7 ) and at least two Xn groups are independently selected from CH and CRg; values and specific values for the remainder of the variables are as described above in the tenth specific embodiment.
  • one of the Xn group is N, N(O), or N + (Ri 7 ) and the remaining Xn groups are independently selected from CH and CRp.
  • R 41 is a lower alkyl, C3-C6 cycloalkyl, lower alkoxy, a lower alkyl sulfanyl, Or -NRi 0 Rn- Values and specific values for the remainder of the variables are as described above in the twenty-third specific embodiment.
  • the compound of formula (IIA) is represented by the following Structural Formula: wherein the variables are as described above in the eighteenth specific embodiment.
  • variables can each be independently selected from the following lists of specific values (values and specific values for the remainder of the substituents are as defined above in the twenty-third specific embodiment):
  • X 4I can be NR 42 and X 42 can be CR 44 ;
  • X 4I can be NR 42 and X 42 can be N;
  • R 4I can be selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy;
  • R 4I can be selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy;
  • X 4I can be NR 42 , and R 42 can be selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, -C(O)N(R 27 ) 2 , and -R 0 , wherein R 0 is a protected carboxyl group as defined above, and each R 27 is independently -H or a lower alkyl;
  • X 4 i can be NR 42 , and R 42 can be selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, f ⁇ -r-butyl, n-pentyl, n-hexyl, -R 0 , -(CH ⁇ R c , -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , and -C(O)N(CH 3 ) 2 , wherein
  • R 43 and R 44 can be, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy;
  • X 42 can be CR 44 ;
  • Y 40 can be CR 43 ; and
  • R 43 and R 44 together with the carbon atoms to which they are attached can form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring;
  • R 43 and R 44 together with the carbon atoms to which they are attached can form a C 5 -C 8 cycloalkenyl or a C 5 -C 8 aryl;
  • R 45 or CR 45 can be selected from the group consisting of -H, -OR p i, -SRp 2 , -NHR p3 ,
  • R 45 can be selected from the group consisting of -H, -OR p1 , methoxy and ethoxy;
  • X 4I can be O.
  • the compound of formula (IIA) is represented by the following Structural Formula:
  • R 21 is O.
  • Values and specific values for the remainder of the substituents are as defined above in the twenty-third specific embodiment.
  • variables can each be independently selected from the following lists of specific values:
  • X 42 can be CR 44 , and R 43 and R 44 can be, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy;
  • X 42 can be CR 44 , and R 43 and R 44 , taken together with the carbon atoms to which they are attached, can form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring;
  • R 43 and R 44 taken together with the carbon atoms to which they are attached, can form a C 5 -C 8 cycloalkenyl or a Cs-C 8 aryl;
  • X 42 can be CR 44 ;
  • X 42 can be N.
  • the compound of Structural Formula (IIA) is represented by the following Structural Formula:
  • X 45 is CR 54 or N; R 2 1 is O;
  • R 56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl;
  • R 52 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CH 2 ) 2 OCH 3 , -(CH 2 ) m R « wherein R 0 is a protected carboxyl moiety and m is 1 or 2, and -C(O)N(CH 3 ) 2 ;
  • R 53 and R 54 are each, independently, -H, methyl, ethyl, or isopropyl; or R 53 and R 54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring; and
  • R 55 is selected from the group consisting of -H, -OH, -OCH 3 , and -OCH 2 CH 3 . Values and specific values for the remainder of the substituents are as described in the twenty-fourth specific embodiment.
  • the present invention is a method of preparing a compound of Structural Formula (XXXIA)
  • the molar ration of the POCl 3 to the compound of Structural Formula (XXXA) can be, for example, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1.5:1, 1.2:1. ort 1.1:1.
  • the molar ration is 5:1 to 1.5:1. More preferably, the moral ratio is 3:1 to 2:1.
  • the product of the reaction between the compound of Structural Formula (XXXA) and POCl 3 in dimethyl formamide (DMF) is further reacted with a hydroxide base, such as NaOH.
  • a hydroxide base such as NaOH.
  • an excess of the base with respect to the starting reagent is used. In one embodiment, 12 equivalents of NaOH is used.
  • R 30 ] and R 302 are each independently -H, an alkyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, each optionally substituted by one or more of an alkyl, alkoxy, haloalkyl, halogen nitro, cyano or alkyl alkanoate groups.
  • R 301 and R 3 0 2 are each independently -H, an optionally substituted Cl- C6 alkyl, an optionally substituted phenyl, an optionally substituted benzyl, or an optionally substituted six-member heteroaryl. In one embodiment, R301 and R 30 2 are not simultaneously hydrogens.
  • R 3 oi and R 3 o 2 are each independently -H, an optionally substituted C1-C6 alkyl. Even more preferably, R 3 o 2 is H and R 3 oi is isopropyl, such that the compound of Structural Formula (XXXA) is compound HA:
  • the present invention is a method of synthesis of a compound of formula (XXA), comprising reacting a compound of formula (XXIA):
  • the oxidizing agent is K 3 Fe(CN) 6 .
  • the compound of formula (XXIA) is prepared by reacting a compound of formula (XXIIA)
  • the compound of formula (XXA) is further deprotected, thereby producing a compound of formula (XXIVA):
  • the methods of present invention further comprises the step of deprotecting the compounds of Structural Formulas (I), (IA) and (IB).
  • General conditions for deprotecting the compounds of Structural Formulas (I), (IA) and (IB) are known in the art and depend on the nature of the protecting group used. Examples are provided above with reference to Greene.
  • the methods of the present invention comprise the step of deprotecting the compound of the following Structural Formula:
  • the polar solvent is ethanol. More specifically, the reaction temperature is between 50 °C - 60 0 C.
  • the method further comprises the step of deprotecting the compound represented by the following Structural Formula: wherein R 3b and R 25 are -ORmo, thereby forming a triazole compound represented by the following Structural Formula:
  • the method further comprises the step of deprotecting the thioamide compounds represented by the following Structural Formula:
  • R 5 is represented by the following Structural Formula:
  • the second starting compound of Structural Formula (LVIIIB) used in the disclosed method III is prepared by reacting a thionation reagent with a compound represented by the following formula:
  • the present invention comprises the step of deprotecting a compound of Structural Formulas (T), (IA), (EB) 5 (IVB), (VIIB) and (XEB).
  • a compound of Structural Formulas (T), (IA), (EB) 5 (IVB), (VIIB) and (XEB) are known in the art and depend on the nature of protecting group used. Examples are provided above with reference to Greene.
  • the deprotection of compounds of Structural Formulas (T), (IA), (IB), (IVB), (VIIB) and (XIB) can be accomplished by catalytic hydrogenation.
  • Any hydrogenation catalyst can be used, either soluble or insoluble in the reaction medium. Typical catalysts include palladium-on- charcoal, Raney nickel, NaBHj-reduced nickel, platimum metal or its oxide, rhodium rhuthenium or zinc oxide.
  • Hydrogenation reactions are typically carried aout at temperature from about 0 0 C to about 50 0 C, preferably at 15-35 0 C at atmospheric or slightly above atmospheric pressure.
  • the compounds of Structural Formulas (I), (IA), (IB), (IVB), (VIIB) and (XIB) are typically reacted with hydrogen at room temperature in a polar solvent.
  • a polar solvent Preferably, palladium-on-charcoal is used as a catalyst.
  • the polar solvent can be one or more of a polar protic solvent, such as water or an alcohol; an ethereal solvent such as THF, dioxane and the like.
  • the solvent can be a mixture of THF and methanol.
  • the mixture (by volume) can be 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1 :1, 1 :2, 1 :3, 1:4, 1:5, 1:6, 1 :7, 1 :8, 1:8, 1:9, or 1 :10.
  • the THF/MeOH mixture is from about 4:1 to about 1:1 by volume.
  • R 3 of Structural Formula (I) is -OR A ; R 2 0 in
  • Structural Formula (IA) is -ORpi; or R 3b of Structural Formula (IB) is -OR 10 O 5 wherein R A , Rpi and Rioo are benzyl groups
  • the deprotection step of compounds of Structural Formulas (I), (IA), (IB), (IVB), (VIIB) and (XIB) comprises reacting a compound of Structural Formulas (I), (IA), (IB), (IVB), (VIIB) and (XIB) with ammonium formate in the presence of a hydrogen catalyst.
  • the hydrogen catalyst is palladium on activated carbon.
  • the step of deprotecting is carried out at a temperature from 45 to 65 0 C.
  • the step of deprotecting is carried out at about 55 0 C.
  • the compound of Structural Formulas (I), (IA), (IB), (IVB), (VIIB) or (XIB) and the ammonium formate are reacted for about 1 to 5 hours in the presence of the palladium on activated carbon.
  • the compound of Structural Formulas (I), (IA) or (IB) and the ammonium formate are reacted for about 1 hour in the presence of the palladium on activated carbon.
  • the compound of Structural Formulas (I), (IA) or (IB) and the ammonium formate are reacted for about 12 hours in the presence of the palladium on activated carbon.
  • the purity of the deprotected product of a compound of Structural Formulas (I) 5 (IA), (IB), (IVB), (VIIB) or (XIB) is 99.0% or greater. In another aspect, the purity is 99.5% or greater. In a further aspect, the purity is 99.8% or greater.
  • Exemplary compounds that can be prepared by the disclosed method I and method III are depicted in Tables 1 and 2 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs and synthetic intermediates thereof represented by Structural Formula (II), (III), or (IV).
  • Exemplary compounds that can be prepared by the disclosed method II include compounds 97, 137-173, 176, 220, and 232 depicted in Table 1 below.
  • 5-isopropyl-2,4-dimethoxy-N-l-methyl-lH-indol-5-yl)-benzamide was prepared reacting 2,4-dimethoxy-5-isopropylbenzoic acid with l,3-dimethyl-5-aminoindole by a procedure similar that described in Example 1.
  • the corresponding thioamide was prepared by reacting the amide with Lawesson's reagent by a similar procedure as described in Procedure 1 of Example 1.
  • a flask was charged wiht the thiobenzamide (123 mg, 0.33 mmol), dioxane (2 DiL), and hydrazine (0.5 mL).
  • Step 2 Synthesis of N-(I -methyl- lH-indol-5-yl)hydrazinecarboxamide 6A
  • Step 3 Synthesis of 3-(2,4-Bis-benzyloxy-5-isopropyl)benzylideneamino-l-(l-Methyl-lH- indoi-'-yl)-urea 8A
  • Step 4 Synthesis of 5-(2,4-Bis-benzyloxy-5-isopropylphenyI)-4-(l-methyI-lH-indol-5-yl)- 4H-[l,2,4]triazol-3-ol 9A
  • Step 5 Synthesis of 4-(5-hydroxy-4-(l-methyl-lH-indol-5-yl)-4H-l,2,4-triazol-3-yl)-6- isopropylbenzene-l,3-diol (XXIVA)
  • Step 5b Synthesis of 4-(5-hydroxy-4-(l-methyl-lH-indol-5-yl)-4H-l,2,4-triazol-3-yl)-6- isopro
  • Exemplary compounds of formula (IA') that can be synthetized by the method II of the present invention are compounds 97, 137-173, 176, 220, and 232 depicted in Table 1 above, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof .
  • Step 1 The off-white solid (4 mmol) of the amide obtained above was treated with Lawesson's reagent (970 mg, 0.6 equiv.) in 40 mL toluene at 110 0 C for 1.5 hour. Water was added and extracted with ethyl acetate, washed with water 2 times. Dried, concentrated and crystallized by the combination of sonication and addition of hexanes to give an orange solid (80% yield)
  • Step 2 The off-white solid (4 mmol) of the amide obtained above was treated with Lawesson's reagent (970 mg, 0.6 equiv.) in 40 mL toluene at 110 0 C for 1.5 hour. The reaction was allowed to cool. Aqueous ammonium hydroxide solution was added (2 mol equiv.) and stirred vigorously at room temperature for 10 min. Water (200 mL) and ethyl acetate (100 mL) were added. The organic layer was washed wiht water (2 x 200 mL). The organic layer was then treated with activated carbon (10 g) and stirred at room temperature for 1 hour. Filtration and removal of solvent under reduced pressure gave a bright yellow solid.
  • Lawesson's reagent 970 mg, 0.6 equiv.

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Abstract

The present invention provides novel methods of preparing triazole compounds which inhibit the activity of Hsp90. One embodiment of the invention is directed to methods for preparing a triazole compound represented by the following Structural Formula: or a tautomer, a pharmaceutically acceptable salt, solvate, or clathrate, or a prodrug thereof, comprising the steps of: a) reacting an amide represented by the following Structural Formula: with a thionation reagent to form a thioamide; b) reacting the thioamide of step a) with hydrazine to form a hydrazonamide; c) reacting the hydrazonamide of step b) with a carbonylation or a thiocarbonylation reagent. In one embodiment, the present invention is a method of synthesis of a compound of formula (IA) or a tautomer, a pharmaceutically acceptable salt, solvate, or clathrate, or a prodrug thereof, comprising reacting a compound of formula (IIA) with an oxidizing agent, thereby producing a compound of formula (IA). The present invention is also directed to a method of preparing a compound or a tautomer thereof represented by the following Structural Formula: (IB) or a tautomer, a pharmaceutically acceptable salt, solvate, or clathrate, or a prodrug thereof. The method comprises the step of reacting a first starting compound represented by the following Structural Formula: (HB) in the presence of a mercuric salt, with a second starting compound represented by the following Structural Formula: (IIIB).

Description

SYNTHESIS OF TRIAZOLE COMPOUNDS THAT MODULATE HSP90 ACTIVITY
RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 60/808,342, filed on May 25, 2006, U.S. Provisional Application No. 60/808,376, filed on May 25, 2006, U.S. Provisional Application No. 60/808,375, filed on May 25, 2006, and U.S.
Provisional Application No. 60/902,031, filed on February 16, 2007. The entire teachings of the above applications are incorporated herein by reference.
BACKGROUND OF THE INVENTION
Certain triazole-based hsp90 inhibitors, such as the compounds described in U.S. Publication No. 20060167070, 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 commercial scale synthesis. Therefore, the need exists for improved synthese of these compounds.
SUMMARY OF THE INVENTION
The present invention is directed to novel synthetic methods for preparing certain [1 ,2,4]-trizole compounds, which are suitable for industrial-scale synthesis with minimal purification required. One embodiment of the invention is directed to a method (method I) of preparing a triazole compound represented by Structural Formula (I):
Figure imgf000003_0001
(J) or a tautomer, a pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. The method of preparing a [l,2,4]triazole compound comprises the steps of: a) reacting an amide represented by Structural Formula (II):
Figure imgf000004_0001
(II) with a thionation reagent to form a thioamide represented by Structural Formula
(HI):
Figure imgf000004_0002
(III)
b) reacting the thioamide of Step a) with hydrazine to form a hydrazonamide represented by the Structural Formula (IV):
Figure imgf000004_0003
(IV) c) reacting the hydrazonamide of step b) with a carbonylation, a thiocarbonylation reagent or a compound of structural formula R7N=C(X)2 to form the [ 1 ,2,4]triazole compound. Any protecting groups on the product formed in step c) are removed. In Structural Formulas (I) - (IV), variables are defined as the following: ring A is an aryl or a heteroaryl optionally further substituted with one or more substituents in addition to Ry, R3 is -OR26, -SR26, -O(CH2)mORA, -O(CH2)mSRB, -O(CH2)mNR7Rc,
-S(CHZ)111ORA, -S(CH2)mSRB) -S(CH2)mNR7Rc, -OS(O)PR7, -SS(O)PR7, -S(O)pOR7, -NR7S(O)PR7, -OS(O)PNR1ORi I5 -SS(O)PNR1ORn, -NR7S(O)pNRI0R,i, -SS(O)POR7, -NR7S(O)POR7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NRi0Rn, -NR7C(S)NRi0R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRg)NR10Rn, -SC(NR8)NR1ORH5 -NR7C(NR8)NR10RI U -OP(O)(OR7)2, or -SP(O)(OR7)2, -ORA, -SR8, -NR7RC, -NR26RC, or -N(Rc)2, wherein RA is a hydroxyl protecting group; RB is a thiol protecting group, Rc, for each occurrence, is H or an amine protecting group, provided at least one Rc is an amine protecting group;
R5 is an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted cycloaliphatic, or an optionally substituted alkyl;
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 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 Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a C1-C6 alkyl; p, for each occurrence, is, independently, 0, 1 or 2; m, for each occurrence, is independently, 1, 2, 3, or 4; in Structural Formula (I), Ri is -OH, -SH or -NHR7; and X is a leaving group.
More specifically, the present invention is directed to a method of preparing a triazole compound represented by the Structural Formula (V):
Figure imgf000005_0001
(V) or a tautomer, a pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. The method of preparing the [l,2,4]triazole compound comprises the steps of: a) reacting an amide represented by Structural Formula (VI):
Figure imgf000006_0001
(Vl) with a thionation reagent to form a thioamide represented by Structural Formula (VII):
Figure imgf000006_0002
(VII) b) reacting the thioamide of step a) with hydrazine to form a hydrazonamide represented by Structural Formula (VIII):
Figure imgf000006_0003
(VIII) c) reacting the hydrazonamide of step b) with a carbonylation reagent to form a • protected triazole compound; and d) deprotecting the protected triazole compound formed in step c) to form the triazole compound; wherein RA is a hydroxyl protecting group.
Another embodiment of the invention is directed to a method of preparing the thioamide represented by Structural Formula (III) by reacting the amide represented by Structural Formula (II) with thionation reagent. The present invention is also directed to a method of preparing the hydrazonamide represented by Structural Formula (FV) by reacting the thioamide of Structural Formula (III) with hydrazine.
Another embodiment of the invention is directed to a method of preparing the [l,2,4]triazole compound by reacting the hydrazonamide of Structural Formula (IV) with a carbonylation reagent, a thiocarbonylation reagent or an isocyanide.
Other embodiments of the present invention are synthetic intermediates in the preparation of the [ 1 ,2,4]triazole compound represented by Structural Formula (III) and Structural Formula (IV) by the methods disclosed herein. In one embodiment, the present invention is a method (method II) of synthesis of a compound of Structural Formula (IA)
Figure imgf000007_0001
a tautomer, a pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, comprising reacting a compound of Structural Formula (IIA)
Figure imgf000007_0002
("A) with an oxidizing agent, thereby producing a compound of Structural Formula (IA). In Structural Formulas (IA) and (IIA): 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; Rs 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;
R20 is -ORpi, -NHRp3 or -N(Rp3)2, wherein Rpi, for each occurrence, is independently selected from groups suitable for protecting hydroxyl, and Rp3, for each occurrence, is independently selected from groups suitable for protecting an amino group; R21 is O, NH, or NR26, and R2)a is OH, NH2 or NHR26; and R26 is a C 1-C6 alkyl- In another embodiment, the present invention is a method of synthesis of a compound of Structural Formula (IIA),
Figure imgf000008_0001
(HA) comprising reacting a compound of Structural Formula (IIIA)
Figure imgf000008_0002
(HIA) with a compound of Structural Formula (IVA)
Figure imgf000008_0003
GVA) R20 3 in the presence of an acid, thereby producing a compound of Structural Formula (IIA). The values of the substituents in Structural Formulas (HlA) and (FVA) are as defined with reference to Structural Formulas (IIA) and (IA).
In another embodiment, the present invention is a method of synthesis of a compound of Structural Formula (XXXIA)
Figure imgf000008_0004
comprising the step of reacting the compound of for Structural Formula (XXXA)
Figure imgf000008_0005
(XXXA)5 with POCl3 in dimethyl formamide (DMF). Substituents R30] and R302 are each independently -H, an alkyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, each optionally substituted by one or more of an alkyl, alkoxy, haloalkyl, halogen nitro, cyano or alkyl alkanoate groups.
In another embodiment, the present invention is a method of synthesis of the compound of Structural Formula (XXA)
Figure imgf000009_0001
(XXA) comprising reacting a compound of Structural Formula (XXIA)
Figure imgf000009_0002
(XXIA) with an oxidizing agent, thereby producing a compound of formula (XXA).
In another embodiment, the present invention is a compound of Structural Formula (UA):
Figure imgf000009_0003
(IIA)
The values and the preferred values of the substituents in Structural Formula (IIA) are as defined above.
Another embodiment of the present invention is directed to a method (method III) of preparing a compound thereof represented by the following Structural Formula:
Figure imgf000009_0004
or a tautomer, a pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. The method comprises the step of reacting a first starting compound represented by the following Structural Formula:
Figure imgf000010_0001
in the presence of a mercuric salt, with a second starting compound represented by the following Structural Formula:
Figure imgf000010_0002
Rib is -OH, -SH or -NHR60; preferably, RIb is -OH or -SH. R60 is H, an optionally substituted alkyl group, or an optionally substituted cycloalkyl group.
Ring A is an aryl or a heteroaryl, wherein the aryl group and the heteroaryl group represented by ring A is optionally further substituted with one or more substituents in addition to R3b.
R3b is -OR100, -SRioi, -N(R,02)2, -NR7Ri025 -OR26, -SR26, -NR26Ri02, -O(CH2)mOR100, -O(CH2)mSR101, -O(CH2)mNR7R,02, -S(CH2)mOR,00, -S(CH2)mSR,Oi, -S(CH2)H1NR7R1O25 -OC(O)NR10Rn, -SC(O)NR10Rn, -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)NR10Ri1, -SCH2C(O)NRi0R11, -NR7CH2C(O)NR10Rn5 -OS(O)PR7, -SS(O)PR7, -S(O)-OR7, -NR7S(O)PR7, -OS(O)PNR1ORI U -SS(O)PNR10R11, -NR7S(O)PNR10RΠ, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR73 -SC(S)OR7, -NR7C(S)OR75 -OC(S)NR10R11, -SC(S)NR10Rn, -NR7C(S)NRIOR1 U -OC(NR8)R7,
Figure imgf000010_0003
-NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NRs)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10R115 -NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2. Preferably, R3b is -ORi00, -SR10I5 -N(R,02)2 , -NR7R102, -OR26, -SR26, -NR26R,02, -0(CHz)1nOR100, -O(CH2)mSR10i, -O(CH2)mNR7Ri02, -S(CH2)mOR100, -S(CH2)mSR101, and -S(CH2)mNR7R102. Each Rioo, independently, is a hydroxy 1 protecting group. Each Rioi, independently, is a thiol protecting group.
Each R-102, independently, is -H or an amino protecting group, provided that at least one group represented by R102 is a protecting group.
R5 is an optionally substituted aryl group, an optionally substituted heteroarylgroup, an optionally substituted cycloalkyl group, an optionally substituted cycloakenyl group, or a substituted alkyl group, wherein each of the aryl group, heteroaryl group, cycloaryl group, cycloalkyl group, cycloalkenyl group, and alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkyl group, an optionally substituted alkynyl, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted heteroaryl group, an optionally substituted aralyalkyl group, or an optionally substituted heteraralkyl group.
R7 and Rs, 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, an optionally substituted heteraralkyl, or R7, taken together with the oxygen atom to which it is bonded, forms an optionally substituted heterocyclyl or an optionally substituted heteroaryl.
Rio and Rn, for each occurrence, are, independently, amine protecting group, 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 Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.
R26 is a lower alkyl group.
R50 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, or an optionally substituted heteraralky.
Figure imgf000011_0001
p, for each occurrence, is, independently, 0, 1 or 2. m, for each occurrence, is, independently, 1, 2, 3, or 4. In another embodiment, the present invention is directed to a method of preparing a compound thereof represented by the following Structural Formula:
Figure imgf000012_0001
or a tautomer, a pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. The method comprises the step of reacting a first starting compound represented by the following Structural Formula:
Figure imgf000012_0002
in the presence of a mercuric salt, with a second starting compound represented by the following structural formula
Figure imgf000012_0003
Each Rioo, independently, is a hydroxyl protecting group; and R50 is an alkyl. In alternative embodiment, the present invention is directed to a method of preparing a compound thereof represented by the following Structural Formula:
Figure imgf000013_0001
(VIIB) or a tautomer, a pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. The method comprises the steps of:
1) reacting a thionation reagent with a compound represented by the following Structural Formula:
Figure imgf000013_0002
(VIIIB), thereby forming a first product represented by the following Structural Formula:
Figure imgf000013_0003
2) in the presence of a mercuric salt, reacting the first product with
Figure imgf000013_0004
thereby forming a second product represented by the following Structural Formula:
Figure imgf000013_0005
(XIB); and 3) deprotecting the second product, thereby forming the compound represented by
Structural Formula (XIB).
Values for ring A, R3b, R5, R71R8, Rio, Rn.Rzβ, R50, Rsu Rioo, Rioi, R102, P, and m are as described above in Structural Formulas (IB)-(IIIB). Preferably, R3b is -ORi00, -SRioi, -N(R,02)2 , -NR7Ri02, -OR26, -SR26, -NR26R102,
-O(CH2)mORI00, -O(CH2)mSR10), -0(CH2)JSfR7R102, -S(CH2)mOR100, -S(CH2)mSR10I, or -S(CH2)mNR7R,02.
The methods of the present invention described above overcomes the problem of poor selectivity and eliminates the need of high temperature heating in the prior methods. Instead, the methods provides compounds in high yield and with clean crystallization that is obtained under moderate temperature.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a synthetic scheme for preparing [1 ,2,4]triazole compound represented by Structural Formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to novel synthetic methods for synthesizing certain [l,2,4]-triazole compounds, which inhibit the activity of Hsp90 and are useful in the treatment of proliferative disorders, such as cancer. Unless otherwise specified, the 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, /erf-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, 2-methyIhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3- dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4- dimethylhexyl, 2,5-dimethylhexyI, 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-methy 1-3 -ethylhexyl, 2-methyl-4- ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. The term "(CrCfi)alkyP' 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-Ci0)alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-l-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-l-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, A- 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 "(Ce)aryl."
As used herein, the term "aralkyl" means an aryl group that is attached to another group by a (Ci-Ce)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 (Ci -C6)alkylene groups are preferred. Non-limiting examples of alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CHaCH(CHa)-), 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 morpholiηyl, 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 quatemized; 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 (Cs)heteroaryls include fiiranyl, thienyU 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 of the 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)R3], -NR30C(S)R3I, -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)OR3I, -NR30C(S)OR3I, -NR30C(NR32)OR3I, -S(O)11R30, -OS(O)pR30, , -NR30S(O)pR30, -S(O)PNR28R29, -OS(O)PNR28R29, or -NR30S(O)pNR28R29, wherein R2g 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, for each occurrence are, independently, H, alkyl, alkenyl, alkynyl, an cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteraralkyl; or R28 and R29 taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl. In certain embodiments, the substituents are HOt -C(O)NR28R29, -NR30C(O)R3I, -C(O)OR30, -NR30C(O)NR28R29, -OC(O)NR28R29, -NR30C(O)OR3I.
R30 and R3] 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 =0, =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-(Ci-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, hydroxy, thiol, and amino moieties) also include protected derivatives thereof, such as those found in T.W. Greene, Protecting Group in Organic Synthesis, Wiley & Sons, Inc. 1999 (hereinafter "Greene"), the entire teachings of which are incorporated by reference. "Protected derivatives" are those compounds in which a reactive site or sites are blocked with one ore more protecting groups.
Examples of suitable protecting groups for hydroxy 1 groups include ethers {e.g., methoxymethyl, methylthiomethyl, (phenyldimethylsiyl)methoxymethyl, benzyloxymethyl, p-methoxben2yloxymethyl5j!?-nitrobenzyloxymethyl, o-nitrobenzyloxymethyl, (4-methoxyphenoxy)methyI, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methy 1, 2-(trimethy Isi Iy l)ethoxy methyl, menthoxymethy 1, tetrahydropyranyls, 1-ethoxyethyl, l-(2-chloroethoxy)ethyl, l-[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, diethylisopropylsily], dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, 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, phenylacetate,/7-P-phenylacetate, and diphenylacetate, nicotinate and the like), and 3-phenylpropionate), carbonates (e.g., methoxylmethyl, 9-fluorenylmethyl, 2,2,2-trichloroethyl, l,l-dimethyl-2,2,2-trichloroethyl, 2-(trimethyIsilyl)ethyl, 2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, />-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, andp-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)ethoxymethyI, methylthiomethyl, phenylthiomethyl, azidomethyl, cyanomethyl, 2,2-dichloro-l,l-difluoroethyl, 2-chloroethyl, and 2-bromoethyl) tetrahydropyranyl, and 1-ethoxyethyl), silyl ethers (e.g. trimethylsilyl, f-butyldimethylsilyl, *-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). Examples of suitable protecting groups for thiol groups include thioethers (e.g., iS-alkyl, S-benzyl, S-p-methoxybenzyl, S-o-or /?-hydroxy-or acetoxybenzyl, S-p-nitrobenzyl, 5-2,4,6-trimethylbenzyl, 5-2,4,6-trimethoxybenzyl, 5-4-picolyI, 5'-2-quinolinylmethyl, 5-2-picolyl N-oxido, 5-9-anthrylmethyl, S-phenyl, >S'-2,4-dinitrophenyl3 ^-/-butyl, 5-methoxymethyl, 5-isobutoxymethyl, and S'-benzyloxymethyl), thioesters (e.g., ^-acetyl, iS-benzoyl, iS-trifluro acetyl,
5-N-[[(p-biphenylyl)isopropoxy]carbonyl]-n-methyl-γ-aminothiobutyrate, -S'-Λ/-(r-butoxycarbonyl)-n-methyl-γ-aminothiobutyrate, and the like), thiocarbonated derivatives (e.g., 5-2,2,2-trichloroethoxycarbonyl,
Figure imgf000020_0001
5-benzyloxycarbonyl, iS-p-methoxybenzyloxycarbonyl and the like), thiocarbamate derivatives (e.g., ^-(N-ethyl), 5-(N-methoxymethyl)).
Examples of suitable protecting groups for amino groups include carbamates (e.g, methyl, ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylrnethyl, 9-(2,7-dibromo)fluorenylmethyl, 17-tetrabenzo[αf,c,#, /]fluoernylthmethyl, 2-chloro-3-indenylmethyl, benz[/]inden-3-ylmethyl- 2,'7-di-/-butyl-[9-(l 0,10-dioxo-l 0, 10, 10, 10-tetrahydrothioxanthyl)]methyl,
1 , 1 -dioxobenzo[ό]thiophene-2-ylmethyl, 2,2,2-tricholoroethyl, 2-trimethyIsilylethyl, 2-ρhenylethyl, l-(l-adamantyl)-l-methylethyl, 2-chloroethyl, l,l-dimethyl-2-haloethyI, 1 , 1 -dimethyl-2-dibromethyl, 1 , 1 -dimethyl-2,2,2-trichloroethyI, l-methyl-l-(4-biphenylyl)ethyl, l-(3,5-di-f-butylphenyl)-l-methylethyl, ^-butyl, 1-adamantyl, 2-adamantyl, vinyl, allyl, 1 -isopropylallyl, cinnamyl, 4-nitrocinnamyl, benzyl, p-methoxybenzy 1, /?-nitrobenzyl, p-bromobenzyl, />-chlorobenzyl, 2,4-dichlorobenzy 1, m-nitrophenyl, 3,5-dimethoxybenzyl, 1 -methyl-1 -(3,5-dimethoxypheny l)ethyl, α-methylnitropiperonyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o-nitrophenyl)methyl), amides (e.g., H-formyl, w-acetyl, n-chloroacetyl, n-trichloroacetyl, rø-trifluoroacetyl, n-phenylacetyl, and M-3-phenylpropionyl), N-alkyl and N-aryl amines (e.g., rø-methyl, M-f-butyl, n-allyl, ra-benzyl, n-4-methoxybenzyl, «-2,4-dimethoxybenzyl, and «-2-hydroxybenzyl).
Other suitable protecting groups are well known to those of ordinary skill in the art and include those found in T. W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981, the entire teachings of which are incorporated herein by reference.
As used herein, the term "compound(s) of Structural Formulas (I)-(VIII), (IA), (IA'), (1IA)-(IVA)8 (XXA), (XXIA), (XXXA), (XXXIA) or (IB)-(XIB)" and similar terms refers to a compound of Structural Formulas (I)-(VIII), (IA), (IA'), (IIA)-(IVA), (XXA)5 (XXIA), (XXXA), (XXXIA) or (IB)-(XIB), or Tables 1 and 2, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph or prodrug thereof, and also include protected derivatives thereof.
The compounds synthesized 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. The compounds synthesized by the methods of the present invention can be obtained in a form of polymorphs, salts, including a pharmaceutically acceptable salt, solvates or clathrates.
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.
As used herein and unless otherwise indicated, the term "prodrug" means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may become active upon such reaction under biological conditions, or they may have activity in their unreacted forms. Examples of prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of Structural Formulas (I), (V)5 (IA), (IA'), (XXA), (EB), (IVB), (VIIB), (XIB)3 or Tables 1 and 2 that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of compounds of
Structural Formulas (I), (V), (IA), (IA'), (XXA)5 (IB), (IVB), (VIIB), (XIB) or Tables 1 and 2 that comprise -NO, -NO2, -ONO5 or -ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described by 1 BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5* ed). As used herein and unless otherwise indicated, the terms "biohydrolyzable amide",
"biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide" and "biohydrolyzable phosphate analogue" mean an amide, ester, carbamate, carbonate, ureide, or phosphate analogue, respectively, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as improved water solubility, improved circulating half-life in the blood (e.g., because of reduced metabolism of the prodrug), improved uptake, improved duration of action, or improved onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound. Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
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 Structural Formulas (I), (V), (IA), (IA'), (XXA), (IB), (IVB), (VIIB), (XIB), or Tables 1 and 2. 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,/?-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 of Structural Formulas (I), (V), (IA), (IA'), (XXA), (IB), (IVB), (VIIB), (XIB), or Tables 1 and 2 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 trialkylamines; dicyclohexylamine; triburyl 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 compound of Structural Formulas (I), (V), (IA), (IA'), (XXA), (IB), (IVB), (VIIB), (XIB), or Tables 1 and 2 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)5 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 of Structural Formulas (I), (V), (IA), (IA'), (XXA), (IB), (IVB), (VIIB), (XIB), or Tables 1 and 2. The term solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).
A pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compounds. The pharmaceutically acceptable carriers should be biocompatible, i.e., non-toxic, non-inflammatory, non-immunogenic and devoid of other undesired reactions upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, ibid. Suitable pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg/ml benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer's-lactate and the like. Methods for encapsulating compositions (such as in a coating of hard gelatin or cyclodextran) are known in the art (Baker, et al., "Controlled Release of Biological Active Agents", John Wiley and Sons, 1986).
The compounds synthesized by the methods of the present 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.
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.
In certain instances, tautomeric forms of the compounds disclosed herein exist, such as the tautomeric structures shown below:
Figure imgf000025_0001
I5 = O, S orMl7 Tautomer
It is to be understood that when a compound is represented by a structural formula herein, all other tautomeric forms which may exist for the compound are encompassed by the structural formula.
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 present invention provides novel synthetic methods (methods I, II and III) suitable for manufacturing [l,2,4]-triazole compounds on an industrial scale.
For method I5 the synthesis begins with an amidation reaction of the starting carboxylic acid represented by the following structural formula:
Figure imgf000026_0001
with an amine R5NH2 to form an amide represented by Structural Formula (II). The amide is then thionated to form a thioamide represented by Structural Formula (III). The thioamide is reacted with hydrazine to form a hydrazonamide compound represented by Structural Formula (IV), which is cyclized with a carbonylation reagent, thoicarbonylation reagent or an isocyanide to form the [l,2,4]trizole compound represented by Structural Formula (I). This synthesis is shown schematically in Figure 1. A detailed description of each reaction in the synthesis is provided below.
The starting carboxylic acid is first converted to the amide intermediate represented by Structural Formula (II) by reacting the starting carboxylic acid of Structural Formula
(VI) with the amine RsNH2. Methods for converting a carboxylic acid to an amide are well known in the art.
Typically, the carboxylic acid is first converted into a more reactive derivative with a leaving group that is more readily displaced by an amine group than -OH. A "leaving group" is a group which can readily be displaced by a nucleophile. For example, a carboxylic acid can be converted to a more reactive acyl halide, typically acyl chloride. Suitable reagents and conditions for converting a carboxylic acid to an acyl halide are well known in the art and are described, for example, in March, "Advanced organic Chemistry — Reactions, Mechanisms and Structure", 5th Edition, John Wiley & Sons, 2001, pages 523 — 524, and references cited therein. Examples of suitable reagents include thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorous pentachloride. Typically, each carboxylic acid group is reacted with about one equivalent or a slight excess of thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorous pentachloride in an inert solvent such as an ethereal solvent (e.g., diethyl ether, tetrahydrofuran or 1,4-dioxane), a halogenated solvent (e.g. methylene chloride or 1 ,2-dichloroethane) or aromatic solvent (e.g., benzene or toluene). When the carboxylic acid is amidated following an initial conversion of carboxylic acid to acyl halide, stoichiometric amount of the carboxylic acid and amine can be used. Alternatively, excess of either the carboxylic acid or amine can be used. When oxalyl chloride is used, a tertiary amine is often added to accelerate the reaction in quantities ranging from a catalytic amount to about one equivalent relative to oxalyl chloride. Typically tertiary amine can be used is triethylamine. The reaction is generally carried in inert, aprotic solvents, for example, halogenated solvents such as methylene chloride, dichloroethane and dimethylformamide. Suitable reaction temperature generally range from between about 0 0C to 100 0C, preferably between about 0 0C to about ambient temperature.
Alternatively, the carboxylic acid is first converted into an "activated ester". An ester -COOR is said to be "activated" when -OR is readily displaced by an amine or hydrazine. -OR is more easily displaced as R becomes more electron withdrawing. Some activated esters are sufficiently stable that they can be isolated, e.g., esters wherein R is phenyl or substituted phenyl. For example, diphenylmalonate can be prepared from malonyl chloride and phenol, both commercially available from Aldrich Chemical Co., Milwaukee, WL, by procedures described above Other activated esters are more reactive and are generally prepared and used in situ.
Formation of an activated ester in situ requires a "coupling agent", also referred to as a "carboxylic acid activating agent", which is a reagent that replaces the hydroxyl group of a carboxyl acid with a group which is susceptible to nucleophilic displacement. Examples of coupling agents include l,l'-carbonyldiimidazole (CDI), isobutyl chloroformate, dimethylaminopropylethyl-carbodiimide (EDC), dicyclohexyl carbodiimide (DCC). When amidating a carboxylic acid by in situ activation using a coupling reagent, stoichiometric amount of the carboxylic acid and amine can be used. Alternatively, excess of either the carboxylic acid or the amine can be used. The reaction is generally carried in inert, aprotic solvents, for example, halogenated solvents such as methylene chloride, dichloroethane and dimethylformamide.
The amide of Structural Formula (II) is then reacted with a thionation reagents to form a thioamide. "Thionation reagent" is a reagent which, under suitable conditions, can convert a ketone, ester, or amide into a thioketone, thioester or thioamide, respectively. There are many thionation reagents known to one of ordinary skill in the art. Examples include Lawesson's Reagent, tetraphosphorous pentasulfide, Scheeren's reagent (P4S10- Na2S), P4Sio-N(ethyl)3, Davy's Reagent and Heimgarner's reagent. Also known are conditions suitable for carrying out these conversions with thionation reagents. . For example, such conditions are disclosed in Fieser and Fieser, "Reagents for Organic Synthesis", Volume 1, John Wiley & Sons (1975) page 870-871, Fieser and Fieser, "Reagents for Organic Synthesis", Volume 5, John Wiley & Sons, (1975) page 653 and publication cited therein. Suitable conditions are also described in March, "Advanced Organic Chemistry - Reactions, Mechanisms and Structure", Fifth Edition, John Wiley & Sons, 2001, pages 496, 509, 1184-1185, 1331 ; Bull. Soc. Chim. BeIg. 87:223, 229, 525 (1978), Synthesis 1979: 941 (1979), Tetrahedron 35: 2433 (1979) Tetrahedron 21 : 4061 (1980); Tetrahedron, (1985), 41, 2567; Org. Synth. VII, 372; and Tetrahedron Lett., (1986), 27, 3445; and references cited therein. (All of these references are incorporated herein.). There are many thionation reagents known to one of ordinary skill in the art. Descriptions of these reagents can also be found in Metzner and Thuillier "Sulfur Reagents in Organic Synthesis", Academic Press, 1994. The relevant portions of these publications are incorporated herein by reference.
To thionate the amide of Structural Formula (II), it may be desirable to use a slight excess of the amide, for example up to about 5 equivalents, preferably no more than about 1.5 equivalents. It may also be desirable to use excess thionation reagent. In some cases, it may be desirable to use equal equivalents of the amide and the thionation reagent. Suitable inert solvents include ethereal solvents (e.g., diethyl ether, tetrhydrofuran, glyme and 1,4- dioxane), aromatic solvents (e.g., benzene and toluene) or chlorinated solvents (e.g., methylene chloride and 1,2-dichloroethane). The reaction is carried out at temperatures ranging from about room temperature to about 1500C, preferably from about 75° C to about 125° C. In a preferred embodiment, the thionation reagent is Lawesson's reagent. Representative conditions for carrying out thionation reaction are found in Examples 1 and 2.
Preferably, the reaction mixture of the amide and thionation reagent is treated with a water soluble amine after completion of the reaction. As used herein, a "water soluble amine" may include any amines (e.g., methylammine), ammonium hydroxide, and hydrazines. In a more specific embodiment, the water soluble amine is aqueous ammonium hydroxide. In another more specific embodiment, the water soluble amine is hydrazine. Typically, excess ammonium hydroxide solution is used, for example up to 10 equivalents, preferably up to 5 equivalents, even more preferably up to 2 equivalents. Detailed description of a representative procedure is found in Example 1. The thioamide of Structural Formula (II) is then converted to hydrazonamide of
Structural Formula (III) by reacting the thioamide with hydrazine in an inert solvent. Preferably, excess of hydrazine is used, for example up to 100 equivalents, up to 50 equivalents, up to 10 equivalents. In some cases, it may be desirable to use excess of thioamide or equal equivalents of thioamide and hydrazine. Suitable inert solvents include ethereal solvents (e.g., diethyl ether, tetrhydrofuran, glyme and 1 ,4-dioxane), aromatic solvents (e.g., benzene and toluene) or chlorinated solvents (e.g., methylene chloride and 1,2-dichloroethane). The reaction is carried out at temperatures ranging from about room temperature to about 150° C, preferably from about 80° C to about 100° C. Representative conditions for carrying out these reactions are found in Examples 1 and 2. The thioamide of Structural Formula (ITI) is then cyclized with a carbonylation reagent, a thiocarbonylation reagent or a compound of structural formula R7N=C(X)2, wherein X is a leaving group, to form the [l,2,4]triazole compound of Structural Formula
(I)- As used herein, a "carbonylation reagent" is a compound represented by a structural formula of X-C(=O)-X, where X a readily displaced leaving group to facilitate the cyclization reaction with the hydrazonamide of Structural Formula (FV) to form the triazole compound of Structural Formula (T), wherein Ri is -OH. As used herein, a "leaving group" is a group that can be displaced by a nucleophile. For example, X can be a imidazoly group, a halide, more specifically, a chloride. Examples of carbonylation reagent may be used include phosgene, carbonyldiimidazole, diphenyl carbonate, bis(4-nitrophenyl) carbonate, bis(pentafluorophenyl) carbonate, bis(trichloromethyl) carbonate, 4-nitrophenyl chloroformate, phenyl chloroformate, trichloromethyl chloroformate. In a specific embodiment, the carbonylation reagent is carbonyldiimidazole. The hydrazonamide of Structural Formula (IV) is converted to the triazole compound of Structural Formula (I) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, by reacting the hydrazonamide with a carbonylation reagent in an inert solvent. Suitable inert solvents include ethereal solvents (e.g., diethyl ether, tetrhydrofuran, glyme and 1,4- dioxane), aromatic solvents (e.g., benzene and toluene), chlorinated solvents (e.g., methylene chloride and 1 ,2-dichloroethane) or ethyl acetate. The reaction is carried out at temperatures ranging from about room temperature to about 15O0C3 preferably from about room temperature to about 100° C, more preferably from about room temperature to about 40 0C. Typically, excess of the carbonylation reagent is used, for example, up to 10 equivalent, more preferably, up to 5 equivalent, even more preferably, up to 1.5 equivalent. In some case, it may be desirable to use excess of the hydrazonamide, or equal equivalents of the hydrazonamide and the carbonylation reagent.
As used herein, a "thiocarbonylation reagent" is a compound represented by a structural formula of X-S(=O)-X, where X a readily displaced leaving group to facilitate the cyclization reaction with the hydrazonamide of Structural Formula (FV) to form the triazole compound of Structural Formula (I), wherein Rj is -SH. For example, X can be a imidazoly group, a halide, more specifically, a chloride. Examples of thiocarbonylation reagent may be used include thiocarbonyldiimidazole and thiophosgene. In a specific embodiment, the thiocarbonylation reagent is thiocarbonyldiimidazole. The hydrazonamide of Structural Formula (IV) is converted to the triazole compound of Structural Formula (T) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, by reacting the hydrazonamide with a thiocarbonylation reagent in an inert solvent. Suitable inert solvents include ethereal solvents (e.g., diethyl ether, tetrhydrofuran, glyme and 1,4-dioxane), aromatic solvents (e.g., benzene and toluene), chlorinated solvents (e.g., methylene chloride and 1 ,2-dichIoroethane) or ethyl acetate. The reaction is carried out at temperatures ranging from about room temperature to about 15O0C, preferably from about room temperature to about 100° C, more preferably from about room temperature to about 400C. Typically, excess of the carbonylation reagent is used, for example, up to 10 equivalent, more preferably, up to 5 equivalent, even more preferably, up to 1.5 equivalent. In some case, it may be desirable to use excess of the hydrazonamide, or equal equivalents of the hydrazonamide and the thiocarbonylation reagent.
In accordance with the present invention, the hydrazonamide of Structural Formula (IV) can react with a compound of structural formula R7N=C(X)2 to form the triazole compound of Structural Formula (I), wherein Ri is — NHR7. X is a readily displaced leaving group that facilitates the cyclization reaction OfR7N=C(X)2 with the hydrazonamide of Structural Formula (IV). For example, X can be a imidazolyl group, a halide, more specifically a chloride. In a specific embodiment, X is -Cl. The hydrazomide of Structural Formula (FV) is converted to the triazole compound of Structural Formula (I) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, by reacting the hydrazonamide with R7N=C(X)2 in an inert solvent. Suitable inert solvents include ethereal solvents (e.g., diethyl ether, tetrhydrofuran, glyme and 1,4-dioxane), aromatic solvents (e.g., benzene and toluene), chlorinated solvents (e.g., methylene chloride and 1,2-dichloroethane) or ethyl acetate . The reaction is carried out at temperatures ranging from about room temperature to about 150° C, preferably from about room temperature to about 100° C, more preferably from about room temperature to about 400C, even more preferably, the reaction is carried out at room temperature. Typically, excess of the carbonylation reagent is used, for example, up to 5 equivalent, more preferably, up to 5 equivalent, even more preferably, up to 1.5 equivalent. In some case, it may be desirable to use excess of the hydrazonamide, or equal equivalents of the hydrazonamide and the thiocarbonylation reagent.
In a specific embodiment, the compound of Structural Formula (V) is prepared by the disclosed methods. The synthesis of the compound of Structural Formula (V) comprises an inital step of thionating the amide of Structural Formula (VI) with a thionation reagent to form a thioaminde of Structural Formula (VII). The thioamide is then reacted with hydrazine to form a hydrazonamide of Structural Formula (VIII). The hydrazonamide is reacted with a carbonylation reagent to form the compound of Structural Formal (V). More specifically, the thionation reagent is Lawesson's reagent and the thionation reagent is carbonyldiimidazole. Any remaining protecting groups can be removed by standard methods following formation of the hydrazonamide.
Method II of the present invention provides a method of synthesizing a compound of Structural Formula (IA):
Figure imgf000031_0001
The method comprises reacting a compound of Structural Formula (IIA)
Figure imgf000031_0002
(HA) with an oxidizing agent, thereby producing a compound of Structural Formula (IA). Specifically, by reacting a compound of Structural Formula (TTIA)
Figure imgf000031_0003
(MA) with a compound of Structural Formula (IVA)5
Figure imgf000031_0004
(IVA) 1^ZO in the presence of an acid, a compound of Structural Formula (IIA)
Figure imgf000031_0005
(HA) is prepared.
By reacting a compound of Structural Formula (IIA):
Figure imgf000032_0001
(HA) with an oxidizing agent, a compound of Structural Formula (IA)
Figure imgf000032_0002
is prepared.
By removing any protecting groups present in the compound of Structural Formula (IA) (i.e. "deprotecting the compound"),
Figure imgf000032_0003
a compound of Structural Formula (IA')
Figure imgf000032_0004
can be prepared.
The list of values and preferred values in formulas (IA), (IA'), (IIA), (IIIA) and (IVA) are defined above. Additionally, in formula (IA'), R22 is -OH, or -NH2. The conditions for the above reactions will be described below.
Preferably, the oxidizing agent is K3Fe(CN)6, Mnθ2, Br2, N-bromosuccinimide or N-chlorosuccinimide. More preferably, the oxidizing agent is K3Fe(CN)6. One skilled in the art will appreciate that some oxidizing agents (e.g., K3Fe(CN)6, MnO2) are commonly used in combination with a base. Where a base is used, any organic or inorganic base can be used, such as a hydroxide base (e.g., NaOH, KOH, LiOH), amine bases (e.g., ammonia, allylamide, dialkylamine) or 1,1,1,3,3,3-hexamethyl-disilazane (HMDS). Preferably, the base is non-nucleophilic. The molar ratio of the base to the oxidizing agent can be about 5:1, 4;1, 3: 1, 2: 1; 1:1, 1 :2, 1:3, 1:4 or 1 :5. Preferably, equimolar ratio of the oxidizing agent and the base is used. The oxidizing cyclization is generally carried out in polar solvent. The polar solvent can be a polar protic solvent, such as water or an alcohol; a polar aprotic aromatic solvent such as nitrobenzene; or a polar aprotic solvent such as nitromethane, dimethyl acetamide (DMA), N,N-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), hexamethyl phosphoramide (HMPA), or N-methyl pyrrolidone (NMP). The molar ratio of the compound of Structural Formula (IIA) to the oxidizing agent can vary greatly. Although equimolar amount can be used, the compound of formula (II) is typically used in excess. Generally, the molar ratio of the compound of formula (II) to an oxidizing agent can be 1000:1, 900:1, 800:1, 700:1, 600:1, 500:1, 400:1, 300:1, 200:1, 100: 1, 50:1 , 20:1, 10:1 For example, when KFe(CN)6/NaOH is used, the molar ratio of the compound (IIA) to KFe(CN)6 is from about 500:1 to about 200:1, preferably from 350:1 to 300:1; and the molar ration of the compound (IIA) to NaOH is from about 600:1 to 400:1, preferably from 550:1 to 450:1.
Generally, the reaction temperature can be from about 50 0C to about 150 0C, preferably, from about 700C to about 1200C, more preferably, from about 900C to about 1 10 0C.
Specific examples of a cyclization reaction that converts a compound of formula (IIA) into a compound of Structural Formula (IA') are described in the Exemplification section.
In another embodiment, the compound of Structural Formula (IIA) is prepared by reacting a compound of Structural Formula (HIA)
Figure imgf000033_0001
(MA) with a compound of Structural Formula (IVA),
Figure imgf000033_0002
R
(IVA) •.20 in the presence of an acid. Typically, a catalytic amount of acid is used. "Catalytic amount" typically means a molar ratio from about 0.1 to about 0.001 of the acid catalyst to the reagents. In one embodiment, catalytic amount is 0.01 equivalents. Any acid catalyst can be used, such as organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid), sulfonic acids (e.g., methanesulfonic acid, benzenesulfonic acid and the like), and mineral acids (sulfuric acid, hydrochloric acid, and the like).
General conditions for such a reaction 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). While excess of one reagent over the other can be used, typically, equimolar amounts of the compounds of formulas (IIIA) and (WA) are employed.
Any suitable solvent in which reagents are soluble and with which reagents do not react can be used. The reaction is most commonly carried out in an alcoholic solvent such as methanol or ethanol with water as co-solvent (e.g., between 0% and about 50% volume/volume (v/v), preferably between about 5% and about 15% v/v).
The reaction is allowed to proceed at a temperature from about 300C to about 150 0C, preferably from about 40 0C to about 130 0C, more preferably, from about 50 0C to about 120 0C, even more preferably, from about 60 0C to about 1000C.
Specific examples of a reaction of a compound of Structural Formula (IIIA) and a compound of Structural Formula (IVA) are described in the Exemplification section.
The compound of Structural Formula (IA) can further be deprotected, thereby producing a compound of Structural Formula (IA')
Figure imgf000034_0001
In Structural Formula (IA'), R22 is -OH, or -NH2. In another embodiment, the present invention is a method of synthesis of a compound of Structural Formula (HA),
Figure imgf000034_0002
(HA) comprising reacting a compound of Structural Formula (IIIA)
Figure imgf000035_0001
<ΠIA) with a compound of Structural Formula (FVA)
Figure imgf000035_0002
OVA) R2°5 in the presence of acid catalyst. The conditions for this reaction are described above.
Methods of preparing the compound of formula (IIIA) are illustrated in the Exemplification section and can be used generally by selecting appropriate starting materials.
In a specific embodiment, in formulas (IA), (IIA), (IIIA) and (IVA), R2o is -ORpi, Rpi is a benzyl group and the step of deprotecting the compound of formula (IA) comprises reacting a compound of formula (IA) with hydrogen in the presence of palladium-on- charcoal catalyst.
In another specific embodiment, formulas (IA), (IIA), (IIIA) and (IVA)5 R2o is -ORpi, Rpi is a benzyl group and the step of deprotecting the compound of formula (IA) comprises reacting a compound of formula (IA) with ammonium formate in the presence of a hydrogen catalyst.
Method III of the present invention begins with an amidation reaction of the starting carboxylic acid represented by the following Structural Formula:
Figure imgf000035_0003
with an amine R5NH2 to form an amide represented by Structural Formula (XIIB). The amide is then thionated to form a thioamide represented by Structural Formula (DCB).
Figure imgf000035_0004
F?3b (XIIB). Values for R3b, R5 and ring A in Structural Formula (XIIB) are as described in Structural
Formulas (IB) -(HIB).
The thioamide is reacted with hydrazino carboxylate in the presence of a mercuric salt to form the [l,2,4]-trizole compound represented by Structural Formula (D3). This synthesis is shown schematically in Scheme 1 of Example 5. A detailed description of each reaction in the synthesis is provided below.
The starting carboxylic acid is first converted to the amide intermediate represented by Structural Formula (XIIB) by reacting the starting carboxylic acid with the amine R5NH2.
Methods for converting a carboxylic acid to an amide are well known in the art and as described above for method I.
The amide of Structural Formula (XIIB) is then reacted with a thionation reagents to form a thioamide. "Thionation reagent" is as described above for method I.
To thionate the amide of Structural Formula (XIIB), it may be desirable to use a slight excess of the amide, for example up to about 5 equivalents, preferably no more than about 1.5 equivalents. It may also be desirable to use excess thionation reagent. In some cases, it may be desirable to use equal equivalents of the amide and the thionation reagent.
Suitable inert solvents include ethereal solvents (e.g., diethyl ether, tetrhydrofuran, glyme and 1,4-dioxane), aromatic solvents (e.g., benzene and toluene) or chlorinated solvents (e.g., methylene chloride and 1 ,2-dichloroethane). The reaction is carried out at temperatures ranging from about room temperature to about 150° C, preferably from about 75° C to about
125° C. In a preferred embodiment, the thionation reagent is Lawesson's reagent.
Representative conditions for carrying out thionation reaction are found in Exemplification. The thioamide is then reacted with a hydrazino carboxylate in the presence of a mercuric salt. Although equal molar amounts of hydrazino carboxylate, thioamide and mercuric salt can be used, typically, an excess amount of the hydrazino carboxylate and mercuric salt (e.g., from 1-10 equivalents, 1-5 equivalents or 1-2.5 equivalents) relative to the thioamide is employed for this synthesis. More typically, at least about two molar equivalents of the hydrazino carboxylate and mercuric salt relative to the thioamide, or preferably from 2.0 to about 2.5 equivalents. Optionally, an excess of the thioamide can be used.
Suitable solvent can be any inert organic solvent which is able to dissolve the hydrazino carboxylate, the thioamide and the mercuric salt when mixed. The organic solvent can generally be selected from a C1-C4 aliphatic alcohol (e.g., methanol, ethanol,
1-propanol, 2-propanol, or the like), a C1-C4 aliphatic ketone (e.g., acetone, methyl ethyl ketone, 2-butanone, or the like), a C2-C8 aliphatic ether (e.g., diethyl ether, THF, dioxane, dipropyl ether, diisopropyl ether, or the like), a glycol (e.g., ethylene glycol, propylene glycol, tetramethylene glycol, or the like), an alkyl glycol ether (e.g., ethylene glycol dimethyl ether, or the like), an aromatic solvent (e.g., benzene, toluene, or the like) and acetonitrile. Preferably, the organic solvent can be selected from tetrahydrofuran or dioxane, and more preferably, dioxane.
Suitable reaction temperature ranges between about 50 0C and about 150 0C, preferably between about 90 0C and about 120 0C.
Suitable mercuric salts include mercuric halides (HgF2, HgCb and HgBr2), mercury acetate and HgO, preferably, mercuric halides, and more preferably, HgCl2. Optionally, a base such as an amine base (e.g. ammonia, alkyl amines, dialkyl amines, trialkyl amines, optionally substituted amines, optionally substituted cycloalkylamines, N-alkylphthalimide, pyridine, aminopyridines, pyrrolidine, /7-toluidine, aniline, /?-nitroaniline, azetidine, morpholine, piperidine or the like) can be added to the mixture of the hydrazino carboxylate, thioamide and mercuric salt. Typically, concentration of the reagents is between 0.005 M and 1.0 M, or preferably, between 0.010 M and 0.500 M.
The synthesis of the triazole compound further includes the step of deprotecting the compound represented by Structural Formula (IB). The products of this deprotecting reaction are triazole-based hsp90 inhibitors. Variables in Structural Formulas (I)-(IV), (IA)-(IVA), (EB)-(IIIB) are as described above.
In a first specific embodiment, R5 in Structural Formulas (I)-(IV), (IA), (IA*), (ILA), (IIIA), (IB), (HIB), (VIIB), (VIIIB), (KB) and (XIB) is optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl. The remainder of the variables are as described in Structural Formulas (I)-(IV), (IA), (IA'), (HA), (IHA), (IB), (IHB), (VIIB), (VIIIB), (DCB) and (XtB).
In a second specific embodiment, R5 in Structural Formulas (I)-(IV), (IA), (IA'), (HA), (IIIA), (IB), (lire), (Vile), (VIΠB), (IXB) and (XlB) is a substituted phenyl. The remainder of the variables are as described in Structural Formulas (I)-(IV), (IA), (IA'), (HA), (IIIA), (IB), (IIIB), (VIIB), (VIIIB), (DCB) and (XIB).
In a third specific embodiment, R5 in Structural Formulas (I)-(rV), (IA), (IA'), (HA), (IIIA), (EB), (HIB), (VIIB), (VIIEB), (IXB) and (XIB) is an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, or a substituted alkyl.
In a fourth specific embodiment, R5 in Structural Formulas (I)-(EV), (IA), (IA'), (HA), (IIIA), (EB), (HEB), (VIEB)5 (VIIIB), (DCB) and (XEB) is an optionally substituted naphthyl. The remainder of the variables are as described in Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB), (VIIB), (VIIIB), (DCB) and (XIB).
In a fifth specific embodiment, R5 in Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (πiA), (IB), (IIIB), (VIIB), (VIBB), (KB) and (XIB) is represented by the following Structural Formula:
Figure imgf000038_0001
wherein: for Structural Formulas (I)-(IV), 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, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10Rn (provided Rj0 and Rn are not -H), -OR7 (provided R7 is not -H), -SR7 (provided R7 is not H), -S(O)PR7, -OS(O)PR7, -NR8S(COpR7, -S(O)pNR,0Rii, -OP(O)(OR7)2, or -SP(O)(OR7)2, -ORA, -SRB, -N(R0J2 or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; for Structural Formulas (IA), (IA'), (IIA), and (IIIA), R9, for each occurrence, is independently a substituent selected from: -ORp i, -NHRp3, -N(Rp3)2, -O(CH2)mORpi, or -(CH2)HiORp1; 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; -NRκ>Rn, or -OR7; -O(CH2)mNR7Rp3; -C(O)R7, -C(O)OR7; -C(O)NR10Rn; -OC(O)R7, -OC(O)OR7, -OC(O)NR10Ri1; -NR8C(O)R7, or -NR7C(O)NRi0R11; -NR7C(O)OR7; -S(O)PR7, -OS(O)PR7, -OS(O)POR7, -OS(O)pNR10Rn, -S(O)POR7; -S(O)pNR10Rn; -NRsS(O)pR7, -NR7S(O)pNR10Rn, -NR7S(O)POR7. Aleterantively, two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; 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 R10 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; for Structural Formulas (IB), (IIIB), (VIEB), (VIIIB), (IXB) and (XIB)5 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, protected hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRioRn, -ORioo and -C(O)R7; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and m for Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (D3), (IIIB), (VHB), (VIIB), (IXB) and (XIB) is zero or an integer from 1 to 7.
The remainder of the variables are as described in Structural Formulas (I)-(FV), (IA), (IA'), (HA), (IIIA), (IB), (IIIB), (VIIB), (VIIB), (KB) and (XIB).
In a sixth specific embodiment, R5 in Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB), (VIIB), (VIIB), (IXB) and (XIB) is represented by the following Structural Formula:
Figure imgf000040_0001
wherein q is zero or an integer from 1 to 7; and u is zero or an integer from 1 to 8. The remainder of the variables are as described in the fifth specific embodiment.
In a seventh specific embodiment, R5 in Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB), (VIIB), (VIIB), (IXB) and (XIB) is an optionally substituted indolyl. Preferably, R5 is an indolyl represented by the following Structural Formula:
Figure imgf000040_0002
wherein: for Structural Formulas (I)-(IV), R33 is a halo, a lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, or a lower alkyl sulfanyl; R34 is H. or a lower alkyl;
Ring B and Ring C are optionally substituted with one or more substituents in addition to R33 and R34. The remainder of the variables are as described in Structural Formulas (I)-(IV); for Structural Formulas (IA)5 (IA'), (IIA), and (IIIA), R33 is H; -ORpi, -NHRp3 or -N(Rp3)2, a halo, a lower alkyl, a lower alkoxy, a lower haloalkyl, or a lower haloalkoxy; R34 is H, -ORpi, -NHRp3 or -N(Rp3)2, a C1-C6 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. The remainder of the variables are as described in Structural Formulas (IA), (IA'), (HA), and (IIIA); for Structural Formulas (IB), (IIIB), (VIIB), (VIIIB), (IXB) and (XIB), R33 is a halo, a lower alkyl, a lower alkoxy, a lower haloalkyl, and a lower haloalkoxy, and a lower alkyl sulfanyl; R34 is -H, a lower alkyl, or a lower acyl; Rings B and Ring C are optionally substituted with one or more substituents in addition to R33 and R34; and the remainder of the variables are as described in Structural Formulas (IB)3 (IIIB), (VIIB)5 (VIIIB), (IXB) and (XIB).
In a eighth specific embodiment, R5 in Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB), (VIIB), (VIIB), (IXB) and (XB) is a substituted phenyl. For Structural Formulas (I)-(IV), the phenyl group is optionally substituted with: i) one substituent selected from nitro, cyano, a haloalkoxy, 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, guanadino, -NRi0Ri i (provided Rio and Rn are not -H) -0-R20, -SR7 (provided R7 is not H), -S(O)PR7, -OS(O)nR7, -NRgS(O)pR7, -S(O)pNRI0R,,, -OP(O)(OR7)2, -SP(O)(OR7)2, -ORA, -SR8, Or-N(Rc)2; or ii) two to five substituents 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, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR]0RI i (provided Ri0 and Rn are not H) -OR7-SR7, -S(O)PR7, -OS(O)PR7, -NRsS(O)pR7, -S(O)pNR]0Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2, -S(O)POR7, -ORA, -SRB, or -N(Rc)2, wherein R7, R8, Ri0, Rn, RA. RB, RC, and p are as described above for Structural Formulas (I)-(IV).
For Structural Formulas (IA), (IA'), (IIA), and (IIIA), the substituents for the phenyl group is selected from the group consisting of -ORpi, -NHRp3, -N(Rp3)2, -O(CH2)mORpi, or -(CH2)mORpi, 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; -NR10Rn, or -OR7; -O(CH2)mNR7Rp3; -C(O)R7, -C(O)OR7; -C(O)NRi0Rn; -OC(O)R7, -OC(O)OR7, -OC(O)NR10Rn; -NR8C(O)R7, or -NR7C(O)NR10R11; -NR7C(O)OR7; -S(O)PR7, -OS(O)PR7, -OS(O)POR7, -OS(0)pNRioRn, -S(O)POR7, -S(O)pNR,0R,,; -NR8S(O)PR7, -NR7S(0)pNR,oRn, -NR7S(O)15OR7. Values and specific values for R1,,, Rp3, R7, R8, Rio, Rn, p and m are as defined above with reference to formulas (IA), (IA'), (IIA), and (IIIA) For Structural Formulas (IB)5 (HIB)5 (VIIB), (VIIIB)5 (DCB) and (XIB), the phenyl group is substituted with: i) the one substituent selected from nitro, cyano, a haloalkoxy, 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, protected hydroxylalkyl, alkoxyalkyl, guanadino, - OR10O, -SRioi, -N(Rio2)2, -NRi0Ri j, -OR7, or -C(O)R7; or ii) two to five substituents 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, protected hydroxyalkyl, alkoxyalkyl, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, - ORiOO5 — SRiou — N(RIO2)2J -NRJORI I, -ORIOO, or -C(O)R7; and; and the values and preferred values of the remaining variables are as described in Structural Formulas (IB), (IIIB), (VIEB), (VIIIB), (DCB) and (XEB).
Preferably, for Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (EB)5 (HIB)5 (VIEB), (VIIEB), (DCB) and (XEB), R5 is represented by the following structural formula:
Figure imgf000042_0001
Rio and Rn are as described above.
In a ninth specific embodiment, R5 in Structural Formulas (I)-(EV), (IA), (IA'), (HA), (IHA), (EB), (IIIB), (VIEB), (VIIB), (EXB) and (XEB) is selected from the group
Figure imgf000042_0002
Figure imgf000043_0001
Figure imgf000044_0001
wherein:
X6, for each occurrence, is independently CH, CR9, 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+(Rn), provided that at least three X7 groups are independently selected from CH and CRg;
X8, for each occurrence, is independently CH2, CHR9, C(Rg)2, S, S(O)p, NR7, or NR17;
X9, for each occurrence, is independently N or CH; X10, for each occurrence, is independently CH, CR9, N, N(O), N+(Rn), provided that at least one X10 is selected from CH and CR9;
Rn, for each occurrence, is independently -H5 an alkyl, an aralkyl. For Structural Formulas (IA), (IA'), (IIA), and (IIIA), Rn can also be -C(O)R7, - C(O)OR7 Or -C(O)NR10Rn. For Structural Formulas (IB), (IIIB), (VIIB), (VIIIB), (DCB) and (XIB), R17 can also be -C(O)R7.
Values and specific values for the remainder of the variables are as described above in the fifth specific embodiment.
Preferably, for the ninth specific embodiment, 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]pyridinyl5 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]pyridinyl5 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.
In a tenth specific embodiment, Rs in Structural Formulas (I)-(IV)5 (IA), (IA'), (IIA), (IIIA), (E3), (IIIB), (VIIB)5 (VIIIB)5 (IXB) and (XIB) is selected from the group consisting of:
Figure imgf000045_0001
wherein:
Xn, for each occurrence, is independently CH5 CRg5 N5 N(O)5 or N+(Rn), provided that at least one Xn is N5 N(O)5 or N+(R^) and at least two Xi i groups are independently selected from CH and CR9;
Xi2, for each occurrence, is independently CH, CRg5 N5 N(O)5 N+(Ri7), provided that at least one Xi2 group is independently selected from CH and CRg;
Xi3, for each occurrence, is independently O5 S, S(O)p, NR7, or NRn. Values and specific values for the remainder of the variables are as described in the ninth specific embodiment.
In a eleventh specific embodiment, R5 in Structural Formulas (I)-(TV)5 (IA), (LV)5 (IIA), (IIIA), (ffi), (IIIB), (VIIB), (VIIB), (EXB) and (XIB) is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the following groups: for Structural Formulas (I)-(FV), the one or more substituents for the alkyl group are independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRi0Rn (provided R]0 and Ru is not H), -OR7 (provided R7 is not H)5 -SR7 (provided R7 is not H)3 -S(O)PR7, -OS(O)PR7, -NRsS(O)pR7, -S(0)pNRioRu, -ORA, -SRB, Or -N(Rc)2, wherein values and specific values for R7, R8, Rio, Rn. RA> RB> RC5 and p are as described for the Structural Formulas (I)-(FV); for Structural Formulas (IA), (IA'), (FIA), and (FIIA), the one or more substituents for the alkyl or the cycloalkyl group are independently selected from the group consisting of -ORp1, -NHRp3, -N(Rp3)2, -O(CH2)mORpI, or -(CH2)mORpr, 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; -NRi0Rπ, or -OR7; -0(CH2)JSIR7Rp3; -C(O)R7, -C(O)OR7; -C(O)NRi0Rn; -OC(O)R7, -OC(O)OR7, -OC(O)NR] 0Rπ; -NR8C(O)R7, or -NR7C(O)NR10R11; -NR7C(O)OR7; -S(O)PR7, -OS(O)PR7, -OS(O)POR7, -OS(O)pNR10R,,, -S(O)POR7, -S(O)pNR,0Rii; -NRsS(O)pR7, -NR7S(O)pNR,0Ri,, -NR7S(O)11OR7. Values and preferred values for Rpi, Rp3, R7, R8, R]0, Rn, p and m are as defined above with reference to Structural Formulas (IA), (IA'), (1IA)5 and (IIIA). for Structural Formulas (FB), (IFIB), (VIFB), (VIIFB)5 (IXB) and (XFB)5 the one or more substituents for the alkyl group are independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Rn, -OR10O, and -C(O)R7.
Values and specific values for the remainder of the variables are as described above for Structural Formulas (I)-(FV), (IA), (IA'), (FFA), (IIIA), (FB), (FIIB), (VIFB), (VIIB), (DCB) and (XFB).
Fn a more specific embodiment, R5 in Structural Formulas (F)-(FV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB), (VIFB), (VIIIB), (FXB) and (XFB) is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl. The remainder of the variables are as described above in the eleventh specific embodiment. In another more specific embodiment, R5 in Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IIIA), (IB), (IIIB), (VIIB), (VIIIB), (EKB) and (XIB), is a substituted alkyl. The remainder of the variables are as described above in the eleventh specific embodiment.
In a twelfth specific embodiment, ring A in Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IVA), (IB), (IIIB), (VIIB), (VIIIB), (DCB), and (XEB) is presented by Structural Formula (DC):
Figure imgf000047_0001
(IX) wherein: For Structural Formulas (I)-(IV), R300 is Rj as described in Structural Formulas (I)-
(IV). Rfi, for each occurrence, is independently 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 heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR10Ru (provided Rio and Rn are not -H), -OR7 (provided R7 is not H), -C(NR8)OR7, -C(NR8)NR1ORH, -C(NRg)SR7, -OC(S)OR7, -OC(NR8)OR7, -SC(NR8)OR7-SC(S)OR7, -OC(S)NR10Rn, -OC(NRg)NR,0Ri 1, -SC(NR8)NR10R1,, -SC(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(NR8)OR7, -NR7C(S)NR10R11 , -NR7C(NRs)NRi0Ri 1 , -SR7 (provided R7 is not H), -S(O)PR7, -OS(O)PR7, -OS(O)pNR10Rii, -S(O)POR7, -NR8S(O)11R7, -NR7S(O)pNR10Rn, -NR7S(O)15OR7, -S(O)pNR10Rn, -SS(O)PR7, -SS(O)POR7, -SS(0)pNR,oRn, -OP(OXOR7),, or -SP(O)(OR7)2, -ORA, -SRB, Or -N(Rc)2;
For Structural Formulas (IA), (IA'), (IIA) and (IVA), R30O is R2oas described in Structural Formulas (IA), (IA'), (IIA) and (FVA). R6, for each occurrence, is independently a substituent selected from: -ORpi, -NHRp3, -N(Rp3)2, -O(CH2)mORpi, or -(CH2)H1ORp1; 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; -0(CHz)1nNR7Rp3; -C(O)R7, -C(O)OR7; -C(O)NR10Rn; -OC(O)R7, -OC(O)OR7, -OC(O)NR10Rn; -NR8C(O)R7, or -NR7C(O)NR10Ri1; -NR7C(O)OR7; ~S(O)pR7, -OS(O)PR7, -OS(O)pOR7j -OS(O)PNR1ORI 15 -S(O)POR75 -S(O)PNR1OR1I; -NR8S(O)PR7, -NR7S(O)PNR10RΠ, -NR7S(O)POR7;
For Structural Formulas (IB)5 (HIB)5 (VIIB), (VIIIB)5 (IXB)5 and (XIB)5 R300 is R3b as described above in Structural Formulas (IB), (HIB)5 (VIIB)5 (VIIIB)5 (IXB)5 and (XIB). R4, for each occurrence, is independently 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 heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, a protected hydroxyalkyl, haloalkoxy, -NR10RM, -ORIOO, -C(O)R7, or -SRioύ or two R5 groups, taken together with the carbon atoms to which they are attached, form a fused ring,
For Structural Formulas (I)-(IV)5 (IA)5 (LV)5 (HA), (IVA), (IB)5 (HIB)5 (VIIB), (VIIIB), (DCB)5 and (XIB), n is zero or an integer from 1 to 4. The remainder of the variables are as described above in Structural Formulas (I)-(IV), (IA)5 (IA'), (HA), (IVA)5 (IVA)5 (DB)5 (HIB), (VIIB)5 (VIIIB), (DCB), and (XlB).
In a more specific embodiment, R5 in compounds of Structural Formulas (I)-(IV)5 (IA), (IA'), (HA), (IB), (IHB), (VIIB), (VIHB), (DCB)5 and (XIB) is an optionally substituted phenyl, wherein the phenyl group is substituted with substituents as described in the eighth specific embodiment. Values and specific values for the remainder of the variables are as described in the twelfth specific embodiment. Preferably, for Structural Formulas (I)-(IV),
Figure imgf000048_0001
In another more specific embodiment, Rs in compounds of Structural Formulas (I)- (IV), (IA)5 (IA'), (HA), (IB), (HIB)5 (VIIB), (VIIIB), (DCB), and (XIB)5 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group described above in the eleventh specific embodiment. Values and specific values for the remainder of the variables are as described in the twelfth specific embodiment. In a even more specific embodiment, R5 is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl. In another even more specific embodiment, Rs is an optionally substituted alkyl.
In another more specific embodiment, R5 in the compounds of Structural Formulas (I)-(IV)5 (IA)5 (IA'), (HA), (IB), (HIB), (VIIB)5 (VIIIB)5 (DCB)5 and (XIB) is represented by the following structural formula:
Figure imgf000049_0001
wherein Rg and m are as described in the fifth specific embodiment. Values and specific values for the remainder of the variables are as described the twelfth specific embodiment.
In another more specific embodiment, R5 in compounds of Structural Formulas (I)- (IV)5 (IA), (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), is selected from the group consisting of the following structural formulas:
Figure imgf000049_0002
Figure imgf000050_0001
wherein Xβ, X7, Xs, X9, Xio and Rn are as described in the ninth specific embodiment. Values and specific values for the remainder of the variables are as described in the twelfth specific embodiment. Preferably, Rs 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- ajpyridiπyl, 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.
In another more specific embodiment, R5 in the compounds of Structural Formulas (I)-(IV), (IA), (IA5), (HA), (IB), (HIB)5 (VIIB), (VIIIB), (DCB), and (XDB), is selected from the group consisting of the following structural formulas:
Figure imgf000051_0001
wherein Xn, X!2, X13, Rg and Rn are defined as described in the tenth specific embodiment. Values and specific values for the remainder of the variables are as described in the twelfth specific embodiment. In another more specific embodiment, R5 in the compounds of Structural Formulas
(I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (EXB), and (XIB) is an optionally substituted indolyl. Preferably, R5 is an indolyl represented by the following Structural Formula:
Figure imgf000052_0001
wherein R33, R34, ring B and ring C are as described above in the seventh specific embodiment. Values and specific values for the remainder of the variables are as described above in the twelfth specific embodiment.
In the thirteenth specific embodiment, ring A in compounds represented by Structural Formulas (I)-(IV), (IA)9 (IA'), (IIA), (IVA), (IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB) is represented by the Structural Formula (X):
Figure imgf000052_0002
(X) wherein: for Structural Formulas (I)-(FV), 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 heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, or -NR10R11 (provided Rio and Rn are not H); for Structural Formulas (IA), (IA'), (IIA), and (IVA), R25 is -ORpl, -NHRp3, -N(Rp3)2, -O(CH2)mORpl, or -(CH2)mORpi; 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; -0(CH2)JnNR7Rp3; -C(O)R7, -C(O)OR7; -C(O)NR10Rn; -OC(O)R7, -OC(O)OR7, -OC(O)NRi0Ru; -NR8C(O)R7, or -NR7C(O)NR10Rn; -NR7C(O)OR7; -S(O)PR7, -OS(O)PR7, -OS(O)POR7, -OS(O)pNR,0Rii, -S(O)POR7, -S(0)pNR,oRπ; -NR8S(O)PR7, -NR7S(O)pNR10Rn, or -NR7S(O)POR7; for Structural Formulas (IB), (IIIB), (VIIB), (VIIIB)5 (EXB), and (XEB)5 R25 is 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, protected hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRioRn, -ORi00, and -C(O)R7; r for Structural Formulas (I)-(IV), (IA), (IA'), (ILA), (IVA), (IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XEB) is zero or an integer from 1 to 3. Values and specific values for the remainder of the variables are as described above in the twelfth specific embodiment.
In a more specific embodiment, R25 in Structural Formulas (I)-(FV) is -ORA. -SRB, - N(Rc)2, -OC(S)OR7, -OC(NR8)OR7, -SC(NR8)OR7, -SC(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -OS(O)PR7, -S(O)POR7, -SS(O)POR7, - SS(O)pR7, -OP(O)(ORv)2, or -SP(O)(OR7)2, wherein p is 0, 1 , or 2; Values and specific values for the remainder of the variables are as described in the thirteenth specific embodiment.
In another more specific embodiment, R25 in Structural Formulas (IA), (IA'), (IIA), and (FVA)is a -OR,,,, -NHRp3, -N(R^)2, -0(CHa)1nORp1, or -(CHa)1nORp1. In another more specific embodiment, R33 is H, -ORpi, -NHRp3, -N(Rp3)2,
-O(CH2)mORpi, or -(CH2)mORpl; and R34 is a C1-C6 alkyl.
In another more specific embodiment, R3b and R25 in Structural Formulas (IB), (IIIB), (VIIB), (VIIIB), (JXB), and (XEB) are -ORi00, -SRiβi, or -N(RiO2)2. Even more specifically, R^ is -SH or -OH; R3b and R2s are -OR100; and R51 is =O or =S. Even more specifically, Rlb is -SH or -OH; R3b and R25 are -OR100; R51 is =O or =S; and Rs is an optionally substituted lower alkyl, a C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl, Or-NRi0Rn.
In another more specific embodiment, R5 in Structural Formulas (I)-(FV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (EXB), and (XEB) is an optionally substituted phenyl, wherein the phenyl group is substituted with substituents as described in the eighth specific embodiment. Values and specific values for the remainder of the variables are as described in the thirteenth specific embodiment. Preferably, R3 is -ORA, SRB, N(RC)2.
In another more specific embodiment, R5 in compounds of Structural Formulas (I)- (TV), (IA), (IA'), (IIA), (IB), (IIIB), (VIEB), (VIIIB), (EXB), and (XEB), is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group as described above in the eleventh specific embodiment. The remainder of the variables are as described in the thirteenth specific embodiment. In a even more specific embodiment, R5 is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl. In another even more specific embodiment, R5 is an optionally substituted alkyl.
In another more specific embodiment, R5 in the compounds of Structural Formulas (I)-(IV), (IA)5 (IA'), (IIA), (IB), (Urn), (Vim), (VπiB), (KB), and (XEB) is represented by the following structural formula:
Figure imgf000054_0001
wherein R9 and m are as described in the fifth specific embodiment. Values and specific values for the remainder of the variables are as described the thirteenth specific embodiment.
In another more specific embodiment, R5 in compounds of Structural Formulas (I)- (IV), (IA), (IA'), (IIA), (IB), (IHB), (VIIB), (VIIIB), (DCB), and (XlB), is selected from the group consisting of the following structural formulas:
Figure imgf000054_0002
Figure imgf000055_0001
wherein X6, X7, X8, X9, X10 and Rn are as described in the ninth specific embodiment. The remainder of the variables are as described in the thirteenth specific embodiment. Preferably, 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 IH- 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[354]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.
In another more specific embodiment, R5 in Structural Formulas (I)-(FV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB)5 (VIIIB), (EXB), and (XIB) is an optionally substituted indolyl. Preferably, R5 is an indolyl represented by the following Structural Formula:
Figure imgf000056_0001
wherein R33, R34, ring B and ring C are as described above in the seventh specific embodiment. Values and specific values for the remainder of the variables are as described above in the thirteenth specific embodiment. In a even more specific embodiment, for
Structural Formulas (IA), (IA') and (IIA), R25 is a -ORP,, -NΗRp3, -N(Rp3)2, -O(CH2)mORpi, or -(CH2)HiOPpI. In another even more specific embodiment, for Structural Formulas (IA)5 (IA') and (IIA), R33 is H, -ORp1, -NHRp3, -N(Rp3)2, -O^H^ORp:, or -(CH2)mOPpl and R34 is a C1-C6 alkyl. In another even more specific embodiment, for Structural Formulas (IA), (IA') and (IIA), R25 is a -ORpl, -NHRp3, -N(Rp3)2, -O(CH2)mORp,, or -(CH2)mOPpI; R33 is H, -ORp1, -NHRp3, -N(Rp3)2, -O(CH2)mORpl, or -(CH2)mOPpi and R34 is a C1-C6 alkyl. In a even more specific embodiment, for Structural Formulas (IA), (IA') and (IIA), R2i is O; Re is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C3-C6 cycloalkyl or -NRj oRπ. In another even more specific embodiment, for Structural Formulas (IA), (IA') and (IIA), R6 is a C1-C6 alkyl and R33 is H. In another even more specific embodiment, for Structural Formulas (IA), (IA') and (IIA), R33 is -H and ring B is unsubstituted. In another even more specific embodiment, for Structural Formulas (IA)3 (IA') and (IIA), R2o and R2s are -OH, and Re is a C1-C6 alkyl. In another even more specific embodiment, for Structural Formula (IA), (IA') and (IIA), R2i is O; R6 is a C1-C6 alkyl and R33 is H. In another even more specific embodiment, for Structural Formulas (IA), (IA') and (IIA), R2i is O; R6 is a Cl -C6 alkyl; R33 is H and ring B is unsubstituted. In yet another even more embodiment, for Structural Formula (IA), (IA') and (IIA), R2J is O; R6 is a C1-C6 alkyl; R33 is H; ring B is unsubstituted; R2o and R25 are -OH, and R6 is a Cl- C6 alkyl. hi another more specific embodiment, Rs in the compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (DCB), and (XIB), is selected from the group consisting of the following structural formulas:
Figure imgf000057_0001
wherein Xn, X)2, Xi3, Rg and Rn are defined as described in the tenth specific embodiment. Values and specific values for the remainder of the variables are as described in the thirteenth specific embodiment.
In a fourteenth specific embodiment, ring A of the compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IVA), (IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XEB), is represented by Structural Formula (XI):
Figure imgf000058_0001
(XI) wherein Ri, R300, R5, Re, and R25 are defined as the thirteenth specific embodiment. More specifically, R25 in Structural Formulas (I)-(W) is -ORA, -SRB, -N(Rc)2, -OC(S)OR7, -OC(NR8)OR7, -SC(NR8)OR7, -SC(S)OR7, -OC(S)NRi0Rπ, -SC(S)NR10Rm -OC(NR8)R7, -SC(NR8)R7, -OS(O)PR7, -S(O)POR7, -SS(O)POR7, -SS(O)PR7, -OP(O)(OR7)2, or -SP(O)(OR7)2, wherein p is O, 1, or 2. In a more specific embodiment, for Structural Formulas (I)-(TV), R3 and R2s are -ORA- Even more specifically, R6 is a lower alkyl, C3-C6 cycloalkyl, lower alkoxy, a lower alkyl sulfanyl, or -NRi0Ri 1. In a more specific embodiment, for Structural Formulas (IA'), (IIA) and (IVA), R2i 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 -NRi0R] 1. In another more specific embodiment, for Structural Formulas (IA'), (HA) and (IVA), R6 is a C1-C6 alkyl and R33 is H. In another more specific embodiment, for Structural Formulas (IA'), (IIA) and (IVA), R33 is -H and ring B is unsubstituted. In yet another more specific embodiment, for Structural Formulas (IA'), (IIA) and (IVA), R20 and R25 are -OH, and R5 is a C1-C6 alkyl.
In another more specific embodiment, for Structural Formulas (IB), (IIIB), (VIIB), (VIIIB), (DCB), and (XIB), R3b and R25 are -OR10O, -SR101, or -N(R,02)2. In another more specific embodiment, for Structural Formulas (IB), (IIIB), (VIIB), (VIIIB), (DCB), and (XIB), R, is -SH, R3 and R25 are -ORi00; and R5] is =O or =S.
In another more specific embodiment, for Structural Formulas (IB), (IIIB), (VIIB), (VIIIB), (DCB), and (XIB), Rib is -SH or -OH; R3b and R25 are -ORmol R5I is =O or =S; and R5 is an optionally substituted lower alkyl, a C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl, or — NRioRπ. In another more specific embodiment, R5 in Structural Formulas (I)-(FV), (IA),
(IA'), (HA), (IB), (IIIB), (VIIB), (VIIIB), (DCB), and (XIB), is an optionally substituted phenyl, wherein the phenyl group is substituted with substituents as described above in the eighth specific embodiment. Values and specific values for the remainder of the variables are as described above in the fourteenth specific embodiment. Even more specifically, for Structural Formulas (I)-(IV), R3 and R25 are -ORA. Even more specifically, for Structural Formulas (I)-(TV), R3 and R25 are -ORA; Rs is a lower alkyl, C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl, or -NRi0Rn. In another more specific embodiment, Rs in the compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIEB), (VIIIB), (DCB), and (XIB), is represented by the following structural formula:
Figure imgf000059_0001
and values and specific values for the remainder of the variables are as described in the fourteenth specific embodiment. Preferably, Rio and Rn are each independently a hydrogen, a C1-C6 straight or branched alky I, optionally substituted by -ORA, -CN, -SRA, N(Rc).:. a C1-C6 alkoxy, alkylsulfanyl, dialkylamino or a cycloalkyl; or R]0 and Rn taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl. More preferably, Ri0 and Rn are each independently a hydrogen, methyl, ethyl, propyl, isopropyl, or taken together with the nitrogen to which they are attached, are:
Figure imgf000059_0002
In another more specific embodiment, R5 in compounds of Structural Formulas (I)-
(IV), (IA), (IA'), (UA), (IB), (IIIB), (VIIB), (VIIIB), (IXB)5 and (XEB), is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group desribed above in the eleventh specific embodiment. Values and specific values for the remainder of the variables are as described in the fourteenth specific embodiment. In a even more specific embodiment, R5 is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl. In another even more specific embodiment, R5 is an optionally substituted alkyl.
In another more specific embodiment, R5 in the compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (EKB), and (XIB) is represented by the following structural formula:
Figure imgf000060_0001
wherein R9 and m are as described in the fifth specific embodiment. Values and specific values for the remainder of the variables are as described the fourteenth specific . embodiment. In a even more specific embodiment, for Structural Formulas (I)-(IV), R3 and R25 are -ORA, R6 is a lower alkyl, a C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl, or — NRjoRii; and R9 for each occurrence, is independently selected from the group consisting of-ORA, -SRB, halo, a lower haloalkyl, cyano, a lower alkyl, a lower alkoxy, and a lower alkyl sulfanyl.
In another more specific embodiment, R5 in compounds of Structural Formulas (I)- (IV), (IA)5 (IA'), (IIA), (IB)5 (HIB)5 (VIIB)5 (VIIIB)5 (IXB), and (XIB), is selected from the group consisting of the following structural formulas:
Figure imgf000060_0002
Figure imgf000061_0001
wherein Xg X7, X8, X9, Xio and Rn are as described in the ninth specific embodiment. The remainder of the variables are as described in the fourteenth specific embodiment. Preferably, 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 IH- imidazot4,5-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. In a even more specific embodiment, R6 is a lower alkyl, a C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl, or — NRioRπ- In another even more specific embodiment, Rg is a lower alkyl, a C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl, or -NRioRn; and R3 and R2S are -ORA.
In another more specific embodiment, R5 is represented by the following Structural Formula:
Figure imgf000062_0001
wherein values and specific values for the variables are as described below in the eighteenth specific embodiment. In a even more specific embodiment, R6 is selected from the group consisting of -Η, a lower alkyl, a lower alkoxy, a lower cycloalkyl. and a lower cycloalkoxy.
In another more specific embodiment, R5 in the compounds of Structural Formulas (I)-(IV)5 (IA), (IA'), (UA), (IB), (ITTB), (VIIB), (VIIIB), (DCB), and (XIB), is selected from the group consisting of the following structural formulas:
Figure imgf000063_0001
wherein Xn, X12, XB, R9 and Rn are defined as described in the tenth specific embodiment. The remainder of the variables are as described in the fourteenth specific embodiment. In a even more specific embodiment, Re is a lower alkyl, a C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl, or —NR10R11. In another even more specific embodiment, R6 is a lower alkyl, a C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl, or -NR10R11; and R3 and R25 are -ORA.
In another more specific embodiment, R5 in Structural Formulas (I)-(TV), (IA), (IA'), (IIA), (IB), (HIB), (VIIB), (VIIIB), (IXB), and (XIB) is an optionally substituted indolyl. Preferably, R5 is an indolyl represented by the following Structural Formula:
Figure imgf000063_0002
wherein R33, R34, ring B and ring C are as described above in the seventh specific embodiment. Values and specific values for the remainder of the variables are as described above in the thirteenth specific embodiment. In a even more specific embodiment, for Structural Formulas (IA)5 (IA') and (IIA), R25 is a-ORpb -NHRp3, -N(Rp3)2, -O(CH2)mORpi, Or -(CHz)1nORp,; R33 is H, -ORp1, -NHRp3, -N(Rp3)2, -O(CH2)mORpi, Or -(CHz)1nORp1; and R34 is a C1-C6 alkyl. In another more specific embodiment, for Structural Formulas (IA), (IA') and (IIA), R21 is O; R5 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C3-C6 cycloalkyl or -NR]0RiI. In another even more specific embodiment, for Structural Formulas (IA), (IA') and (IIA), R6 is a C1-C6 alkyl and R33 is H. In another even more specific embodiment, for Structural Formulas (IA), (IA') and (IIA), R33 is -H and ring B is unsubstituted. In another even more specific embodiment, for Structural Formulas (IA), (IA') and (IIA), R5 is a C1-C6 alkyl; R33 is H; and ring B is unsubstituted. In yet another even more embodiment, In another even more specific embodiment, for Structural Formulas (IA), (IA') and (UA), R20 and R25 are -OH, and R6 is a Cl -C6 alkyl. In a fifteenth specific embodiment, ring A in compounds of Structural Formulas (I)- (IV), (IA), (IA'), (IIA), (IVA)5 (IB), (DIB), (VIIB), (VIIIB), (DCB)5 and (XIB), is represented by one of Structural Formulas (XII):
Figure imgf000064_0001
(XII)
X3 and X4 are each, independently, N, N(O), N+(R]7), CH or CR6; and X5 is O, S, NR17, CH=CH, CH=CR5, CR6=CH, CR6=CR6, CH=N, CR6=N, CH=N(O)5 CR6=N(O), N=CH, N=CR5, N(O)=CH, N(O)=CR6, N+(Rn)=CH, N+(Rn)=CR6, CH=N+(Ri7), CR6=N+(Rn), or N=N; wherein Rn is defined as in the ninth specific embodiment. Values and specific values for the remainder of the variables is as described in the twelfth specific embodiment.
In a more specific embodiment, R5 in the compounds of Structural Formulas (I)- (IV), (IA)5 (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), is an optionally substituted phenyl, wherein the phenyl group is substituted with substituents as described in the eighth specific embodiment. The remainder of the variables are as described in the fifteenth specific embodiment. More specifically, for Structural Formulas (I)-(IV), R3 and R25 are -ORA- Even more specifically, R6 is a lower alkyl, C3-C6 cycloalkyl, lower alkoxy, a lower alkyl sulfanyl, or -NRi0Rn.
In another more specific embodiment, R5 in compounds of Structural Formulas (I)- (IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIBB), (VIIIB), (IXB), and (XIB), is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group described above in the eleventh specific embodiment. The remainder of the variables are as described in the fifteenth specific embodiment. In a more specific embodiment, R5 is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl. In another more specific embodiment, R5 is an optionally substituted alkyl.
In another more specific embodiment, R5 in the compounds of Structural Formulas (I)-(IV), (IA)5 (IA'), (IIA), (IB)5 (HIB)5 (VIIB)5 (VIIIB)5 (DCB)5 and (XIB) is represented by the following structural formula:
Figure imgf000065_0001
wherein R9 and m are as described in the fifth specific embodiment. Values and specific values for the remainder of the variables are as described the fifteenth specific embodiment.
In another more specific embodiment, R5 in compounds of Structural Formulas (I)- (IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), is selected from the group consisting of the following structural formulas:
Figure imgf000065_0002
Figure imgf000066_0001
wherein XO1X7, XS5 X9» XIO and Rn are as described in the ninth specific embodiment. Values and specific values for the remainder of the variables are as described above in the fifteenth specific embodiment. Preferably, R5 is an optionally substituted indolyl, an optionally substituted benzoimidazoly!, an optionally substituted indazolyl, an optionally substituted 3H-indazoIyl, 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]ρyridinyl, 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-cjpyridinyl, 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.
In another more specific embodiment, Rs in the compounds of Structural Formulas (I)-(IV)3 (IA), (IA'), (IIA), (EB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB), is selected from the group consisting of the following structural formulas:
Figure imgf000067_0001
wherein Xn. Xn, Xn5 R9 and Rn are defined as described in the tenth specific embodiment. Values and specific values for the remainder of the variables are as described in the fifteenth specific embodiment. In another more specific embodiment, R5 in Structural Formulas (I)-(IV), (IA),
(IA'), (UA), (IB), (IIIB), (VIIB), (VIIIB), (LXB), and (XlB) is an optionally substituted indolyl. Preferably, Rs is an indolyl represented by the following Structural Formula:
Figure imgf000068_0001
wherein R33, R34, ring B and ring C are as described above in the seventh specific embodiment. Values and specific values for the remainder of the variables are as described above in the thirteenth specific embodiment. In a even more specific embodiment, for Structural Formulas (XIIA), R2i 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 -NRioRu. In another even more specific embodiment, for Structural Formula (XIIA), Re is a C1-C6 alky I and R33 is H. In another even more specific embodiment, for Structural Formula (XIIA), R33 is -H and ring B is unsubstituted. In yet another even more embodiment, for Structural Formula (XIIA), R2o and R25 are -OH, and R5 is a C1-C6 alkyl.
In a sixteenth specific embodiment, ring A in compounds represented by Structural Formulas (D-(IV), (IA), (IA'), (IIA), (IVA), (IB), (IIIB), (VIIB), (VIIIB), (DCB), and (XIB), is selected from Structural Formula (XIII):
Figure imgf000068_0002
Figure imgf000069_0001
(XIII) wherein Ri, R300, Rs, and R25 are as described above in the thirteenth specific embodiment. Specifically, for Structural Formulas (IB), (HIB), (VIIB), (VIIIB)5 (IXB), and (XIB), R25 is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, -OR100, -SR101, -N(RiCo)2, -NR7R102, -OR26, -SR26, -NR26R102, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OCH2C(O)R7, -SCH2C(O)R7, and -NR7CH2C(O)R7. k is 1, 2, 3, or 4. The values and specific values of the remaining variables are as described above in the fifteenth specific embodiment.
In a more specific embodiment, R5 in the compounds of Structural Formulas (I)- (IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (EXB), and (XIB), is an optionally substituted phenyl, wherein the phenyl group is substituted with substituents as described in the eighth specific embodiment. Values and specific values for the remainder of the variables are as described in the sixteenth specific embodiment. Even more specifically, for Structural Formulas (I)-(IV), R3 and R25 are -ORA- Even more specifically, R6 is a lower alkyl, C3-C6 cycloalkyl, lower alkoxy, a lower alkyl sulfanyl, or -NRioRu.
In another more specific embodiment, R5 in compounds of Structural Formulas (I)- (IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIEB), (VIIIB), (IXB), and (XIB), is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group described above in the eleventh specific embodiment. Values and specific values for the remainder of the variables are as described in the sixteenth specific embodiment. In a more specific embodiment, R5 is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl. In another more specific embodiment, R5 is an optionally substituted alkyl.
In another more specific embodiment, R5 in the compounds of Structural Formulas (I)-(IV)3 (IA), (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (DCB), and (XIB) is represented by the following structural formula:
Figure imgf000070_0001
wherein R9 and m are as described in the fifth specific embodiment. The remainder of the variables are as described the sixteenth specific embodiment.
In another more specific embodiment, R5 in compounds of Structural Formulas (I)- (IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (EXB), and (XEB), is selected from the group consisting of the following structural formulas:
Figure imgf000070_0002
Figure imgf000071_0001
wherein Xe1X7, Xs, X9, X10 and Rn are as described in the ninth specific embodiment. Values and specific values for the remainder of the variables are as described in the sixteenth specific embodiment. Preferably, 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]ρyridinyl, 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.
In another more specific embodiment, R5 in the compounds of Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB)5 (HIB)3 (VIIB)5 (VIIIB)5 (DCB)5 and (XIB), is selected from the group consisting of the following structural formulas:
Figure imgf000072_0001
wherein Xn, Xi2, Xn, R9 and R)7 are defined as described in the tenth specific embodiment. Values and specific values for the remainder of the variables are as described in the sixteenth specific embodiment. In another more specific embodiment, R5 in Structural Formulas (I)-(IV), (IA),
(IA'X (UA)5 (IB)5 (HIB)5 (VIIB), (VIIIB), (IXB)5 and (XIB) is an optionally substituted indolyl. Preferably, R5 is an indolyl represented by the following Structural Formula:
Figure imgf000073_0001
wherein R33, R34, ring B and ring C are as described above in the seventh specific embodiment. Values and specific values for the remainder of the variables are as described above in the thirteenth specific embodiment. In a even more specific embodiment, for Structural Formulas (XUA), R21 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 -NRioRπ. In another even more specific embodiment, for Structural Formula (XIIA), Re is a C1-C6 alkyl and R33 is H. In another even more specific embodiment, for Structural Formula (XIIA), R33 is -H and ring B is unsubstituted. In yet another even more embodiment, for Structural Formula (XIIA), R2o and R25 are -OH, and R6 is a C1-C6 alkyl.
In a seventeenth specific embodiment, compounds of Structural Formulas (I)-(IY), (IA), (IA'), (IIA), (IB), (HIB)5 (VIIB), (VIIIB), (IXB), and (XIB) are defined as the following:
Rs 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, or an optionally substituted heteraralkyl; ring A is represented by Structural Formulas(XIV):
Figure imgf000073_0002
(XIV) wherein,
X14 is O, S, or NR7; for Structural Formulas (I)-(IV): R22, for each occurrence, is independently an -H or is 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, or an optionally substituted heteraralkyl, a haloalkyl, -S(O)PR.7, or ~S(0)pNRioRn; and
R23 and R24, for each occurrence, are independently -H or are 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, or an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10R11 (provided Rio and Rn are not H), -OR7 (provided R7 is not H), -SR7(provided R7 is not H), -S(O)PR7, -OS(O)pR7, -NR8S(OpR7, or -S(O)pNR]0Rl i; for Structural Formulas (IA), (IA') and (IIA):
R22, for each occurrence, is independently an -H or is 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, or an optionally substituted heteraralkyl, a haloalkyl, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, - NR8C(O)R7, -S(O)PR7, -S(O)POR7 or -S(O)pNR,0Rii; and
R23 and R24, for each occurrence, are independently -H or are 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, or an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0Ri 1, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR,0R,,s -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -NR8S(O)PR75 Or -S(O)pNR10R,,; for Structural Formulas (IB), (IIIB), (VIIB), (VIIIB), (IXB), and (XIB): R22, for each occurrence, is independently an -H or is 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, or an optionally substituted heteraralkyl, a haloalkyl, or -C(O)R7;
R23 and R24, for each occurrence, are independently -H or are 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, or an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRioRn, -OR7, or -C(O)R7; Values and specific values for the remainder of the variables are as described in
Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (DCB), and (XIB).
In a more specific embodiment, R5 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. The remainder of the variables are as described in the seventeenth specific embodiment.
In another mroe specific embodiment, R22 is — H, or an alkyl, an aralkyl. The remainder of the variables are as described in the seventeenth specific embodiment.
In another more specific embodiment, X14 is O. The remainder of the variables are as described in the seventeenth specific embodiment. In a eighteenth specific embodiment, the compounds of Structural Formulas (I)-
(IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB)3 (VIIIB), (IXB), and (XIB) are defined as the following or tautomers, pharmaceutically acceptable salts, solvates, clarthrates, or prodrugs thereof:
Ring A is represented by the following Structural Formula:
Figure imgf000075_0001
R5 is represented by the following Structural Formula:
Figure imgf000075_0002
wherein:
X4J is O5 S, or NR42; X42 is CR44 or N; Y40 is N or CR43; Y4] is N or CR45;
Y42, for each occurrence, is independently N5 C or CR46; R4I, R42, Rt3, Rt4, R4S, R46, and R40O are defined as the following: for Structural Formulas (I)-(IV), R4I is -H, -ORA, -SRB, 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, -NRi0Ru (provided Rj0 and Rn are not H), -OR7 (provided R7 is not H), -C(NR8)OR7, -C(NR8)R7, -C(NRs)NR10R, i , -C(NR8)SR7, -OC(S)OR7, -OC(NR8)OR7, -SC(NR8)OR7, -SC(S)OR7, -OC(S)NR10Ri i, -OC(NR8)NR1ORn, -SC(NR8)NRIORI I, -SC(S)NR10Rn3 -OC(NR8)R7, -SC(NR8)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(NR8)OR7, -NR7C(S)NRi0Ri i, -NR7C(NRg)NRi0Rn, -SR7 (provided R7 is not H), -S(O)PR7, -OS(O)PR7, -OS(O)11NR10R11, -S(O)POR7, -NR8S(O)PR7, -NR7S(O)pNR10Rn, -NR7S(O)POR7, -S(O)pNR10Rπ, -SS(O)PR7, -SS(O)POR7, -SS(O)pNR)0Ri i, -OP(O)(OR7)23 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, a haloalkyl, a heteroalkyl, -S(O)PR7, or -S(O)PNR1ORiI;
R43 and R44 are, independently, -H, -ORA, 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, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -SR7 (provided R7 is not H), -S(O)PR7, -OS(O)PR7, -NR8S(O)15R7, -S(O)pNR|0Rπ, or R« 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, -ORAs -SRB, -N(RC)2, -OR26, -SR26, -O(CH2)mORA, -O(CH2)raSRB, -O(CH2)inNR7RCj -S(CH2)mORA, -S(CH2)mSRB, -S(CH2)mNR7Rc, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7> -OS(O)pNR10Rl u -SS(O)pNR10R, ,, -NR7S(O)pNR10Rπ, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR,0Rn, -SC(S)NR10RI I, -NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7,
-OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR10R1I, or -NR7C(NR8)NR10Rn;
R46, for each occurrence, is independently, selected from the group consisting 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, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRioRn (provided R10 and R11 are not H), -OR7 (provided R7 is not H), -SR7 (provided R7 is not H), -S(O)PR7, -OS(O)PR7, -NR8S(O)PR75 or -S^NR^R, , ;
R40O is RA as described for Structural Formulas (I)-(IV). for Structural Formulas (IA), (IA') and (HA), R41 is -H, -ORpl, -NHRp3> -N(Rp3)2, -O(CH2)mORpi, or -(CH2)U1ORp1; 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; -NR10Rn, or -OR7; -0(CH2)JSIR7Rp3; -C(O)R7, -C(O)OR7; -C(O)NR10Rn; -OC(O)R7, -OC(O)OR7, -OC(O)NR10R1,; -NR8C(O)R7, or -NR7C(O)NR10R11; -NR7C(O)OR7; -S(O)PR7, -OS(O)PR7, -OS(O)POR7, -OS(O)pNRI0Rπ, -S(O)POR7, -S(O)11NR10R11; -NR8S(O)11R7, -NR7S(O)pNR10Rπ, -NR7S(O)POR7;
R42 is -H, -ORp1, -NHRp3, -N(Rp3)2, -O(CH2)mORp,, or -(OHb)1nORp1; 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; -NRioRn, or -OR7;-O(CH2)mNR7Rp3;-C(O)R7, -C(O)OR7J-C(O)NR10R11; -OC(O)R7, -OC(O)OR7, -OC(O)NR10R11; -NR8C(O)R7, or -NR7C(O)NR10RH; -NR7C(O)OR7; -S(O)pR7, -OS(O)PR7, -OS(O)POR7, -OS(0)pNR,oRii, -S(O)POR7, -S(O)15NR10R1,; -NR8S(O)15R7, -NR7S(0)pNR,oRiu -NR7S(O)11OR7;
R43 and R44 are, independently, -H, -ORpi, -NHRp3, -N(Rp3)2, -O(CH2)mORpl, or -(CH2)mORpi; 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; -NR10Rn, or -OR7; -O(CH2)mNR7Rp3; -C(O)R7, -C(O)OR7; -C(O)NR10Rn; -OC(O)R7, -OC(O)OR7, -OC(O)NR10Ri , ; -NR8C(O)R7, or -NR7C(O)NR10Ri i ; -NR7C(O)OR7; -S(O)PR7, -OS(O)PR7, -OS(O)pOR7j -OS(0)pNR,oRπ, -S(O)POR7, -S(O)pNR10Rπ; -NRsS(O)pR7, -NR7S(O)pNR10R,,5 -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, -ORpi, -NHRp3, -N(Rp3)2, -O(CH2)mORpU or -(CHz)1nORp,; 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; -NR10Rn, or -OR7; -O(CH2)mNR7Rp3; -C(O)R7, -C(O)OR7; -C(O)NR10Ru; -OC(O)R7, -OC(O)OR7, -OC(O)NR10RM; -NR8C(O)R7, or -NR7C(O)NR10Ri ύ -NR7C(O)OR7; -S(O)pR7, -OS(O)PR7, -OS(O)15OR7, -OS(O)pNR10Rπ, -S(O)POR7, -S(O)pNR10Rπ; -NR8S(O)15R7, -NR7S(O)PNR10R1 ,, -NR7S(O)POR7;
R)6, for each occurrence, is independently, a lower alkyl; R400 is Rp1 as described in Structural Formulas (IA), (IA') and (IIA); for Structural Formulas (IB), (HIB), (VIIB), (VIIIB), (KB), and (XIB), 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, protected hydroxyalkyl that is optionally substituted, an optionally substituted alkoxyalkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, and -C(O)R7. R43 and R44 are, independently, -H, -OR100, — N(R1O2)2> 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, protected hydroxy alkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -C(O)R7, or -SR101. 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, -OR10O, -SR1Oi, -N(R102) 2, -0(CH2)mOR]0o, -O(CH2)mSR101,
-0(CH2)mN(R,o2)2, -NR10R11, S(CH2)mOR,00j -S(CHj)1nSR1O1, -S(CH2)mN(RI02)2, -OCH2C(O)R7, -SCH2C(O)R7, or -NR7CH2C(O)R7; and
R4S, for each occurrence, is independently, selected from the group consisting 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, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0R11, -OR100, -C(O)R7, and-SR101. Or two R)6 groups taken together with the carbon atoms to which they are attached form a fused ring;
R41 is -H, -ORA, -SRB, 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, -NRi0Ri 1 or -C(O)R7. More specifically, Rn is selected from the group consisting of -H, a lower alkyl, a lower alkoxy, a lower cycloalkyl and a lower cycloalkoxy.
R400 is R100 as described in Structural Formulas (IB), (IIIB), (VIIB), (VIIlB), (DCB), and (XIB).
Values and specific values for the remainder of the variables are as described in Structural Formulas (I)-(IV), (IA), (IA'), (IIA), (IB), (IIIB), (VIIB), (VIIIB), (DCB) and (XIB). In a more specific embodiment, for Structural Formulas (I)-(IV), X4] is NR42 and X42 is CR44. The remainder of the variables are as described in the eighteenth specific embodiment.
In another more specific embodiment, for Structural Formulas (I)-(IV)5 X41 is NR42 and X42 is N. Values and specific values for the remainder of the variables are as described in the eighteenth specific embodiment.
In another more specific embodiment, for Structural Formulas (I)-(IV), R4] is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. More specifically, R4I is selected from the group consisting of H, methyl,βthyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. Values and specific values for the remainder of the variables are as described in the eighteenth specific embodiment.
In another more specific embodiment, for Structural Formulas (I)-(FV), X41 is NR42, and R42 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, wherein each R27 is independently -H or a lower alkyl. More specifically, 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. Values and specific values for the remainder of the variables are as described in the eighteenth specific embodiment. In another more specific embodiment, for Structural Formulas (I)-(FV), R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. Values and specific values for the remainder of the variables are as described in the eighteenth specific embodiment. In another more specific embodiment, for Structural Formulas (F)-(FV), 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. In a more specific embodiment, X4i is O. In a even more specific embodiment, R43 and R44 together with the carbon atoms to which they are attached form a C5-C8 cycloalkenyl or a C5-Cg aryl. In another even more specific embodiment, R45 or CR4S is selected from the group consisting of -H, -ORA, -SRB, -N(Rc)2, a lower alkoxy, and a lower dialkyl amino. Even more specifically, R45 is selected from the group consisting of -H, -ORA, methoxy and ethoxy. Values and specific values for the remainder of the variables are as described in the eighteenth specific embodiment.
In another more specific embodiment, for Structural Formulas (IA), (IA') and (FIA), the variables can each be independently selected from the following lists of preferred values (values and specific values for the remainder of the substituents are as defined above in the eighteenth specific embodiment):
X4I can be NR42 and X42 can be CR44;
X41 can be NR« and X42 can be N; R41 can be selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy;
R41 can be selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cycloprppyl, methoxy, ethoxy, propoxy, and cyclopropoxy;
X41 can be NR42, and R42 can be selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, -C(O)N(R27)2, and -R0 , wherein R0 is a protected carboxyl group as defined above, and each R27 is independently -H or a lower alkyl;
X41 can be NR42, and R42 can be selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, -R-, -(CH2)H1R5, -CH2OCH3, -CH2CH2OCH3, and -C(O)N(CH3)2, wherein R0 is a protected carboxyl group and m is 1 or 2;
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; Y40 can be CR43; and R43 and R44 together with the carbon atoms to which they are attached can form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring; R43 and R44 together with the carbon atoms to which they are attached can form a
C5-C8 cycloalkenyl or a C5-C8 aryl;
R45 or CR45 can be selected from the group consisting of -H, -ORpi, -SRp2, -NHRp3, -N(Rp3)2, a lower alkoxy, -(CH2)m-NHRp3> and -(CH2)m-N(Rp3)2, wherein m is an integer from 1 to 6; R45 can be selected from the group consisting of -H5 -ORpi, methoxy and ethoxy;
X41 can be O.
In another more specific embodiment, for Structural Formulas (IB), (IIIB), (VIIB), (VIIlB), (IXB), and (XIB), R,b is -SH or -OH; R3b and R25 are
-OR100; R51 is =O or =S. More preferably, R^ is -SH or -OH; R3b and R25 are -ORiooϊ R51 is =O or =S; and R45 is selected from the group consisting of -H, -OR)0o, -SRioi, and
-N(Rio2)2> a lower alkoxy and a protected lower alkyl amino. Values and specific values for the remainder of the variables are as described above in the eighteenth specific embodiment.
In another more specific embodiment, for Structural Formulas (IB), (IIIB), (VIIB), (VlIlB), (IXB), and (XlB), X41 is NR42 and X42 is CR44 or N; and values and specific values of the remaining variables are as described above in the eighteenth specific embodiment. More preferrably, X41 is NR42; and Rj2 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, and an optionally substituted alkyl; and the values and specific values of the remaining variables are as described above in the eighteenth specific embodiment. In another more specific embodiment, for Structural Formulas (IB), (IHB), (VIIB),
(VIIIB), (DCB), and (XIB), X41 is NR42; 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, heteroaryl ring. The values and specific values of the remaining variables are as described above in the eighteenth specific embodiment. In another more specific embodiment, for Structural Formulas (IB), (HIB), (VIIB).
(VIIIB), (IXB), and (XIB)3 R]b is -OH or -SH; and the values and specific values of the remaining variables are as described above in the eighteenth specific embodiment.
In a nineteenth specific embodiment, the compounds of Structural Formulas (I)- (IV), (IA), (IA'), (HA), (IB), (IHB)5 (VIIB), (VIIIB), (IXB) and (XIB) are defined as the following or a tautomer, a pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof: ring A is represented by the following Structural Formula:
Figure imgf000082_0001
R5 is represented by the following Structural Formula:
Figure imgf000082_0002
wherein values and specific values for the variables are as described in the eighteenth specific embodiment.
In a more specific embodiment, for Structural Formulas (I)-(IV), X42 is CR44. Even more specifically, R43 and R44 are, independently, selected from the group consisting of — H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methooxy, ethoxy, propoxy, and cyclopropoxy. In another even more specific embodiment, R43 and R44 taken together with the carbon atoms to which they are attached, form a cycloalkyenyl, aryl, heterocyclyl, or heteroaryl ring. Even more specifially, R43 and R44, taken together with the carbon atoms to which they are attached, form a Cs-Cg cycloalkyenyl or a C5-Cs aryl. Values and specific values for the remainder of the variables are as described in the nineteenth specific embodiment.
In another more specific embodiment, for Structural Formulas (I)-(FV), X42 is N. Values and specific values for the remainder of the variables are as described in the nineteenth specific embodiment.
In another more specific embodiment, for Structural Formulas (I)-(IV), X42 is CR44 or N;
R4I is selected from the group consisting of — H, methyl, ethyl, isopropyl, and cyclopropyl; R42 is selected selected from the group consisting of -H, methyl, ethyl, n- propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CH2)2OCH3;
R43 and R44 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
R4S is selected from the group consisting of -H, -OCH3,-OCH2CH3 and -OR40O. Values and specific values for the remainder of the variables are as described in the nineteenth specific embodiment. In a more specific embodiment, for Structural Formula (IIA), R2J is O. Values and specific values for the remainder of the variables are as described in the nineteenth specific embodiment.
In another more specific embodiment, for Structural Formulas (IA), (IA') and (ILA), the variables can be each be independently selected from the following lists of preferred values:
X42 can be CRμ, 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 Cs-C8 cycloalkenyl or a C5-C8 aryl; X42 can be CR44; and X42 can be N. In another more specific embodiment, for Structural Formulas (IB), (HB), (IIIB), (VIIB), (VIIIB), (DCB) and (XIB), X42 is CR44, and R43 and R44 are, independently, -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, cyclopropoxy, or, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring. Values and specific values for the remainder of the variables are as described above in the nineteenth specific embodiment.
In another more specific embodiment, for Structural Formulas (IB), (IIB), (IIIB), (VIIB), (VIIIB), (DCB) and (XIB), X42 is CR44; R43 and R44 are are, independently, -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, cyclopropoxy, or, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring; and R^ are selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl. Values and specific values for the remainder of the variables are as described above in the nineteenth specific embodiment.
In a twentieth specific embodiment, the compounds of Structural Formulas (I)-(FV), (IA), (IA'), (HA), (IB), (IIIB), (VIIB), (VlIlB), (IXB) and (XIB) are defined as the following or a tautomer, a pharmaceutically acceptable salt, solvate, clarthrate, or a prodrug thereof: ring A is represented by the following Structural Formula:
Figure imgf000084_0001
R5 is represented by the following Structural Formula:
Figure imgf000084_0002
wherein:
X45 is CR54 or N;
R52 for Structural Formulas (I)-(IV)5 (IB), (IIIB), (VIIB), (VIIIB), (DCB) and (XIB) is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CH2)2OCH3, -CH2C(O)OH, and -C(O)N(CH3)2; R52 for Structural Formulas (IA), (IA') and (ΪIA) is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, - (CH2)2OCH3, ~(CH2)mRc, wherein Re is a protected carboxyl moiety and m is 1 or 2, and
-C(O)N(CH3)2. 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;
R55 is selected from the group consisting of -H, -OH, -OCH3, and -OCH2CH3; and R56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl; and the remainder of the variables are as described in the nineteenth specific embodiment.
In a more specific embodiment, R53 is H or a lower alkyl. Values and specific values for the remainder of the variables are as described in the twentieth specific embodiment. In another more specific embodiment, X45 is CR54. Preferably, R54 is H or a lower alkyl. Values and specific values for the remainder of the variables are as described in the twentieth specific embodiment.
In another specific embodiment, X45 is N. Values and specific values for the remainder of the variables are as described in the twentieth specific embodiment. In a twenty-first specific embodiment, the compounds of Structural Formulas (I)-
(IV), (IA), (IA'), (IIA), (IB), (IHB), (VIIB), (VIIIB), (IXB) and (XIB) are defined as the following: ring A is represented by the following Structural Formula:
Figure imgf000085_0001
R5 is represented by the following Structural Formula:
Figure imgf000085_0002
wherein: X44, for each occurrence, is independently, O, NR42 or C(R)O)2;
Figure imgf000086_0001
Y-U5 Y42J Z, R41, RJ)2, and R46 are as described in the eighteenth specific embodiment.
In a more specific embodiment, R4I is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. Values and specific values for the remainder of the variables are as described in the twenty-first specific embodiment.
In another more specific embodiment, R4J is selected from the group consisting of - H5 methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. Values and specific values for the remainder of the variables are as described in the twenty-first specific embodiment.
In another more specific embodiment, R42 is selected from the group consisting of - H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, .sec-butyl, tert-buty\, n-pentyl, n- hexyl, -C(O)OH, -(CH2)mC(O)OH, -CH2OCH3, -CH2CH2OCH3, and -C(O)N(CH3)2. Values and specific values for the remainder of the variables are as described in the twenty-first specific embodiment.
In another more specific embodiment, Y41 is CR45. Preferably, R45 is H, a lower alkoxy, or -OH. Values and specific values for the remainder of the variables are as described in the twenty-first specific embodiment. In another more specific embodiment, Y42 is CH. Values and specific values for the remainder of the variables are as described in the twenty-first specific embodiment.
In another more embodiment, Y43 is CH2. Values and specific values for the remainder of the variables are as described in the twenty-first specific embodiment.
In another more specific embodiment, Y43 is NR42, wherein R42 is H or a lower alkyl. Values and specific values for the remainder of the variables are as described in the twenty-first specific embodiment.
In another more specific embodiment, one of X44 is NR42 and the other is CH2 or C(Re)2. Preferably, one of X44 is NR42 and the other is CH2. Values and specific values for the remainder of the variables are as described in the twenty-first specific embodiment. In a twenty-second specific embodiment, the compounds of of Structural Formulas
(I)-(IV)5 (IA), (IA'), (IIA), (IB), (IHB)3 (VIIB), (VIIIB), (DCB) and (XEB) are defined as the following: ring'A is represented by the following Structural Formula:
Figure imgf000087_0001
R5 is represented by the following Structural Formula:
Figure imgf000087_0002
wherein the variables are as defined in the eighteenth specific embodiment. In a more specific embodiment, R4) is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. Values and specific values for the remainder of the variables are as described in the twenty-second specific embodiment.
In another more specific embodiment, R41 is selected from the group consisting of - H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. The remainder of the variables are as described in the twenty-second specific embodiment.
In another more specific embodiment, X41 is NR42. Preferably, 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, -C(O)OH, -(CH2)mC(O)OH, -CH2OCH3,
-CH2CH2OCH3, and -C(O)N(CH3)2. More preferably, R42 is H or a lower alkyl. Values and specific values for the remainder of the variables are as described in the twenty-second specific embodiment.
In another more specific embodiment, X41 is O. Values and specific values for the remainder of the variables are as described in the twenty-second specific embodiment.
In another more specific embodiment, X41 is S. Values and specific values for the remainder of the variables are as described in the twenty-second specific embodiment.
In another more specific embodiment, Y4] is CR45. Preferably, R45 is H, a lower alkoxy, or -OH. Values and specific values for the remainder of the variables are as described in the twenty-second specific embodiment. In another more specific embodiment, Y42 is CH. Values and specific values for the remainder of the variables are as described in the twenty-second specific embodiment.
In another more specific embodiment, R46 is H or a lower alkyl. Values and specific values for the remainder of the variables are as described in the twenty-second specific embodiment.
In a twenty-third specific embodiment, the compounds of of Structural Formulas (I)-(IV), (LA), (IA'), (IIA), (LB), (IID3), (VILB), (VIIIB), (EKB) and (XDB) are defined as the following: ring A is represented by the following Structural Formula:
Figure imgf000088_0001
Rs is represented by the following Structural Formula:
Figure imgf000088_0002
wherein Xn, for each occurrence, is independently CH, CR9, N, N(O), or N+(R]7), provided that at least one Xn is N, N(O), or N+(Ri7) and at least two Xn groups are independently selected from CH and CRg; values and specific values for the remainder of the variables are as described above in the tenth specific embodiment.
In a more specific embodiment, one of the Xn group is N, N(O), or N+(Ri7) and the remaining Xn groups are independently selected from CH and CRp. More specifically, R41 is a lower alkyl, C3-C6 cycloalkyl, lower alkoxy, a lower alkyl sulfanyl, Or -NRi0Rn- Values and specific values for the remainder of the variables are as described above in the twenty-third specific embodiment.
In a twenty-fourth specific embodiment, the compound of formula (IIA) is represented by the following Structural Formula:
Figure imgf000089_0001
wherein the variables are as described above in the eighteenth specific embodiment.
In a more specific embodiment, the variables can each be independently selected from the following lists of specific values (values and specific values for the remainder of the substituents are as defined above in the twenty-third specific embodiment):
X4I can be NR42 and X42 can be CR44;
X4I can be NR42 and X42 can be N;
R4I can be selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy; R4I can be selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy;
X4I can be NR42, and R42 can be selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, -C(O)N(R27)2, and -R0 , wherein R0 is a protected carboxyl group as defined above, and each R27 is independently -H or a lower alkyl; X4i can be NR42, and R42 can be selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, fø-r-butyl, n-pentyl, n-hexyl, -R0, -(CH^Rc, -CH2OCH3, -CH2CH2OCH3, and -C(O)N(CH3)2, wherein R0 is a protected carboxyl group and m is 1 or 2;
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; Y40 can be CR43; and R43 and R44 together with the carbon atoms to which they are attached can form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring;
R43 and R44 together with the carbon atoms to which they are attached can form a C5-C8 cycloalkenyl or a C5-C8 aryl; R45 or CR45 can be selected from the group consisting of -H, -ORpi, -SRp2, -NHRp3,
-N(Rp3)2, a lower alkoxy, -(CH2)m-NHRp3, and -(CH2)m-N(Rp3)2, wherein m is an integer from 1 to 6;
R45 can be selected from the group consisting of -H, -ORp1, methoxy and ethoxy;
X4I can be O. In a twenty-fifth specific embodiment, the compound of formula (IIA) is represented by the following Structural Formula:
Figure imgf000090_0001
, wherein the variables are as described above in the twenty-third specific embodiment.
In a more specific embodiment, R21 is O. Values and specific values for the remainder of the substituents are as defined above in the twenty-third specific embodiment.
In another more specific embodiment, the variables can each be independently selected from the following lists of specific 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 Cs-C8 aryl;
X42 can be CR44; and
X42 can be N.
In a twenty-sixth specific embodiment, the compound of Structural Formula (IIA) is represented by the following Structural Formula:
Figure imgf000090_0002
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, -(CH2)2OCH3, -(CH2)mR« wherein R0 is a protected carboxyl moiety and m is 1 or 2, and -C(O)N(CH3)2;
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 specific values for the remainder of the substituents are as described in the twenty-fourth specific embodiment.
In one embodiment, the present invention is a method of preparing a compound of Structural Formula (XXXIA)
Figure imgf000091_0001
comprising the step of reacting the compound of for Structural Formula (XXXA)
Figure imgf000091_0002
(XXXA) 5 with POCl3 in dimethyl formamide (DMF). In one embodiment of the present invention, POCl3 (typically in excess over the compound of Structural Formula (XXXA)) is added to cold DMF. Because the reaction is exothermic, the reagents arecommonly added with cooling.
The molar ration of the POCl3 to the compound of Structural Formula (XXXA) can be, for example, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1.5:1, 1.2:1. ort 1.1:1. Preferably, the molar ration is 5:1 to 1.5:1. More preferably, the moral ratio is 3:1 to 2:1.
Preferably, the product of the reaction between the compound of Structural Formula (XXXA) and POCl3 in dimethyl formamide (DMF) is further reacted with a hydroxide base, such as NaOH. Typically, an excess of the base with respect to the starting reagent is used. In one embodiment, 12 equivalents of NaOH is used.
In Structural Formulas (XXXA) and (XXXIA)5 wherein R30] and R302 are each independently -H, an alkyl, an aryl, a heteroaryl, an aralkyl, a heteraralkyl, each optionally substituted by one or more of an alkyl, alkoxy, haloalkyl, halogen nitro, cyano or alkyl alkanoate groups.
Preferably, R301 and R302 are each independently -H, an optionally substituted Cl- C6 alkyl, an optionally substituted phenyl, an optionally substituted benzyl, or an optionally substituted six-member heteroaryl. In one embodiment, R301 and R302 are not simultaneously hydrogens.
More preferably, R3oi and R3o2 are each independently -H, an optionally substituted C1-C6 alkyl. Even more preferably, R3o2 is H and R3oi is isopropyl, such that the compound of Structural Formula (XXXA) is compound HA:
Figure imgf000092_0001
and the compound of formula (XXXIA) is compound 12A:
Figure imgf000092_0002
In another embodiment, the present invention is a method of synthesis of a compound of formula (XXA), comprising reacting a compound of formula (XXIA):
Figure imgf000092_0003
(XXIA) with an oxidizing agent, thereby producing a compound of formula (XXA):
Figure imgf000093_0001
(XXA) wherein Bn is a benzyl group.
The conditions for the reactions are described above with reference to Structural Formulas (IA)5 (IA'), (HA), (IIIA) and (IVA). Preferably, the oxidizing agent is K3Fe(CN)6.
Preferably, the compound of formula (XXIA) is prepared by reacting a compound of formula (XXIIA)
Figure imgf000093_0002
(XXIIA) with a compound of formula (XXIIIA)
Figure imgf000093_0003
(XXIIIA) in the presence of an acid. Preferably, a catalytic amount of acid is used. The condition for this reaction are described above with reference to formulas (IA), (IA'), (IIA), (HIA) and (IVA).
Preferably, the compound of formula (XXA) is further deprotected, thereby producing a compound of formula (XXIVA):
Figure imgf000094_0001
(XXIVA)
In one embodiment, the methods of present invention further comprises the step of deprotecting the compounds of Structural Formulas (I), (IA) and (IB). General conditions for deprotecting the compounds of Structural Formulas (I), (IA) and (IB) are known in the art and depend on the nature of the protecting group used. Examples are provided above with reference to Greene.
In another specific embodiment, the methods of the present invention comprise the step of deprotecting the compound of the following Structural Formula:
Figure imgf000094_0002
by reaction of hydrogen in the presence of ammonium formate in a polar solvent using Pd/C as catalyst, thereby forming a compound represented by the following Structural Formula:
Figure imgf000094_0003
More specifically, the polar solvent is ethanol. More specifically, the reaction temperature is between 50 °C - 60 0C.
In one embodiment, for method III, the method further comprises the step of deprotecting the compound represented by the following Structural Formula:
Figure imgf000095_0001
wherein R3b and R25 are -ORmo, thereby forming a triazole compound represented by the following Structural Formula:
Figure imgf000095_0002
The remaining values and specific values are as described above in the fourteenth specific embodiment.
In another embodiment, for method III, the method further comprises the step of deprotecting the thioamide compounds represented by the following Structural Formula:
Figure imgf000095_0003
wherein:
R5 is represented by the following Structural Formula:
Figure imgf000095_0004
(LVIIB). R3b and R25 are -ORioo, thereby forming a triazole compound represented by the following Structural Formula:
Figure imgf000096_0001
In another specific embodiment, the compounds represented by Structural Formula (IVB) is deprotected, thereby forming a triazole compound of the following Structural Formula:
Figure imgf000096_0002
(LVIIIB).
In a preferred embodiment, the second starting compound of Structural Formula (LVIIIB) used in the disclosed method III is prepared by reacting a thionation reagent with a compound represented by the following formula:
Figure imgf000096_0003
In one embodiment, the present invention comprises the step of deprotecting a compound of Structural Formulas (T), (IA), (EB)5 (IVB), (VIIB) and (XEB). General conditions for deprotecting the compounds of Structural Formulas (I), (IA), (IB)3 (IVB), (VIIB) and (XIB) are known in the art and depend on the nature of protecting group used. Examples are provided above with reference to Greene.
In one embodiment, where a benzyl group is employed as a protecting group, the deprotection of compounds of Structural Formulas (T), (IA), (IB), (IVB), (VIIB) and (XIB) can be accomplished by catalytic hydrogenation. Any hydrogenation catalyst can be used, either soluble or insoluble in the reaction medium. Typical catalysts include palladium-on- charcoal, Raney nickel, NaBHj-reduced nickel, platimum metal or its oxide, rhodium rhuthenium or zinc oxide. Hydrogenation reactions are typically carried aout at temperature from about 0 0C to about 500C, preferably at 15-35 0C at atmospheric or slightly above atmospheric pressure.
The compounds of Structural Formulas (I), (IA), (IB), (IVB), (VIIB) and (XIB) are typically reacted with hydrogen at room temperature in a polar solvent. Preferably, palladium-on-charcoal is used as a catalyst. The polar solvent can be one or more of a polar protic solvent, such as water or an alcohol; an ethereal solvent such as THF, dioxane and the like. For example, the solvent can be a mixture of THF and methanol. The mixture (by volume) can be 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1 :1, 1 :2, 1 :3, 1:4, 1:5, 1:6, 1 :7, 1 :8, 1:8, 1:9, or 1 :10. Preferably, the THF/MeOH mixture is from about 4:1 to about 1:1 by volume. In a specific embodiment, when R3 of Structural Formula (I) is -ORA; R20 in
Structural Formula (IA) is -ORpi; or R3b of Structural Formula (IB) is -OR10O5 wherein RA, Rpi and Rioo are benzyl groups, the deprotection step of compounds of Structural Formulas (I), (IA), (IB), (IVB), (VIIB) and (XIB) comprises reacting a compound of Structural Formulas (I), (IA), (IB), (IVB), (VIIB) and (XIB) with ammonium formate in the presence of a hydrogen catalyst. In one aspect, the hydrogen catalyst is palladium on activated carbon. In one aspect, the step of deprotecting is carried out at a temperature from 45 to 650C. In one aspect, the step of deprotecting is carried out at about 55 0C. In one aspect, the compound of Structural Formulas (I), (IA), (IB), (IVB), (VIIB) or (XIB) and the ammonium formate are reacted for about 1 to 5 hours in the presence of the palladium on activated carbon. In one aspect, the compound of Structural Formulas (I), (IA) or (IB) and the ammonium formate are reacted for about 1 hour in the presence of the palladium on activated carbon. In one aspect, the compound of Structural Formulas (I), (IA) or (IB) and the ammonium formate are reacted for about 12 hours in the presence of the palladium on activated carbon. In one aspect, the purity of the deprotected product of a compound of Structural Formulas (I)5 (IA), (IB), (IVB), (VIIB) or (XIB) is 99.0% or greater. In another aspect, the purity is 99.5% or greater. In a further aspect, the purity is 99.8% or greater.
Specific examples of compounds which can be prepared by the disclosed method III are provided below: 3-(2-Hydroxyphenyl)-4-(naphthalen-l -yl)-5-mercapto~triazole;
3-(2,4-Dihydroxyphenyl)-4-[4-(2-methoxyethoxy)-naphthalen-l-yl]-5-mercapto-tria zole;
3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-bromophenyl)-5-mercapto-triazole;
3-(3,4-Dihydroxyphenyl)-4-(6-methoxy-naphthalen-l-yl)-5-mercapto-triazole; 3-(3,4-Dihydroxyphenyl)-4-(6-ethoxy-naphthalen-l-yl)-5-mercapto-triazole;
3-(3,4-Dihydroxyphenyl)-4-(6-propoxy-naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(5-methoxy-naphthalen-l-yl)-5-mercapto -triazole;
3-(3,4-Dihydroxyphenyl)-4-(6-isopropoxy-naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-DihydroxyphenyI)-4-(2,6~diethylphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2-methy-6-ethylphenyl)-5-rnercapto-triazole;
3-(254-DihydroxyphenyI)-4-(2,6-diisopropylphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(l-ethyI-indol-4-yl)-5-mercapto-triazoIe;
3-(2,4-DihydroxyphenyI)-4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-5-mercapto- triazole;
3-(2,4-DihydroxyphenyI)-4-(3-rnethylphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(4-methylphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2-chlorophenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(3-chlorophenyl)-5-mercapto-triazole; 3-(2,4-Dihydroxyphenyl)-4-(4-chlorophenyl)-5-mercapto-triazole;
3-(2,4-DihydroxyphenyI)-4-(2-methoxyphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(3-methoxyphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(3-fluorophenyl)-5-rnercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2-ethylphenyl)-5-mercapto-triazole; 3-(2-Hydroxy-4-fIuorophenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2-Hydroxy-4-aminophenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-butyl-phenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2,4-dimethyl-phenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2,6-dimethyl-phenyl)-5-mercapto-triazole; 3-(254-Dihydroxyphenyl)-4-(2,6-dimethyl-phenyl)-5-mercapto-triazole; 3-(2,4-Dihydroxyphenyl)-4-(4-fluorophenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2-methylsulfanylphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(naphthalene-2-yl)-5-mercapto-triazole;
3 -(2,4-Dihy droxypheny l)-4-(2,3 -dimethy lpheny l)-5 -mercapto-triazole; 3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-fluorophenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(acenaphthalen-5-yl)-5-mercapto-triazoIe;
3 -(2-Hydroxy-4-methoxy-pheny l)-4-(naphthalen- 1 -y l)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2,3-dichlorophenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(5-methoxynaphthalen-l-yl)-5-mercapto-triazole; 3-(2j4-Dihydroxyphenyl)-4-(pyren-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(quinolin-5-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxypheny])-4-(l,2,3,4-tetrahydronaphthalen-5-yI)-5-mercapto- triazole;
3-(2,4-Dihydroxyphenyl)-4-(anthracen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxyphenyl)-4-(bϊphenyl-2-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-6-methyl-phenyl)-4-(naphthalene-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(4-pentyloxyphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(4-octyloxyphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(4-chIoronaphthalen-l-yl)-5-mercapto-triazole; S^^-Dihydroxy-S-ethyl-pheny^^-Cnaphthalen-l-yO-S-mercapto-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(7-carboxymethoxy-naphthalen-l-yl)-5- mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2-methyl-quinolin-4-yl)-5-mercapto-triazole;
3-(3-Hydroxypyridin-4-yl)-4-(naphthalen-l-yl)-5-mercapto-triazoIe; 3-(2-Hydroxy-4-acetylamino-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(l,2,3,4-tetrahydronaphthalen-l-yI)-5-mercapto- triazole;
3-(2,4-Dihydroxy-phenyl)-4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-5-mercapto- triazole; 3-(2,4-Dihydroxy-phenyl)-4-(3,5-dimethoxyphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(2,3-dimethyl-lH-indol-4-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-3-ρropyI-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(4,6-Dihydroxy-l -ethyl-pyridin-3-yl)-4-(naphthalen- 1 -y l)-5-mercapto-triazole;
3-(4,6-Dihydroxy-l-methyl-pyridin-3-yl)-4-(naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-ρhenyl)-4-(3,5-di-tert-butylphenyl)-5-mercapto-triazole; 3-(2,6-Dihydroxy5-fluoro-pyridin-3-yl)4-(naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-5-methyl-phenyl)-4-(naphthalene-l-yl)-5-mercapto-triazole; 3_[2,4-Dihydroxy-phenyl]-4-(3-benzoylphenyl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-phetιyl)-4-(4-carboxy-naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-phenyl)-4-[4-(N,N-dimethylcarbamoyI)-naphthalen-l-y]]-5- mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(4-propoxy-naphthalen-l-yl)-5-mercapto-triazole; 3-(2>4-Dihydroxy-phenyl)-4-(4-isopropoxy-naphthalen-l-yl)-5-mercapto-triazole; 3-(2s4-Dihydroxy-phenyl)-4-(5-isopropoxy-naphthalen-l-yI)-5-mercapto-triazole; 3-(2,4-Dihydroxy-phenyl)-4-(isoquinolin-5-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(5-propoxy-naphthalen-l-yl)-5-mercapto-triazole; 3-(2-Hydroxy-4-methanesulfonamino-phenyl)-4-(naphthalen-l-yl)-5-mercapto- triazole;
3-(2,4-Dihydroxy-3,6-dimethyl-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-phenyl)-4-[7-(2-methoxyethoxy)-naphthalen-l-yl]-5- mercapto-triazo Ie;
3-(2>4-Dihydroxy-5-hexyl-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(4-methoxy-naphthalen-l-yl)-5- mercapto-triazole; 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(6-methoxy-naphthalin-l-yl)-5- mercapto-triazole;
S^^-Dihydroxy-S-chloro-S-ethyl-phenyO^-Cnaphthalen-l-yO-S-mercapto- triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(253-dimethy-4-methoxy-phenyl)-5- mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(7-isopropoxy-naphthalen-l-yl)-5-mercapto-triazole; 3-(2>4-Dihydroxy-phenyl)-4-(7-ethoxy-naphthalen-l-yl)-5-mercaρto-triazole; 3-(2,4-Dihydroxy-phenyl)-4-(7-propoxy-naphthalen-l-yl)-5-mercapto-triazole; 3-(2-Hydroxy-4-methoxymethyoxy-phenyl)-4-(naphthalen-l -yl)-5-mercapto- triazole;
3-[2-Hydroxy-4-(2-hydroxy-ethoxy)-phenyl]-4-(naphthalen-l-yl)-5-mercapto- triazole;
3-(2,4-Dihydroxyphenyl)-4-(7-methoxy-naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(5-methoxy-naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxyphenyl)-4-(4-hydroxy-naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxyphenyl)-4-(l-isopropyl-indol-4-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-5-tert-butyl-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-5-propyl-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-3-mβthyl-5-ethyl-phenyl)-4-(naphthalen-l-yl)-5-mercapto- triazole;
3-(2,4-Dihydroxy-5-isobutyl-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-pheny])-4-(2,3-dimethoxy-phenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(2-methoxy-3-chloro-phenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(indol-4-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-phenyl)-4-[l-(2-methoxyethoxy)-indol-4-yl]-5-mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-l-yl)-5-hydroxy-triazole;
3-(l-Oxo-3-hydroxy-pyridin-4-yl)-4-(naphthaIen-l-yl)-5-mercapto-triazoIe;
3-(2,5-Dihydroxy-4-carboxy)-4-(naphthalen-l-yI)-5-mercapto-triazole;
S-^^-Dihydroxy-S-ethyl-phenyl^-Cl-isopropyl-indoM-yty-S-mercapto-trϊazole; 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-[l -(dimethyl-carbamoyl)-indol-4-yl]-5- mercapto-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(l-ethyl-benzoimidazol-4-yl)-5-mercapto- triazole;
S^^-Dihydroxy-S-ethyl-phenyO^-Cl ^β-trimethyl-indol-S-yO-S-mercapto- triazole;
3-(2,5-Dihydroxy-4-hydroxymethyl-phenyl)-4-(naphthalen-l-yl)-5-mercapto- triazole;
3-(2-Hydroxy-4-amino-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2-Hydroxy-4-acetylamino-phenyl)-4-(naphthalen-l-yI)-5-mercapto-triazole; 3-(2,4-Dihydroxy-3-chloro-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-methox-phenyl)-5-hydroxy-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-l-yl)-5-hydroxy-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-indol-3-yl)-5-hydroxy-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-indol-4-yl)-5-amino-triazole; 3-(2,4-Dihydroxy-5-ethyl-pheny])-4-(3-methoxy-phenyl)-5-amino-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-l-yl)-5-amino-triazole;
3-(2-Hydroxy-5-ethyloxy-phenyl)-4-(naphthalen-l-yl)-5-hydroxy-triazole;
3-(2-Hydroxy-5-isopropyl-phenyI)-4-(naphthalen-l-yl)-5-hydroxy-triazole;
3-(2-Dihydroxy-phenyl)-4-(7-fluoro-naphthalen-l-yl)-5-hydroxy-triazole; 3-(2,4-Dihydroxy-phenyl)-4-(2,3-difluorophenyl)-5-hydroxy-triazole; 3-(2,4-Dihydroxy-phenyl)-4-[2-(lH-tetrazol-5-yl)-phenyl]-5-hydroxy-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(benzothiazol-4-yl)-5-hydroxy-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(9H-purin-6-yl)-5-hydroxy-triazole;
3-(2,4-Dihydroxy-phenyl)-4-{4-[2-(moropholin-l-yl)-ethoxy]-phenyl}-5- hydroxy-triazole;
3-(2,4-Dihydroxy-phenyl)-4-cyclopentyl-5-hydroxy-triazolβ;
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(5-hydroxy-naphthalen-l-yl)-5-mercapto- triazole; 3-(2,4~Dihydroxy-pheny l)-4-(naphthalen- 1 -y lmethyl)-5-mercapto-triazole;
3-(2-Hydroxy-4-methoxyphenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(biphenyl-3-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(2-methyl-5-hydroxymethyl-phenyl)-5- mercapto-triazole; 3-(2,4-Dihydroxy-phenyl)-4-( 1 -dimethylcarbamoyl-indol-4-y l)-5-mercapto-triazole;
3-(2,4,5-Trihydroxy-phenyl)-4-(naphthalene-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-t-butyl-4-methoxy-phenyl)-5-mercapto- triazole; 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(l-ethyl-lH-benzoimidazol-4-yl)-5- mercapto-triazole, HCl salt;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-7-methoxy-indol-4-yl)-5- mercapto-triazole; and
3-(2,4-Dihydroxy-5-cyclopropyl-phenyl)-4-(naphthalene-l-yl)-5-mercapto-triazole, or a tautomer. pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.
Exemplary compounds that can be prepared by the disclosed method I and method III are depicted in Tables 1 and 2 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs and synthetic intermediates thereof represented by Structural Formula (II), (III), or (IV). Exemplary compounds that can be prepared by the disclosed method II include compounds 97, 137-173, 176, 220, and 232 depicted in Table 1 below.
Table 1
No. Structure Tautomeric Structure Name
Figure imgf000103_0001
1 ■
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
1)
Figure imgf000115_0001
Figure imgf000116_0001
-y 1)
1)
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
I-
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
1-
Figure imgf000136_0001
1-
1-
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000143_0002
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
-
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
The invention is illustrated with the following examples which are not intended to be limiting in any way.
EXEMPLIFICATION Example 1
Figure imgf000151_0002
Figure imgf000151_0003
Preparation of 3-(2,4-dihydroχy-5-isopropyl-phenviy4-fN-methv1-indoI-5-yl)-5-hydroxy- π.2.41triazole
2,4-dibenzyloxy-5-isopropylbenzoic acid (43.0 mmol, 1.00 equiv.) in 300 mL dichloromethane at room temperature was treated with oxalyl chloride (47.3 mmol, 1.10 equiv.) and catalytic amount of DMF (0.5 mL) for 1 hour. Solvent and excess oxalyl chloride were removed on rotary evaporator. The residue was dissolved in 300 mL dichloromethane, and treated with l,3-dimethyl-5-aminoindole (43.0 mmol, 1.00 equiv.) and triethylamine (64.5 mmol, 1.50 equiv.) at 0 0C for 1 hour. Normal aqueous workup and removal of solvent gave a light brown solid which was washed with ether to yield off-white solid (39.95 mmol, 93 %).
Procedure 1. The off-white solid (4 mmol) of the amide obtained above was treated with Lawesson's reagent (970 mg, 0.6 equiv.) in 40 mL toluene at 110 "C for 1.5 hour. Water was added and extracted with ethyl acetate, washed with water 2 times. Dried, concentrated and crystallized by the combination of sonication and addition of hexanes to give an orange solid (80% yield)
Procedure 2. The off-white solid (4 mmol) of the amide obtained above was treated with Lawesson's reagent (970 mg, 0.6 equiv.) in 40 mL toluene at 110 0C for 1.5 hour. The reaction was allowed to cool. Aqueous ammonium hydroxide solution was added (2 mol equiv.) and stirred vigorously at room temperature for 10 min. Water (200 mL) and ethyl acetate (100 mL) were added. The organic layer was washed wiht water (2 x 200 mL). The organic layer was then treated with activated carbon (10 g) and stirred at room temperature for 1 hour. Filtration and removal of solvent under reduced pressure gave a bright yellow solid.
The yellow solid of the thioamide obtained from either Procedure 1 or Procedure 2 was treated with hydrazine (anhydrous, 50.0 equiv.) in ethanol at 80 0C for 1.5 hour. The reaction mixture was subjected to EtOAc/aqueous workup to remove excess hydrazine. The organic layer was dried and filtered to remove drying agent. Carbonyldiimidazole (1.1 equiv.) was added to the solution, and the solution was stirred at 35 0C for 2 hours. Solvent was pumped off, and the residue was treated with 20 mL THF and 10 mL NaOH (2M) to destroy excess carbonyldiimidazole. Normal workup (EtOAc/aqueous) and filtration gave the desired product 5-(2,4-bis(benzyIoxy)-5- isopropylphenyl)-4-(l-methyl-lH-indol-5-yl)-4H-l,2,4-triazole-3-ol as light brown solid. The solid was redissolved in THF/MeOH (1:1 100 mL) and palladium ( 10 wt% on activated carbon) was added. The reaction was stirred under a hydrogen atmosphere (50 psi) for 18 h. Filtration through celite and removal of solvent under reduced pressure produced the desired product (80% yiled).
Example 2
hydrazine
Figure imgf000153_0001
Figure imgf000153_0002
Preparation of 4-isopropyl-6-r4-(l-methyl-lH-indol-5-vπ-5-phenylamino-4H-fl.2.4-triazol- 3-yl]-benzene-l,3-diol
5-isopropyl-2,4-dimethoxy-N-l-methyl-lH-indol-5-yl)-benzamide was prepared reacting 2,4-dimethoxy-5-isopropylbenzoic acid with l,3-dimethyl-5-aminoindole by a procedure similar that described in Example 1. The corresponding thioamide was prepared by reacting the amide with Lawesson's reagent by a similar procedure as described in Procedure 1 of Example 1. A flask was charged wiht the thiobenzamide (123 mg, 0.33 mmol), dioxane (2 DiL), and hydrazine (0.5 mL). The reaction was heated to 1000C for one hour, and the solvent was removed by evaporation to give a solid cake. To the solid cake was added ethyl acetate (10 mL) and 10% aqueous potassium carbonate (ImL), and the mixture was shaken until the solid was completely dissolved. The organic layer was isolated, and dried with sodium sulfate. To the crude intermediate in the organic layer was added diisopropylethylamine (86 mg, 0.66 mmol) and phenylisocyanide dichloride (88 mg, 1.5 equivalent). The reaction was stirred overnight, and washed with saturated aqueous ammonium chloride, dried with sodium sulfate, and the product was purified by column chromatography to give [5-(5-isoproyl-2,4-dimethoxy-phenyl)-4-(l-methyl-lH-indol-5-yl)- 4H-[1 ,2,4]triazol-3-yl]-phenylamine (64 mg).
A flask was charged with [5-(5-isoproyl-2,4-dimethoxy-phenyl)-4-(l -methyl- IH- indol-5-yl)-4H-[l,2,4]triazol-3-yl]-phenylamine (27 mg, 0.06 mmol) and pyridium chloride (2g). The reactants were placed under a nitrogen atmosphere, and the reaction was heated to 210 0C for 25 minutes. To the cooled reaction mixture was added dichloromethane and saturated ammonium chloride solution. The organic fraction was isolated, and the product was purified by column chromatography to give 4-isopropyl-6-[4-(l -methyl- lH-indol-5-yl)- 5-phenylamino-4H-[l,2,4-triazol-3-yl]-benzene-l,3-diol (18 mg, 0.04 mmol). 1H-NMR (CDCl3): 7.70 (d, IH); 7.59 (d, I H); 7.50 (m, 3H); 7.29 (m, 2H); 7.22 (dd, I H); 6.98 (m, IH); 6.62 (d, IH); 6.40 (s, IH); 6.28 (s, IH); 3.95 (s, 2H); 2.83 (q, IH); 0.57 (d, 3H); 0.44 (d, 3H). ESMS calcd (C26H25N5O2): 347.13; Found: 348.1 (M+H)+.
Example 3
The compounds shown below were prepared by similar procedures as described in Procedure 1 of Example 1. Analytical data is provided for these compounds.
Figure imgf000154_0001
ESMS calcd (C18H13N3O3): 319.1; Found: 320 (M+H)+
Figure imgf000154_0002
ESMS calcd (Ci8H14N4O 3): 318.11; Found: 319.2 (M+H)+.
Figure imgf000154_0003
ESMS calcd (C20H17N3O 3): 347.13; Found: 348.1 (M+H)+.
Figure imgf000154_0004
ESMS calcd (C27H27N5O2): 453.22; Found: 454.4 (M+H)+.
Figure imgf000155_0001
1H-NMR (DMSO-d6): 11.85 (s, IH); 9.61 (s, IH); 9.43 (s, IH); 7.30 (d, J=7.5 Hz, 2H); 7.11 (d, J=7.5 Hz, 2H); 6.76 (s, IH); 6.26 (s, IH); 3.50 (s, 2H); 3.00-2.90 (m, IH); 2.47-2.42 (m, 4H); 0.98-0.93 (m, 12H). ESMS calcd (C22H28N4O3): 453.22; Found: 454.4 (M+H)+.
Figure imgf000155_0002
ESMS calcd (C17Hi8N4O3): 326.14; Found: 327.1 (M+H)+.
Figure imgf000155_0003
1H-NMR (DMSO-d6): 11.90 (s, IH); 9.59 (s, IH); 9.44 (s, IH); 7.18 (d, J=8.1 Hz, IH); 7.11 (s, IH); 6.88 (dd, J=8.1, 1.5 Hz, IH); 6.82 (s, IH); 6.25 (s, IH); 4.21-4.15 (m, IH); 3.23 (s, 3H); 3.10-2.93 (m, 3H); 2.88-2.79 (m, 2H); 0.97 (d, J=6.9 Hz, 6H). ESMS calcd (C21H23N3O4): 381.4; Found: 382.4 (M+H)+.
Figure imgf000156_0001
ESMS calcd (C19H2IN3O5): 371.15; Found: 372.2 (M+H)+.
Figure imgf000156_0002
ESMS calcd (C22H26N4O4): 410.20; Found: 411.1 (M+H)+.
Figure imgf000156_0003
ESMS calcd (C19H22N4O3): 354.17; Found: 355.2 (M+H)+.
Figure imgf000156_0004
ESMS calcd (C20H25N5O4): 399.19; Found: 400.1 (M+H)+.
Figure imgf000157_0001
ESMS calcd (C20H25N5O5): 415.19; Found: 416.1 (M+H)+.
Figure imgf000157_0002
ESMS calcd (C23H22N4O3): 402.17; Found: 403.2 (M+H)+.
Figure imgf000157_0003
ESMS calcd (C23H22N4O4): 418.16; Found: 419.2 (M+H)+.
Figure imgf000157_0004
ESMS calcd (C2IH24N4O4): 396.18; Found: 397.2 (M+H)+.
Figure imgf000158_0001
ESMS calcd (C23H30N4Os): 442.22; Found: 443.2 (M+H)+.
Figure imgf000158_0002
1H-NMR (DMSO): 12.01 (s, IH); 9.64 (s, IH); 9.58 (s, IH); 7.61 (d, J=8.4 Hz5 IH); 7.52 (d, J=3.3 Hz, IH); 7.17 (m, IH); 6.92 (d, J==6.9, IH); 6.23 (s, IH); 6.19 (d, J=3.3Hz, IH); 4.79 (m, IH); 2.76 (m, IH); 1.44 (bs, 6H); 0.57 (d, J=6.9Hz, 6H). ESMS calcd (C23H30N4O5): 442.22; Found: 443.2 (M+H)+.
Figure imgf000158_0003
1H-NMR (DMSO): 1 1.89 (s, IH); 9.55 (s, IH); 9.39 (s, IH); 6.88 (d, J=8.7 Hz5 IH); 6.77-6.79 (m, 2H); 6.50 (d, J=2.1 Hz, IH); 6.24 (s, IH); 3.26 (s, 3H); 2.97 (m, IH); 2.79 (t, J=7.5 Hz5 2H); 2.48 (s, 3H); 1.30 (m, 2H); 0.96 (d, J=6.9 Hz5 6H); 0.73 (t, J=7.5 Hz, 3H). ESMS calcd (C22H28N4O4): 412.21; Found: 413.1 (M+H)+.
Figure imgf000159_0001
1H-NMR (DMSO-ds): 11.86 (s, IH); 9.51 (s, IH); 9.43 (s, IH); 7.34 (d, J=6.6 Hz, IH); 7.33 (s, IH); 7.13 (d, J=1.8 Hz, IH); 6.92 (dd, J=6.6 Hz, 1.8 Hz, IH); 6.81 (s, IH); 6.20 (s, IH); 3.70 (s, 3H); 2.93 (hept, J=6.9 Hz, IH); 2.15 (s, 3H); 0.88 (d, J=6.9 Hz, 6H). ESMS calcd (C2IH23N4O3): 378.17; Found: 379.1 (M+H)+.
Example 4
Synthesis of the Compound of Formula (XXIVA) Step 1: Synthesis of phenyl l-methyI-lH-indol-5-ylcarbamate 5A:
Figure imgf000159_0002
To a solution of 5.62g (35.91mmols) of phenylchloroformate 4A in 25mL of dichloromethane at 0 0C was added, a solution of 5.Og (34.20 mmols) of indoleamine 3A in 25mL of dichloromethane drop wise (20 rnin) at 0 0C. The resultant mixture was then stirred for 1 Omin at 0 0C and a solution of 6mL (42.75 mmols) of triethylamine in 1OmL of dichloromethane was added drop wise (15min) at 0 0C 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 hexane:ethylacetate 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 6A
Figure imgf000160_0001
To a stirred suspension of 35.Og (0.13 lmols) of the carbamate SA 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 6A as grey solid.
Step 3: Synthesis of 3-(2,4-Bis-benzyloxy-5-isopropyl)benzylideneamino-l-(l-Methyl-lH- indoi-'-yl)-urea 8A
Figure imgf000160_0002
To a suspension of 23.Og (63.8mmols) of the aldehyde 7A in 15OmL of ethanol was added 2mL of AcOH and stirred. To the resultant mixture was added 13.Og (63.8mmols) of 6A portion wise (solid, lOmin) at room temperature and the resultant mixture was heated at 80° C for 1 h. During this time, stirring was difficult due to precipitate formation, therefore an additional 5OmL of ethanol was added. The mixture was cooled to RT and filtered the precipitate, washed with 5OmL of cold ethanol and 10OmL of ether and dried. Vacuum drying afforded 33.7g (97%) of the product 8A as off-white solid.
ESMS calcd. for C34H34N4O3 (M + H)+: 546.26; Found: 547.3
Step 4: Synthesis of 5-(2,4-Bis-benzyloxy-5-isopropylphenyI)-4-(l-methyI-lH-indol-5-yl)- 4H-[l,2,4]triazol-3-ol 9A
Figure imgf000161_0001
8A 9A
To a stirred suspension of 32.5g (59.49mmols) of 8A in 20OmL of ethanol was added 7.14g (0.178mmols) of NaOH and stirred. To the resultant mixture, was added 39.17g (0.118mmols) OfK3Fe(CN)6 at once and the resultant mixtue was stirred at reflux temperature (100° C oil bath external temperature) for 8h (till the reaction is complete, checked by TLC). The mixture was cooled and the inorganics were filtered off. The residues were thoroughly washed with EtOH (5OmL) and a 1:1 mixture of EtOAc:MeOH (15OmL) and filtrates were collected. The combined filtrates were concentrated and crude mixture was dissolved in approx 20OmL of water (still a suspension). The mixture was then acidified with cHCl till pH 2-3 was reached. The resultant precipitate was filtered, washed thoroughly with water and dried. The crude product was then taken up in 9OmL of MeOH and stirred at 50° C for 30min and the solid obtained was filtered washed with cold MeOH and dried to obtain 27g of the off white solid. From the mother liquor another 3.8g of the grey solid 9A was isolated. Total yield = 3O.8g (95%).
ESMS calcd. for C34H32N4O3 (M + H)+: 544.25; Found: 545.3.
Step 5: Synthesis of 4-(5-hydroxy-4-(l-methyl-lH-indol-5-yl)-4H-l,2,4-triazol-3-yl)-6- isopropylbenzene-l,3-diol (XXIVA)
Figure imgf000161_0002
9A (XXIVA) Compound 9A (Ig, 1.84 mmol, 1.0 eq) was hydrogenated by balloon pressure of hydrogen at room temperature in 8 mL of THF and 4 mL of methanol for 6 h. The reaction mixture was filtered through Celite, and washed with THF and EtOAc. After removal solvents, the reaction mixture was dissolved in 20 mL of 1 N NaOH solution, and acidified with IN HCl until pH is 3~4. The white precipitate thus obtained was filtered, washed with water and dried using the vacuum oven to produce off-white solid of 4-(5-hydroxy-4-(l- methyl-lH-indol-5-yl)-4H-l,2,4-triazol-3-yl)-6-isopropylbenzene-l,3-diol 1OA (0.638 g, 1.75 mmol, 95%).
IH-NMR (DMSO5 300MHz) of (XXIVA). δ 11.86 (s, IH), 9.53 (s, IH), 9.41 (s, IH), 9.40-9.36 (m, 3H), 6.91 (dd,J= 2.1, 9Hz, IH), 6.77 (s, IH), 6.40 (d, J= 3Hz, IH), 6.20 (s, IH), 3.77 (s, 3H)52.90 (hept, J= 6.9Hz, IH), 0.87 (d, J= 6.9Hz5 6H). ESMS calcd. for C20H20N4O3 (M + H)+: 364.15; Found: 365.2
Step 5b: Synthesis of 4-(5-hydroxy-4-(l-methyl-lH-indol-5-yl)-4H-l,2,4-triazol-3-yl)-6- isopro
Figure imgf000162_0001
9A (XXIVA)
5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(l-methyl-lH-indol-5-yl)-4H-l,2,4-triazol-3-ol5 (1.03 g, 1.89 mmol) was stirred with ammonium formate (0.6 g, 9.5 mmol, 5 equiv.) in the presence of palladium on activated carbon (100 mg, 0.1 equiv., 10 wt.%) at 55 0C in reagent grade ethanol (25 ml) and water (0.5 ml) for 1 hour. Completion was judged by TLC. The 'hot' reaction mixture was filtered through Celite and washed with hot ethanol (25 ml x 3), and concentrated to around 1/4 volume. To this mixture was added 100 mL of water. The white precipitate was filtered, washed with water and dried with vacuum oven overnight to give 672 mg of 4-(5-hydroxy-4-(l-methyl-lH-indol-5-yl)-4H-l,2,4-triazol-3-yl)-6- isopropylbenzene-l,3-diol (97.7% yield, 99.8% HPLC purity at 232 nm).
The following table shows the results for various reaction conditions in Step 5b.
Compd Ammonium
Run Catalyst Time Yield Purity 9A Formate
Figure imgf000163_0002
Synthesis of Aldehyde 12A and the Compound of Formula (XXIIIA)
Figure imgf000163_0001
HA 12A
To 7OmL of cold and stirred DMF (ice-bath) was added 3ImL (0.328mols, 2.5eq. of reagent) OfPOCl3 drop wise over 15min. The resultant mixture was stirred at ice-bath temperature (0-5 0C) for 30min. To the mixture was then added 2Og (0.13mols) of HA in 4OmL of anhydrous DMF drop wise at ice-bath temperature (0-5 0C) over 25min. The resultant viscous mixture was stirred at room temperature for Ih and at 50 0C for Ih.
The mixture was then poured cautiously to a cold solution of 63g (12 eq.) of NaOH in 40OmL of water (over lOmin) with vigorous stirring. A red colored solution was then obtained. The mixture was then heated at 70 0C for 15min and then cooled. It was then acidified with ice-bath cooling with cHCl till pH2-3. The solution turned yellow-orange with same colored precipitate formed. The mixture was stirred further (over weekend; alternatively, anywhere between 15min. to Ih stirring should be fine) and filtered. The orange colored precipitate was washed successively with water and vacuum dried at 50 0C to obtain 17.25g (73%) of orange-light brown powder.
The compound of formula (XXIIIA) is synthesized from compound 12A according to the following scheme:
Figure imgf000164_0001
Exemplary Compounds Synthesized by the Methods of the Invention
Exemplary compounds of formula (IA') that can be synthetized by the method II of the present invention are compounds 97, 137-173, 176, 220, and 232 depicted in Table 1 above, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof .
Exmaple 5
Preparation of 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(N-methyl-indol-5-yl)-5-hydroxy- [l,2,4]triazole
Figure imgf000165_0001
STEP 1
Figure imgf000165_0002
STEP 3 deprotection STEP 4
Figure imgf000165_0003
Scheme 1
2,4-dibenzyloxy-5-isopropylbenzoic acid (43.0 mmol, 1.00 equiv.) in 300 mL dichloromethane at room temperature was treated with oxalyl chloride (47.3 mmol, 1.10 equiv.) and catalytic amount of DMF (0.5 mL) for 1 hour. Solvent and excess oxalyl chloride were removed on rotary evaporator. The residue was dissolved in 300 mL dichloromethane, and treated with l,3-dimethyl-5-aminoindole (43.0 mmol, 1.00 equiv.) and triethylamine (64.5 mmol, 1.50 equiv.) at 0 0C for 1 hour. Normal aqueous workup and removal of solvent gave a light brown solid which was washed with ether to yield off-white solid (39.95 mmol, 93 %).
Step 1. The off-white solid (4 mmol) of the amide obtained above was treated with Lawesson's reagent (970 mg, 0.6 equiv.) in 40 mL toluene at 1100C for 1.5 hour. Water was added and extracted with ethyl acetate, washed with water 2 times. Dried, concentrated and crystallized by the combination of sonication and addition of hexanes to give an orange solid (80% yield)
Step 2. The off-white solid (4 mmol) of the amide obtained above was treated with Lawesson's reagent (970 mg, 0.6 equiv.) in 40 mL toluene at 1100C for 1.5 hour. The reaction was allowed to cool. Aqueous ammonium hydroxide solution was added (2 mol equiv.) and stirred vigorously at room temperature for 10 min. Water (200 mL) and ethyl acetate (100 mL) were added. The organic layer was washed wiht water (2 x 200 mL). The organic layer was then treated with activated carbon (10 g) and stirred at room temperature for 1 hour. Filtration and removal of solvent under reduced pressure gave a bright yellow solid.
Step 3
HgCI2 (2.0 equiv.), pyridine dioxanc, reflux, 4 hours
Figure imgf000166_0003
Figure imgf000166_0002
equiv. 10 mmol scale, 79% yield
Figure imgf000166_0001
R = methyl
Thioamide (3.682g, 10.00 mmol, 1.0 equiv), methyl hydrazine carboxylate (1.8Og, 20.0 mmol, 2.0 equiv), pyridine (2.37 mL, around 30.0 mmol, 3.0 equiv) and 40 mL dioxane were mixed in a 100 mL round bottom flask. Mercury (II) chloride (5.43 g, 20.0 mmol, 2.0 equiv) was added to the flask, and stirred at room temperature for half an hour. The mixture was refluxed for 4 hours. Enough Na2S was added to the mixture after it was cooled to room temperature and stirred for 30 minutes to quench excess mercury chloride. Solid was removed by filtration through celite, and the solution was subjected to EtOAc/aqueous workup. Flash chromatography purification gave an off-white solid (3.10 g, 79%). 1H NMR (300 MHz, CDCl3), δ (ppm): 8.96 (br s, IH); 7.40 (dd, J= 2.1 Hz, 0.6 Hz, IH); 7.24-7.26 (m, IH); 7.20 (s, I H); 7.00-7.05 (m, 2H); 6.42 (dd, J= 3.0 Hz, 0.6 Hz, IH); 6.19 (s, IH); 3.77 (s, 3H); 3.76 (s, 3H); 3.38 (s, 3H); 3.15 (hept, J= 7.2 Hz, IH); 1.10 (d, J= 12 Hz, 6H). ESMS calcd. for C22H25N4O3 (M + H)+: 392.2; Found: 392.2.
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 example 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

What is claimed is:
1. A method of preparing a triazole compound represented by the following
Structural Formula:
Figure imgf000167_0001
or a tautomer, a pharmaceutically acceptable salt, a solvate, a clathrate, or a prodrug thereof, comprising the steps of:
a) reacting an amide represented by the following Structural Formula:
Figure imgf000167_0002
with a thionation reagent to form a thioamide represented by the following
Structural Formula:
Figure imgf000167_0003
b) reacting the thioamide of step a) with hydrazine to form a hydrazonamide represented by the following Structural Formula:
c) reacting the hydrazonamide of step b) with a carbonylation, a thiocarbonylation reagent; or a compound of structural formula R7N=C(X)2 wherein: R1 is -OH, -SH or -NHR7; ring A is an aryl or a heteroaryl optionally further substituted with one or more substituents in addition to R3;
R3 is -OR26, -SR26, -O(CH2)mORA, -O(CH2)mSRB, -O(CH2)mNR7Rc,
-S(CH2)mORA, -S(CH2)mSRB, -S(CH2)mNR7Rc, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)pR7, -OS(O)PNR1OR113 -SS(O)PNR1ORU,
-NR7S(O)pNR10Ru, -SS(O)POR7, -NR7S(O)POR7, -OC(S)OR7, -SC(S)OR7,
-NR7C(S)OR75 -OC(S)NRi0Rn5 -SC(S)NR10Rn, -NR7C(S)NR10R115
-OC(NRs)R7, -SC(NRg)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7,
-NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10Rn5 -NR7C(NRs)NR1ORn, -OP(O)(OR7)2, or -SP(O)(OR7)2, -ORA) -SRB, -NR7Rc5 -NR26Rc5 or -N(Rc)2, wherein RA is a hydroxyl protecting group; RB is a thiol protecting group, Rc, for each occurrence, is H or an amine protecting group, provided at least one Rc is an amine protecting group;
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;
R7 and Rs, 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;
R1O 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;
R26 is a Cl-C6 alkyl; p, for each occurrence, is, independently, 0, 1 or 2; m, for each occurrence, is independently, 1, 2, 3, or 4; and X is a leaving group.
2. A method of preparing a triazole compound represented by the following Structural Formula:
Figure imgf000169_0001
or a tautomer, a pharmaceutically acceptable salt, a solvate, a clathrate, or a prodrug thereof, comprising the steps of: a) reacting in a reaction mixture an amide represented by the following Structural Formula:
Figure imgf000169_0002
with Lawesson's reagent to form a thioamide represented by the following Structural Formula:
Figure imgf000169_0003
b) washing the reaction mixture of step a) with a water soluble amine after completion of the reaction; c) reacting the thioamide of step b) with hydrazine to form a hydrazonamide represented by the following Structural Formula:
Figure imgf000170_0001
d) reacting the hydrazonamide of step c) with a carbonylation, a thiocarbonylation reagent; or a compound of Structural Formula R7N=C(X)2 wherein:
R1 is -OH, -SH or -NHR7; ring A is an aryl or a heteroaryl optionally further substituted with one or more substituents in addition to R3; R3 is -OR26, -SR26, -O(CH2)mORA, -O(CH2)mSRB, -O(CH2)mNR7Rc,
-S(CH2)raORA, -S(CH2)mSRB, -S(CH2)mNR7Rc, -OS(O)PR75 -SS(O)PR7> -S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10Rn5 -SS(O)PNR10Rn, -NR7S(0)pNR,oRn, -SS(O)POR7, -NR7S(O)POR7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10RI U -SC(S)NR10Rn, -NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR75 -SC(NR8)OR7,
-NR7C(NR8)OR7, -OC(NR8)NR,oRπ, -SC(NR8)NR10Rn, -NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2, -ORA, -SRB, -NR7Rc, -NR26Rc, or -N(Rc)2, wherein RA is a hydroxyl protecting group; R8 is a thiol protecting group, Rc, for each occurrence, is H or an amine protecting group, provided at least one Rc is an amine protecting group;
Rs 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;
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 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 R)o and Ri1, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a C1-C6 alkyl; p, for each occurrence, is, independently, 0, 1 or 2; m, for each occurrence, is independently, 1, 2, 3, or 4; and X is a levaing group.
3. The method of Claim 2, wherein the water soluble amine is aqueous ammonium hydroxide.
4. A method of preparing a thioamide represented by the following Structural
Formula:
Figure imgf000171_0001
comprising the step of reacting in a reaction mixture an amide represented by the following Structural Formula:
Figure imgf000171_0002
with a thionation reagent, wherein: ring A is an aryl or a heteroaryl optionally substituted with one or more substituents in addition to R3; R3 is -OR26, -SR26, -O(CH2)mORA, -O(CH2)mSRB, -O(CH2)mNR7Rc,
-S(CH2)mORA, -S(CH2)mSRB, -S(CH2)mNR7Rc, -OS(O)PR7> -SS(O)pR7, -S(O)15OR7, -NR7S(O)PR7, -OS(O)pNR10Rπ, -SS(O)pNR10Rπ, -NR7S(0)pNRioRii, -SS(O)POR7, -NR7S(O)POR7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Ri i, -NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR,0R,l5 -SC(NRs)NR10Ri,, -NR7C(NRs)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2, -ORA, -SR8, -NR7Rc, -NR26Rc, or -N(Rc)2, wherein RA is a hydroxyl protecting group; RB is a thiol protecting group, Rc, for each occurrence, is H or an amine protecting group, provided at least one Rc is an amine protecting group;
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;
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 heterocycly], an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and Rj1, 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 R1], taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a C1-C6 alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4.
5. The method of Claim 4, wherein the thionation reagent is selected from the group consisting of Lawesson's Reagent, phosphorus pentasulfide, Scheeren's Reagent (P4S]0-Na2S), P4S10-N(ethyl)3, Davy's Reagent and Heimgarner's reagent.
6. The method of Claim 4, wherein the thionation reagent is Lawesson's reagent.
7. The method of Claim 4, further comprising the step of washing the reaction mixture with aqueous ammonium hydroxide after completion of the reaction.
8. A method of preparing a hydrazonamide represented by the following Structural Formula:
Figure imgf000173_0001
comprising the step of reacting a thioamide represented by the following Structural Formula:
Figure imgf000173_0002
with hydrazine, wherein ring A is an aryl or a heteroaryl optionally substituted with one or more substituents in addition to R3;
R3 is -OR26, -SR26, -O(CH2)mORA, -O(CH2)raSRB, -O(CH2)mNR7Rc, -S(CH2)mORA, -S(CH2)mSRB, -S(CH2)mNR7Rc, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R1 11 -SS(O)PNR1ORI 1, -NR7S(0)pNR,oRii, -SS(O)POR7, -NR7S(O)POR7, -OC(S)OR7, -SC(S)OR7,
-NR7C(S)OR7, -OC(S)NRI0RI i, -SC(S)NR10RiI, -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)NR10R11, -NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2, -ORA, -SRB, -NR7R0 -NR26R0, or -N(Rc)2, wherein RA is a hydroxyl protecting group; RB is a thiol protecting group, R0, for each occurrence, is H or an amine protecting group, provided at least one Rc is an amine protecting group;
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; 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 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 Ri0 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a Cl -C6 alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
9. A method of preparing a triazole compound represented by the following Structural Formula:
Figure imgf000174_0001
or a tautomer, a pharmaceutically acceptable salt, a solvate, a clathrate, or a prodrug thereof, comprising the step of reacting a hydrazonamide represented by the following Structural Formula:
Figure imgf000174_0002
with a carbonylation or a thiocarbonylation reagent, wherein: ring A is an aryl or a heteroaryl optionally substituted with one or more substituents in addition to R3;
R3 is -OR26, -SR26, -O(CH2)raORA, -O(CH2)mSRB, -O(CH2)mNR7Rc, -S(CH2)mORA, -S(CH2)raSRB, -S(CH2)mNR7Rc, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rn, -SS(O)pNR,0R,i5
-NR7S(0)pNR,oRn, -SS(O)POR7, -NR7S(O)POR7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R, ,, -SC(S)NR10Rn, -NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RH5 -SC(NR8)NR1ORiU -NR7C(NR8)NR1ORn, -OP(O)(OR7)2, or -SP(O)(OR7)2, -ORA, -SR8, -NR7Rc, -NR26R0 or N(Rc)2, wherein RA is a hydroxyl protecting group; RB is a thiol protecting group, Rc, for each occurrence, is H or an amine protecting group, provided at least one Rc is an amine protecting group;
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;
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;
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 Rj0 and Rj1, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a Cl-C6 alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
10. The method of Claim 9, wherein the carbonylation reagent is carbonyldiimidazole.
11. The method of Claim 9, wherein the thiocarbonylation reagent is thiocarbonyldiimidazole.
12. The method of Claim 9, wherein the hydrazonamide is reacted with a compound of structural formula R7N=C(X)2.
13. A method of preparing of a triazole compound of Structural Formula (IA), comprising reacting a compound of Structural Formula (IIA):
Figure imgf000176_0001
(IIA) with an oxidizing agent, thereby producing a compound of Structural Formula (IA):
Figure imgf000176_0002
or a tautomer, a pharmaceutically acceptable salt, a solvate, a clathrate, or a prodrug thereof, 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;
R20 is -ORp], -NHRp3 or -N(RP3)2, wherein Rpi, for each occurrence, is independently selected from groups suitable for protecting hydroxyl, and Rp3> for each occurrence, is independently selected from groups suitable for protecting an amino group;
R21 is O, NH, or NR26, and R2ia is OH, NH2 or NHR26; and R26 is a Cl -C6 alkyl.
14. The method of Claim 13, wherein the oxidizing agent is K3Fe(CN)6, MnO2, Br2, N-bromosuccinimide or N-chlorosuccinimide.
15. The method of Claims 14, wherein the oxidizing agent is K3Fe(CN)6.
16. The method of Claim 13, further comprising the step of deprotecting the compound of Structural Formula (IA)
Figure imgf000177_0001
thereby producing a compound of Structural Formula (IA')
Figure imgf000177_0002
wherein R22 is -OH, or -NH2.
17. The method of Claim 16, wherein R2o is -ORpi, RpJ is a benzyl group and the step of deprotecting comprises reacting a compound of formula (IA) with hydrogen in the presence of hydrogenation catalyst.
18. A method of preparing a compound of Structural Formula (ILA),
Figure imgf000177_0003
(IIA) comprising: reacting a compound of Structural Formula (HIA)
Figure imgf000177_0004
(UlA) with a compound of Structural Formula (IVA)
Figure imgf000178_0001
(IVA) R20 5 in the presence of an acid, thereby producing a compound of formula (IIA), 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 R2<>;
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;
R20 is -ORpi, -NHRp3 or -N(Rp3)2, wherein Rpi, for each occurrence, is independently selected from groups suitable for protecting hydroxy!, and
Rp3, for each occurrence, is independently selected from groups suitable for protecting an amino group;
R21 is O, NH, or NR26, and R2!a is OH, NH2 or NHR26; and
R26 is a Cl -C6 alkyl- 19. A method of preparing a triazole compound represented by the following
Structural Formula:
Figure imgf000178_0002
or a tautomer, a pharmaceutically acceptable salt, a solvate, a clathrate, or a prodrug thereof, wherein the method comprises the step of reacting a first starting compound represented by the following Structural Formula:
Figure imgf000178_0003
in the presence of a mercuric salt, with a second starting compound represented by the following Structural Formula:
Figure imgf000179_0001
Rib is -OH, -SH or -NHR6O5 wherein R60 is H, an optionally substituted alkyl group, or an optionally substituted cycloalkyl group; ring A is an aryl or a heteroaryl, wherein the aryl group and the heteroaryl group represented by ring A is optionally further substituted with one or more substituents in addition to R3;
R3b is -OR10O, -SRioi, -N(R102);,, -NR7R102, -OR26, -SR26, -NR26R102, -O(CH2)mOR,00, -O(CH2)mSR10i, -O(CH2)raNR7R102, -S(CH2)mOR10o, -S(CH2)mSRI0I, -S(CH2)mNR7R,o2, -OC(O)NR,0Rn, -SC(O)NR10R11, -NR7C(O)NR10Rn, -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)NRi0Rπ, -SCH2C(O)NR10R11, -NR7CH2C(O)NRi0Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -OS(O)PNR1ORI I5 -SS(O)PNR10R1 1, -NR7S(O)pNRI0R,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)NR10Ri i, -SC(S)NRi0Rn, -NR7C(S)NRi0R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NRS)NR10RI U -NR7C(NR8)NRI0R1 1, -OP(O)(OR7)2, or -SP(O)(OR7)2; each R100, independently, is a hydroxyl protecting group; each R101, independently, is a thiol protecting group; each R)02, independently, is -H or an amino protecting group, provided that at least one group represented by R102 is a protecting group; R5 is an optionally substituted aryl group, an optionally substituted heteroarylgroup, an optionally substituted cycloalkyl group, an optionally substituted cycloakenyl group, or a substituted alkyl group, wherein each of the aryl group, heteroaryl group, cycloaryl group, cycloalkyl group, cycloalkenyl group, and alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkyl group, an optionally substituted alkynyl, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted heteroaryl group, an optionally substituted aralyalkyl group, or an optionally substituted heteraralkyl group;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycJoalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, or R7, taken together with the oxygen atom to which it is bonded, forms an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
Rio and Rn, for each occurrence, are, independently, amine protecting group, 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; R26 is a C1-C6 alkyl group;
R50 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, or an optionally substituted heteraralky;
R51 is =0, =S or =NRδ0; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is, independently, 1, 2, 3, or 4.
20. The method of Claim 19, wherein R3b is -ORi00, -SR101, -N(RiO2)2, -NR7Ri02, -OR26, -SR26, -NR26Ri02, -O(CH2)mORl00, -O(CH2)mSR10i, -O(CH2)mNR7R102,
-S(CH2)mORI00, -S(CH2)mSR,01, or -S(CH2)mNR7RI02.
21. The method of Claim 19, wherein the first compound and the second compound are reacted in the presence of a base.
22. The method of Claim 21, wherein the base is an amine base.
23. The method of Claim 19, wherein the mercuric salt is Hg(Xi)2, wherein X] is a halogen.
24. The method of Claim 23, wherein Xi is a chloride.
25. The method of Claims 19, further comprising the step of reacting the compound formed from the reaction of the first and second starting compounds to remove any protecting groups on the compound.
26. A method of preparing a triazole compound represented by the following Structural Formula:
Figure imgf000181_0001
or a tautomer, a pharmaceutically acceptable salt, a solvate, a clathrate or a prodrug thereof, comprising the steps of:
1) reacting a thionylating agent with a compound represented by the following Structural Formula:
Figure imgf000181_0002
thereby forming a first product represented by the following Structural Formula:
Figure imgf000181_0003
2) in the presence of a mercuric salt, reacting the first product with - ISO -
Figure imgf000182_0001
thereby forming a second product represented by the following Structural
Formula:
Figure imgf000182_0002
3) deprotecting the second product to form the triazole compound; wherein: ring A is an aryl or a heteroaryl, wherein the aryl group and the heteroaryl group represented by ring A is optionally further substituted with one or more substituents in addition to Rj; R3 is -OR100, -SRioi, -N(R,02)2, -NR7R102, -OR26, -SR26, -NR26R102,
-0(CH2)mOR,oo, -O(CH2)mSR,01, -O(CH2)mNR7R102, -S(CH2)mORIOo, -S(CH2)mSR10,, -S(CH2)mNR7R102, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(0)NRioRn, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR75 -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10Ri 1,
-SCH2C(O)NR10R11, -NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -OS(O)-NR10R11, -SS(O)PNR10R11, -NR,S(0)pNR,oRii, -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)NR10R11, -SC(S)NRi0Rn, -NR7C(S)NR10Rn, -OC(NR8)R7,
-SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rn, -SC(NR8)NR10Ri15 -NR7C(NR8)NR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R5 is an optionally substituted aryl group, an optionally substituted heteroarylgroup, an optionally substituted cycloalkyl group, an optionally substituted cycloakenyl group, or a substituted alkyl group, wherein each of the aryl group, heteroaryl group, cycloaryl group, cycloalkyl group, cycloalkenyl group, and alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkyl group, an optionally substituted alkynyl, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted heteroaryl group, an optionally substituted aralyalkyl group, or an optionally substituted heteraralkyl group;
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, an optionally substituted heteraralkyl, or R7, taken together with the oxygen atom to which it is bonded, forms an optionally substituted heterocyclyl or an optionally substituted heteroaryl; Rio and Rn, for each occurrence, are, independently, amine protecting group, 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; R26 is a C1-C6 alkyl group; R50 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, or an optionally substituted heteraralky; Rs i is =O, =S Or =NR60; each R]Oo, independently, is a hydroxyl protecting group; each Rioi, independently, is a thiol protecting group; each RIO2J independently, is — H or an amino protecting group, provided that at least one group represented by Rt02 is a protecting group; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is, independently, 1, 2, 3, or 4. W 2
- 182 -
27. The method of any one of Claims 1-12, wherein Rs is represented by the following Structural Formula:
Figure imgf000184_0001
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, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0Ri i (provided Ri0 and Rn are not -H), -OR7 (provided R7 is not -H), -SR7 (provided R7 is not H), -S(O)PR7, -OS(O)PR7, -NR8S(O)pR7, -S(O)pNR10Rii5 -OP(O)(OR7)2, or -SP(O)(OR7)2, -ORA, -SRB, -N(RC)2 or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring.
28. The method of any one of Claims 13-18, wherein R5 is represented by the following Structural Formula:
Figure imgf000184_0002
wherein:
R9, for each occurrence, is independently a substituent selected from: -ORpi, -NHRp3, -N(Rp3)2, -0(CHa)nORp1, or -(CH2)mORp,; 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, -NR10Ri i, -OR7, -O(CH2)mNR7Rp3, -C(O)R7, -C(O)OR7; -C(O)NRi0Ri ύ -OC(O)R7, -OC(O)OR7, -OC(O)NRi0Ru; -NR8C(O)R7, -NR7C(O)NR10Rn, -NR7C(O)OR7; -S(O)PR7, -OS(O)pR7s -OS(O)POR7, -OS(0)pNR,oRu, -S(O)POR7, -S(O)pNRI0R,i3 -NR8S(O)pR7s -NR7S(0)pNR,oRπ, or -NR7S(O)POR7; 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; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
29. The method of any one of Claims 19-26, wherein wherein R3 is represented by the following Structural Formula:
Figure imgf000185_0001
wherein;
Rg5 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 heteraraikyi, protected hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR,0Rii, -ORioo and -C(O)R7; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and t is zero or an integer from 1 to 7.
30. The method of any one of Claims 27-29, wherein R5 is represented by the following Structural Formulas:
Figure imgf000186_0001
wherein: q is zero or an integer from 1 to 7; and u is zero or an integer from 1 to 8.
31. The method of Claim 27, wherein ring A is represented by the following Structural Formula:
Figure imgf000186_0002
wherein:
Re and R25 are independently 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 heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRioRπ (provided R10 and Rn are not -H), -OR7 (provided R7 is not H), -C(NR8)OR7, -C(NR8)NR10RH, -C(NR8)SR7, -OC(S)OR7, -OC(NR8)OR7, -SC(NRs)OR7-SC(S)OR7, -OC(S)NR10Ri i, -OC(NRs)NR10Rn,
-SC(NRS)NR10RI i, -SC(S)NRi0R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(NR8)OR7, -NR7C(S)NR10RiI, -NR7C(NR8)NR10R1I, -SR7 (provided R7 is not H), -S(O)PR7, -OS(O)PR7, -OS(O)pNRi0Rii, -S(O)POR7, -NRsS(O)pR7, -NR7S(O)pNRI0Rn, -NR7S(O)POR7, -S(O)PNR10R11, -SS(O)PR7, -SS(O)POR7, -SS(O)pNR10R, „ -OP(O)(OR7)2, or -SP(O)(OR7)2, -
Figure imgf000187_0001
32. The method of Claim 31, wherein: R3 is -ORA; R25 is -ORA; Rδ is a lower alkyl, C3-C6 cycloalkyl, lower alkoxy, a lower alkyl sulfanyl, or — NRj0R11; and
R9 for each occurence, is independently selected from the group consisting of -ORA, -SRB, halo, a lower haloalkyl, cyano, a lower alkyl, a lower alkoxy, and a lower alkyl sulfanyl.
33. The method of Claim 28, wherein ring A is represnted by the following
Structural Formula:
Figure imgf000187_0002
wherein:
Rs and R25, for each occurrence, is independently a substituent selected the group consisting of -ORpi, -NHRp3, -N(Rp3)2, -O(CH2)mORp,, -(CH2)mORpl; 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, -NR10Rn, -OR7, -O(CH2)mNR7RP3, -C(O)R7, -C(O)OR7; -C(O)NRi0Ri i; -OC(O)R7, -OC(O)OR7, -OC(O)NRi0Rn; -NR8C(O)R7, -NR7C(O)NR1ORn, -NR7C(O)OR7; -S(O)PR7, -OS(O)PR7, -OS(O)POR7, -OS(O)PNR10R1I, -S(O)POR7, -S(O)pNRi0Rn, -NR8S(O)PR7, -NR7S(O)pNRi0Rn, and -NR7S(O)POR7.
34. The method of Claim 29, ring A is represnted by the following Structural Formula:
Figure imgf000188_0001
wherein:
R25 is 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, protected hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10Rn, -ORi00, and -C(O)R7; Rβ, 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, halo, cyano, nitro, guanadino, a protected hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, -NRi0Rn, -OR100, -C(O)R7 and -SR,Oi; or two R6 groups taken together with the carbon atoms to which they are attached form a fused ring.
35. The method of any one of Claims 1-12, wherein Rs is represented by the following Structural Formula:
Figure imgf000189_0001
wherein: R33 is a halo, a lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, or lower alkyl sulfanyl; R34 is H, or a lower alkyl; and
Ring B and Ring C are optionally substituted with one or more substituents in addition to R33 and R34.
36. The method of any one of Claims 13-18, wherein R5 is represented by the following Structural Formula:
Figure imgf000189_0002
wherein:
R33 is H, -ORpi, -NHRp3, -N(Rp3^, a halo, a lower alkyl, a lower alkoxy, a lower haloalkyl, or a lower haloalkoxy;
R34 is H, -ORpi, -NHRp3, -N(Rp3)2, a C1-C6 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.
37. The method of any one of Claims 19-26, wherein R5 is represented by the following Structural Formula:
Figure imgf000190_0001
wherein:
R33 is a halo, a lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, or lower alkyl sulfanyl;
R34 is H, or a lower alkyl, or a lower acyl; and
Ring B and Ring C are optionally substituted with one or more substituents in addition to R33 and R34.
38. The method of any one of Claims 1-12, wherein R5 is selected from the group
Figure imgf000190_0002
Figure imgf000190_0003
Figure imgf000190_0004
Figure imgf000191_0001
wherein: Xe, for each occurrence, is independently CH, CR9, 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, S(O)p, NR7, or NRn;
X9, for each occurrence, is independently N or CH; Xio, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), 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, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10R11 (provided R10 and Rn are not H) -OR7 (provided R7 is not H), -SR7 (provided R7 is not H), -S(O)PR7, -OS(O)PR7, -NR8S(O)PR7, or -S(O)pNR10R,i, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2, -S(O)POR7, -OP(O)(OR7)2, -SP(O)(OR7)2, -
Figure imgf000192_0001
or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
Ri7, for each occurrence, is independently -H, an alkyl, or an aralkyl.
39. The method of any one of Claims 13-18, wherein R5 is selected from the group consisting of:
Figure imgf000192_0002
Figure imgf000192_0003
Figure imgf000192_0005
Figure imgf000193_0001
wherein:
X6, for each occurrence, is independently CH5 CR9, N, N(O), N+(Ri7), provided that at least three X6 groups are independently selected from CH and CR9;
X7, for each occurrence, is independently CH, CR9, N5 N(O), N+(R]7), provided that at least three X7 groups are independently selected from CH and CR9;
Xg, for each occurrence, is independently CH2, CHR9, C(R9)2, S(0)p, NR7, Or NR17;
X9, for each occurrence, is independently N or CH; Xio, for each occurrence, is independently CH, CRg, N, N(O), N+(Rj7), provided that at least one Xio is selected from CH and CR9;
R9, for each occurrence, is independently a substituent selected from: -ORpl, -NHRp3, -N(Rp3)25 -O(CH2)mORp,, or -(CH2)mORp,; 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, -NR10RiU -OR7, -O(CH2)mNR7Rp3, -C(O)R7, -C(O)OR7; -C(O)NR)0Ri i; -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)PNR10R1 ,, -S(O)POR7, -S(O)pNR,0RH, -NR8S(O)PR7, -NR7S(O)pNR,0R,,, or -NR7S(O)POR7; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
Rn, for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R7, -C(O)OR7, or -C(O)NR10Rn; R.7 and Rs, 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; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
40. The method of any one of Claims 19-26, wherein R5 is selected from the group consisting of:
Figure imgf000194_0001
Figure imgf000194_0003
Figure imgf000194_0004
Figure imgf000194_0005
'
Figure imgf000194_0002
Figure imgf000195_0001
wherein:
Xe, for each occurrence, is independently CH, CR9, N, N(O), N+(Rn), provided that at least three X$ 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;
X8, for each occurrence, is independently CH2, CHR9, C(R9)2, S, S(O)p, NR7, or NR]7;
X9, for each occurrence, is independently N or CH;
Xio, for each occurrence, is independently CH, CR9, N, N(O), N+(Rn), provided that at least one Xj 0 is selected from CH and CR9;
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alky I, 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, protected hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10RH3 -ORIOO, and -C(O)R7; or two R9 groups, taken together with the carbon atoms to which they are attached, form a fused ring; and
R)7, for each occurrence, is independently -H, an alkyl, an aralkyl, or -C(O)R7.
41. The method of any of Claims 38-40, wherein R5 is an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3i/-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 tetrahydro indolyl, an optionally substituted azaindolyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted imidazo^S-ajpyridinyl, an optionally substituted imidazo[l,2-a3pyridinyl, an optionally substituted 3H-imidazo[4,5-b]pyridinyl5 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]ρyrimidyl, 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.
42. The method of any one of Claims 1-12, wherein K5 is selected from the group consisting of:
Figure imgf000197_0001
Xu, 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+(Rn) and at least two Xi 1 groups are independently selected from CH and CR9;
X 12, for each occurrence, is independently CH, CR9, N, N(O), N+(R]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, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR)0Rπ (provided Rio and Rn are not H), -OR7 (provided R7 is not H), -SR7 (provided R7 is not H), -S(O)PR7> -OS(O)PR7, -NR8S(O)pR7, or -S(O)pNR10Rπ, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2, -S(O)POR7, -OP(O)(OR7)2, -SP(O)(OR7)2, -
ORA3 -SRs9 Or -N(Rc)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
Rn, for each occurrence, is independently — H, an alkyl, an aralkyl.
43. The method of any one of Claims 13-18, wherein R5 is selected from the group consisting of:
Figure imgf000198_0001
wherein:
Xn, for each occurrence, is independently CH, CR9, N, N(O), or N+(Rn), provided that at least one Xn is N, N(O), or N+(Rn) and at least two Xn groups are independently selected from CH and CR9;
X]2, for each occurrence, is independently CH, CRp, N, N(O), N+(Rn), provided that at least one X12 group is independently selected from CH and CR9;
Xi3, for each occurrence, is independently O, S5 S(O)p, NR7, or NRnJ R9, for each occurrence, is independently a substituent selected from:
-ORp1, -NHRp3, -N(RpS)2, -O(CH2)mORp,, or -(CH2)mORp,; 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, -NR10R,,, -OR7, -O(CH2)mNR7Rp35 -C(O)R7, -C(O)OR7; -C(O)NR10Rn; -OC(O)R7, -OC(O)OR7, -OC(O)NRI0RI i; -NR8C(O)R7, -NR7C(O)NR10Rii, -NR7C(O)OR7; -S(O)pR7, -OS(O)PR7, -OS(O)POR7,
-OS(O)PNR10R1 ,, -S(O)POR7, -S(O)pNR10R, ,, -NR8S(O)11R7, -NR7S(O)PNR10R1 ,, or -NR7S(O)POR7;
R7 and Rs, 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;
R1O 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 Rπ, 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)NR10R11; and p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
44. The method of any one of Claims 19-26, wherein R5 is selected from the group consisting of:
Figure imgf000199_0001
wherein: Xn, for each occurrence, is independently CH, CRg, N, N(O), or N+(Ri7), provided that at least one Xi i is N, N(O), or N+(R]7) and at least two Xi j groups are independently selected from CH and CR9;
X 12, for each occurrence, is independently CH, CR9, N, N(O), N+(Rj7), provided that at least one X12 group is independently selected from CH and CR9;
Xi3, for each occurrence, is independently O, S, S(O)p, NR7, or NRn;
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, halo, cyano, nitro, guanadino, a protected hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, -NR10Rn, -ORioo, and -C(O)R7; or two R.9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
Ri7, for each occurrence, is independently an alkyl or an aralkyl.
45. The method of any one of Claims 1-12, 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 alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRi0Ri i (provided Ri0 and Rn is not H), -OR7 (provided R7 is not H), -SR7 (provided R7 is not H), -S(O)PR7, -OS(O)PR7, -NR8S(O)-R7, -S(O)pNR10R,,, -ORA, -SR8, and -N(Rc)2.
46. The method of any one of Claims 13-18, 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 : -ORpl, -NHRp3, -N(RpS)2, -O(CH2)mORp,, or -(CH2)mORp, ; 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)mNR7Rp3, -C(O)R7, -C(O)OR7;
-C(O)NRi0Ri,; -OC(O)R7, -OC(O)OR7, -OC(O)NR10Rn; -NR8C(O)R7, -NR7C(O)NRi0Rn, -NR7C(O)OR7; -S(O)PR7, -OS(O)PR7, -OS(O)POR7, -OS(0)pNR,oR,,, -S(O)POR7, -S(O)pNR,0Rii, -NRsS(O)pR7, -NR7S(O)pNR,0R, ,, or -NR7S(O)11OR7; R7 and R8, for each occurrence, 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, 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;
Rn, 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.
47. The method of any one of Claims 19-26, wherein R5 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted . aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NR10Ri 1, -ORi00, and -C(O)R7.
48. The method of any one of Claims 45-47, wherein R5 is optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.
49. The method of any one of Claims 45-47, wherein R5 is a substituted alkyl.
50. The method of any one of Claims 1-12, wherein R5 is a phenyl group substituted with: i) one substituent selected from nitro, cyano, a haloalkoxy, 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, guaπadino, -NR10R1] (provided R10 and Rn are not -H) -0-R20, -SR7 (provided R7 is not H), -S(O)PR7, -OS(O)PR7, -NRgS(O)pR7, -S(O)PNR10R11, -OP(OXOR7)2, -SP(O)(OR7)2, -ORA, -SRB, Or -N(Rc)2; or ii) two to five substituents 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, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR1ORn (provided R1O and Rn are not
H) -OR7-SR7, -S(O)13R7, -OS(O)pR7, -NR8S(O)PR7, -S(O)pNR10Rn, -OP(O)(OR7)2, or -SP(OXOR7)2, -S(O)POR7, -ORA, -SR3, Or-N(Rc)2.
51. The method of any one of Claims 13-18, wherein R5 is a phenyl group substituted with one to five substituents selected from: -ORp1, -NHRp3, -N(Rp3),, -O(CH2)raORpl, or -(CH2)mORpl ; 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)mNR7Rp3, -C(O)R7, -C(O)OR7; -C(O)NR10Rn; -OC(O)R7, -OC(O)OR7, -OC(O)NRi0Rn; -NR8C(O)R7, -NR7C(O)NR10R11, -NR7C(O)OR7; -S(O)PR7, -OS(O)PR7, -OS(O)POR7, -OS(O)pNRI0R, ,, -S(O)POR7, -S(O)pNR,0Ri ,, -NR8S(O)PR7, -NR7S(O)pNR10R, 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;
Ri0 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;
Rn, 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.
52. The method of any one of Claims 19-26, wherein R5 is a phenyl group substituted with: i) the one substituent selected from nitro, cyano, a haloalkoxy, 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, protected hydroxylalkyl, alkoxyalkyl, guanadino, -OR|00, -SRioi, -N(RiO2)2, -NR10RiI, -OR7, or -C(O)R7; or ϋ) two to five substituents 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 heterocycly], an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, protected hydroxyalkyl, alkoxyalkyl, -F,
-Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -ORi00, -SRjoi, - N(Ri(Q)2, -NRioRn, -ORi00, Or -C(O)R7.
53. The method of any one of Claims 1-12, wherein ring A is represented by the following Structural Formula:
Figure imgf000204_0001
wherein:
Rfi, for each occurrence, is independently 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 heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR]0Rn (provided Ri0 and Rn are not -H), -OR7 (provided R7 is not H), -C(NR8)OR7, -C(NRg)NR10Rπ, -C(NR8)SR7, -OC(S)OR7, -OC(NR8)OR7, -SC(NR8)OR7-SC(S)OR7, -OC(S)NR10Ri,, -OC(NRs)NR, 0Rπ, -SC(NR8)NRiORi i, -SC(S)NR10Ri i, -OC(NR8)R7, -SC(NR8)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(NR8)OR7, -NR7C(S)NR10R, ,, -NR7C(NR8)NR10R11, -SR7 (provided R7 is not H), -S(O)pR7, -OS(O)PR7, -OS(O)pNRI0RM, -S(O)POR7, -NR8S(O)PR7, -NR7S(O)pNRI0Riι, -NR7S(O)POR7, -S(O)pNR10Rπ, -SS(O)PR7, -SS(O)pOR7, -SS(O)pNR,0Rii, -OP(O)(OR7)2, or -SP(O)(OR7)2, - ORA, -SRB, or -N(Rc)2;
RA is a hydroxyl protecting group; RB is a thiol protecting group, Rc, for each occurrence, is H or an amine protecting group, provided at least one R0 is an amine protecting group; and p is 0, 1, or 2; n is zero or an integer from 1 to 4.
54. The method of any one of Claims 13-18, wherein ring A is represented by the following Strucutral Formula:
Figure imgf000204_0002
wherein:
Re, for each occurrence, is independently a substituent selected from:
-OR1,,, -NHRp3, -N(Rp3)2, -O(CH2)mORp,, or -(CHj)1nORp1; 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, -NR10Ri i , -OR7, -O(CH2)mNR7Rp3, -C(O)R7, -C(O)OR7;
-C(O)NR10R..; -OC(O)R7, -OC(O)OR7, -OC(O)NR10R, .; -NR8C(O)R7, -NR7C(O)NR10Rn, -NR7C(O)OR7; -S(O)-R7, -OS(O)PR7, -OS(0)POR7, -OS(O)PNR10R11, -S(O)POR7, -S(O)pNR10Rπ, -NR8S(O)11R7, -NR7S(O)pNRI0R,,, or -NR7S(O)POR7; and n is zero of an integer from 1 to 4;
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 Rio 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)NR10R11; and p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
55. The method of Claims 19-26, wherein ring A is represented by the following Strucutral Formula:
Figure imgf000206_0001
wherein: Re, for each occurrence, is independently 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 heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy, protected hydroxyalkyl, haloalkoxy, -NRi0Ri i, -ORioo, -C(O)R7, or -SRioi; or two Rs groups taken together with the carbon atoms to which they are attached form a fused ring; and n is zero of an integer from 1 to 4.
56. The method of Claim 53, wherein R5 is an optionally substituted phenyl, wherein the phenyl group is substituted with: i) one substituent selected from nitro, cyano, a haloalkoxy, 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, guanadino, -NRi0Ri i (provided R10 and Rn are not -H) -O-R20, -SR7 (provided R7 is not H), -S(O)PR7, -OS(O)PR7, -NRgS(O)pR7, -S(O)pNR10Rι ,, -OP(O)(OR7)2, -SP(O)(OR7)2, -ORA, -SRB, or -N(Rc)2; or ii) two to five substituents 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, -F, -Br5 -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0Ri i (provided Rio and Rn are not H) -OR7-SR7, -S(O)PR7, -OS(O)PR7, -NRsS(O)pR7, -S(O)PNR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2, -S(O)POR7; -ORA, -SRB, or -N(Rc)2.
57. The method of Claim 54, wherein R5 is an optionally substitututed phenyl, wherein the phenyl group is substituted with one to five substitutuents selected from the group consisting of the group consisting Of-ORp1, -NHRp3, -N(Rp3)2, -O(CH2)mORpi, or -(CH2)mORpi; 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; -NR10Rn, or -OR7; -O(CH2)mNR7Rp3; -C(O)R7, -C(O)OR7; -C(O)NR10Rn; -OC(O)R7, -OC(O)OR7, -OC(O)NR10R,,; -NR8C(O)R7, or -NR7C(O)NR10R1 , ;
-NR7C(O)OR7; -S(O)PR7, -OS(O)pR7, -OS(O)POR7, -OS^pNR^R,,, -S(O)POR7, -S(O)pNR10Rπ; -NRsS(O)pR7, -NR7S(O)PNR10R11, and -NR7S(O)POR7.
58. The method of Claim 55, wherein R5 is an optionally sustituted phenyl, wherein the phenyl group is substituted with: i) the one substituent selected from the group consisting of nitro, cyano, a haloalkoxy, 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, protected hydroxylalkyl, alkoxyalkyl, guanadino, — OR100, -SRioi, -N(RiM)2, -NR10R1], -OR7, and -C(O)R7; or ii) two to five substituents 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, protected hydroxyalkyl, alkoxyalkyl, -F, -Br5 -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, — ORioo, — SRj oi, ■ N(R102)2, -NR10RiU -OR100, and -C(O)R7.
59. The method of Claim 53, wherein ring A is represented by the following Structural Formula:
Figure imgf000208_0001
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 heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR10Rn (provided Rio and Rn are not -H), -OR7 (provided R7 is not H), -C(NR8)OR7, -C(NR8)NRi0R,,, -C(NR8)SR7, -OC(S)OR7, -OC(NR8)OR7, -SC(NR8)OR7-SC(S)OR7, -OC(S)NRi0Rn, -OC(NR8)NR10Rn, -SC(NR8)NR10R11, -SC(S)NR10Rii, -OC(NR8)R7, -SC(NR8)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(NR8)OR7, -NR7C(S)NRi0R11, -NR7C(NR8)NR10R11, -SR7 (provided R7 is not H), -S(O)nR7, -OS(O)PR7, -OS(O)pNR10Rπ, -S(O)POR7, -NR8S(OpR7, -NR7S(O)PNR10R11, -NR7S(O)POR7, -S(O)pNR,0Rπ, -SS(O)PR7, -SS(O)POR7, -SS(O)PNR10R1 „ -OP(O)(OR7)2, or -SP(O)(OR7)2, - ORA, -SRB, Or-N(Rc)2; and r is zero or an integer from 1 to 3.
60. The method of Claim 59, wherein R25 is -ORA, -SRB, -N(Rc)2, -OC(S)OR7, -OC(NR8)OR7, -SC(NR8)OR7, -SC(S)OR7, -OC(S)NR10R1 ,, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -OS(O)PR7, -S(O)POR7, -SS(O)POR7, -SS(O)PR7, -OP(O)(OR7)2, or -SP(O)(OR7)2, wherein p is O, 1, or 2.
61. The method of Claim 54, wherein ring A is represented by the following Structural Formula:
Figure imgf000209_0001
wherein:
R25 is:
-ORpl, -NHRp3, -N(Rp3)Z, .0(CHa)1nORp1, or -(CH2)H1ORp1; 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)raNR7Rp3, -C(O)R7, -C(O)OR7; -C(O)NR10Ri1; -OC(O)R73 -OC(O)OR7, -OC(O)NR10R11; -NR8C(O)R7, -NR7C(O)NR10Rn, -NR7C(O)OR7; -S(O)PR7, -OS(O)PR7> -OS(O)POR7, -OS(O)pNR10Ru, -S(O)POR7, -S(O)-NR10R11, -NRsS(O)pR7, -NR7S(O)pNR10Rπ, or -NR7S(O)POR7; and r is zero or an integer from 1 to 3.
62. The method of Claim 55, wherein wherein ring A is represented by the following Structural Formula:
Figure imgf000209_0002
wherein:
R2S is 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, protected hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0Ri i, -OR10O, and -C(O)R7; and r is zero or an integer from 1 to 3.
63. The method of Claim 53, wherein R5 is represented by the following Structural Formula:
Figure imgf000210_0001
wherein:
R33 is a halo, a lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, or lower alkyl sulfanyl;
R34 is H, or a lower alkyl; and
Ring B and Ring C are optionally substituted with one or more substituents in addition to R33 and R34.
64. The method of Claim 54, wherein ring A is represented by the following Structural Formula:
Figure imgf000210_0002
wherein:
R33 is H, -ORpi, -NHRp3, -N(Rp3)2, a halo, a lower alkyl, a lower alkoxy, a lower haloalkyl, or a lower haloalkoxy; R34 is H5 -ORpi, -NHRp3, -N(Rp3)2, a Cl -C6 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.
65. The method of Claim 64, wherein R25 is a -ORpi, -NHRp3, -N(Rp3)2j -0(CHa)nORp1, or -(CHb^ORp,.
66. The method of Claim 65, wherein R33 is H3 -ORp], -NHRp3, -N(Rp3)2, -O(CH2)mORpi, or -(CH2)mORpl; and R34 is a C1-C6 alkyl.
67. The method of Claim 55, wherein R5 is represented by the following Structural Formula:
Figure imgf000211_0001
wherein:
R33 is a halo, a lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, or lower alkyl sulfanyl;
R34 is H, or a lower alkyl, or a lower acyl; and
Ring B and Ring C are optionally substituted with one or more substituents in addition to R33 and R34.
68. The method of Claims 59, wherein ring A is represented by the following Structural Formula:
Figure imgf000211_0002
69. The method of Claim 68, wherein R3 and R25 are -ORA-
70. The method of Claim 69 , wherein R6 is a lower alkyl, C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl or -NR]ORU
71. The method of Claim 70, wherein R5 is represented by the following Structural Formula:
Figure imgf000212_0001
wherein Ring D is optionally subsituted.
72. The method of Claim 71, wherein Ri0 and RM are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by -ORA, -CN, -SRA, -N(RC)2, a C1-C6 alkoxy, alkylsulfanyl, dialkylamino or a cycloalkyl; or Rio and Rj i taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl.
73. The method of Claim 72, wherein Rj0 and Ru are each independently a hydrogen, methyl, ethyl, propyl, isopropyl, or taken together with the nitrogen to which they are attached, are:
Figure imgf000212_0002
74. The method of Claim 61, wherein ring A is represented by the following Structural Formula:
Figure imgf000212_0003
75. The method of Claim 74, wherein R2] 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 -NR10R11.
76. The method of Claim 75, wherein R6 is a C1-C6 alkyl and R33 is H.
77. The method of Claim 76, wherein R33 is -H and ring B is unsubstituted.
78. Thβmethod of Claim 77, wherein R2o and R25 are -OH5 and Re is a C1-C6 alkyl.
79. The method of Claim 62, wherein ring A is represented by the following Structural Formula:
Figure imgf000213_0001
80. The method of Claim 79, wherein R3b and R2s are -OR10O5 -SR101, or -N(RiO2)2-
81. The method of Claim 80, wherein Ri is -SH or -OH; R3 and R25 are -ORiooJ and
Figure imgf000213_0002
82. The method of Claim 81, wherein Rg is an optionally subsituted lower alkyl, a C3-C6 cycloalkyl, a lower alkoxy, a lower alkyl sulfanyl or -NR10Rn.
83. The method of any one of Claims 1-12, wherein ring A is represented by the following Structural Formula:
Figure imgf000213_0003
wherein:
X3 and X4 are each, independently, N, N(O), N+(R,7), CH or CR6; and X5 is O5 S, NR17, CH=CH3 CH=CR6, CR5=CH, CR6=CR6, CH=N, CR6=N,
CH=N(O), CR5=N(O), N=CH, N=CR5, N(O)=CH5 N(O)=CR6, N+(Rn)=CH5
Figure imgf000213_0004
or N=N;
Ri7, for each occurrence, is independently — H, an alkyl, an aralkyl; W
- 212 -
R6, for each occurrence, is independently 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 heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRi0Ri i (provided Ri0 and Rn are not — H), -OR7 (provided R7 is not H), -C(NR8)OR7, -C(NRS)NR1ORH, -C(NR8)SR7, -OC(S)OR7, -OC(NR8)OR7, -SC(NR8)OR7-SC(S)OR7, -OC(S)NR, 0Rn, -OC(NR8)NR10RI I, -SC(NRs)NR10Rn, -SC(S)NRi0Ri i, -OCCNR8)R7, -SC(NR8)R7, -NR7C(S)OR7,
-NR7C(NR8)R7, -NR7C(NR8)OR7, -NR7C(S)NRi0Ri i, -NR7C(NR8)NR10RH, -SR7 (provided R7 is not H), -S(O)pR7, -OS(O)PR7, -OS(O)PNR10R11, -S(O)POR7, -NR8S(O)PR7, -NR7S(0)pNR,oRιi, -NR7S(O)pOR7, -S(O)PNRi0Rn, -SS(O)pR7, -SS(O)POR7, -SS(0)pNR,oRu, -OP(O)(OR7)2, or -SP(O)(OR7)2, - ORA, -SRB, Or -N(Rc)2;
RA is a hydroxy! protecting group; R0 is a thiol protecting group, Rc, for each occurrence, is H or an amine protecting group, provided at least one Rc is an amine protecting group; and p is O, 1 , or 2; and n is zero or an integer from 1 to 4.
84. The method of any one of Claims 13-18, wherein ring A is represented by the following Structural Formula:
Figure imgf000214_0001
wherein: X3 and X4 are each, independently, N, N(O), N+(Rn), CH or CR6;
X5 is O, S, NRJ7, CH=CH, CH=CR5, 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+(Rn)=CH, N+(Rn)=CR6, CH=N+(R17), CR6=N+(R17), Or N=N;
R6, for each occurrence, is independently: -ORp1, -NHRp3, -N(RpJ)2, -O(CH2)mORp,, or -(CHj)1nORp,; 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, -NRi0Rn, -OR7, -O(CH2)mNR7Rp3, -C(O)R7, -C(O)OR7; -C(O)NR10Rn; -OC(O)R7, -OC(O)OR7, -OC(O)NR10Ri i; -NR5C(O)R75 -NR7C(O)NR10R1 ,, -NR7C(O)OR7; -S(O)PR7, -OS(O)PR7, -OS(O)POR7,
-OS(O)pNR10Rπ, -S(O)POR7, -S(O)pNR10Rl ls -NR8S(O)11R7, -NR7S(O)13NR10R, ,, or -NR7S(O)POR7; and n is zero or an integer from 1 to 4;
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 Rj j, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R]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.
85. The method of any one of Claims 19-26, wherein ring A is represented by the following Structural Formula:
Figure imgf000216_0001
wherein:
X3 and X4 are each, independently, N, N(O), N+(R17), CH or CR6;
Xs is O, S, NRn, CH=CH, CH=CR6, CR6=CH, CR6=CR6, CH=N5 CR6=N, CH=N(O), CR6=N(O), N=CH, N=CR6, N(O)=CH, N(O)=CR6, N+(Rn)=CH, N+(Rn)=CR5, CH=N+(R17), CR6=N+(R17), or N=N;
R6, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alky], 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, -NRi0Ri u -OR100, -C(O)R7, -C(S)R7, and
Figure imgf000216_0002
or two R6 groups taken together with the carbon atoms to which they are attached form a fused ring;
Ri7, for each occurrence, is independently an alkyl or an aralkyl; and n is zero or an integer from 1 to 4.
86. The method of Claim 83, wherein ring A is selected from the group consisting of:
Figure imgf000216_0003
Figure imgf000217_0001
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 heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR]0Rn (provided Rio and R11 are not -H), -OR7 (provided R7 is not H), -C(NR8)OR7, -C(NR8)NR10RH, -C(NR8)SR7, -OC(S)OR7, -OC(NR8)OR7, -SC(NRs)OR7-SC(S)OR7, -OC(S)NR, 0Rπ, -OC(NRg)NR10R1 I, -SC(NR8)NR10RI 1, -SC(S)NRi0Ri i, -OC(NR8)R7, -SC(NR8)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(NR8)OR7, -NR7C(S)NR10Rn, -NR7C(NR8)NR10R113 -SR7 (provided R7 is not H), -S(O)PR7, -OS(O)PR7, -OS(O)pNRI0Rn, -S(O)POR7, -NR8S(O)PR7, -NR7S(0)pNR,oRπ, -NR7S(O)POR7, -S(O)pNR]0Ri,, -SS(O)pR7s -SS(O)pOR7) -SS(O)pNR]0Rπ, -OP(O)(OR7)2, or -SP(O)(OR7)2, -
Figure imgf000218_0001
The method of Claim 84, wherein ring A is selected from the group consisting of:
Figure imgf000218_0002
wherein: R25 is: -ORp1, -NHRp3, -N(Rp3)2, -O(CH2)mORpb or -(CH2)mORp,; 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, -NR10R11, -OR7, -0(CHz)1nNR7Rp35 -C(O)R7, -C(O)OR7; -C(O)NRi0Ri i; -OC(O)R7, -OC(O)OR7, -OC(O)NR10Rn; -NR8C(O)R7, -NR7C(O)NRi0R1 I, -NR7C(O)OR7; -S(O)PR7> -OS(O)PR7, -OS(O)POR7, -OS(0)pNR,oRπ, -S(O)POR7, -S(O)pNR10R,,, -NRgS(O)pR7, -NR7S(O)pNR10Rιi, or -NR7S(O)POR7.
88. The method of Claim 85, wherein ring A is selected from the group consisting of:
Figure imgf000219_0001
R 3b
Figure imgf000220_0001
wherein:
R25 is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, — ORioo, -SRioi,— N(RI02)23 -NR7R102, -OR26, -SR26, -NR26R102, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OCH2C(O)R7, -SCH2C(O)R7, and -NR7CH2C(O)R7.
The method of any one of Claims 1-12, wherein ring A is represented by the following Structural Formula:
Figure imgf000220_0002
Rs is represented by the following Structural Formula:
Figure imgf000220_0003
wherein:
X4I iS O3 S3 Or NR42;
X42 is CR44 or N;
Y40 is N or CR43;
Y41 Js N Or CR45;
Y42. for each occurrence, is independently N, C or CR46; R4I is -H, -ORA, -SRB, an optionally substituted alky I, 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, -NR!0Ri [(provided R1O and Rn are not H), -OR7 (provided R7 is not H), -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR1ORH, -C(NR8)SR7, -OC(S)OR7, -OC(NR8)OR7, -SC(NR8)OR7, -SC(S)OR7, -OC(S)NRi0R,,, -OC(NR8)NR1ORi], -SC(NR8)NRiORi i, -SC(S)NRi0Ri i, -OC(NR8)R7, -SC(NR8)R7, -NR7C(S)OR7,
-NR7C(NR8)R7, -NR7C(NR8)OR7, -NR7C(S)NR10RH, -NR7C(NRS)NRIORI 1, -SR7 (provided R7 is not H), -S(O)PR7, -OS(O)PR7, -OS(O)pNR|0Rn, -S(O)POR7, -NR8S(O)PR7, -NR7S(0)pNR,oR,,, -NR7S(O)POR7, -S(O)pNR,0Rn, -SS(O)PR7, -SS(O)POR7, -SS(O)PNR10R1 ,, -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, a haloalkyl, a heteroalkyl, -S(O)PR7, or -S(O)pNRi0Rπ;
R43 and R44 are, independently, -H, -ORA, 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, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -SR7 (provided R7 is not H), -S(O)pR7, -OS(O)PR7, -NRj)S(O)pR7, -S(0)pNRioRπ, 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, -ORA, -SR5, -N(RC)2, -OR26, -SR26, -O(CH2)mORA, -O(CH2)mSRB, -O(CH2)mNR7Rc, -S(CH2)mORA, -S(CH2)mSRB, -S(CHz)1nNR7Rc, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)pNR10R, 1, -SS(0)pNR,oRn, -NR7S(O)pNR,0Rii, -SS(O)pOR7, -NR7S(O)15OR7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRI0RI i, -SC(S)NRj0Ru, -NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NRg)NRi0RiI, or -NR7C(NR8)NRi oRin R)6, for each occurrence, is independently, selected from the group consisting 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, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRioRπ (provided R]0 and Rn are not H), -OR7 (provided R7 is not H), -SR7 (provided R7 is not H), -S(O)PR7, -OS(O)PR7, -NRsS(O)pR7, or -S(O)PNRi0R11.
90. The method of Claim 89, wherein X4 j is NR42 and X42 is CR44.
91. The method of Claim 89, wherein X4j is NR42 and X42 is N.
92. The method of Claim 89, wherein R4] is selected from the group consisting of — H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
•93. The method of Claim 89, wherein R4I is selected from the group consisting of
H, methyl.ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
94. The method of Claim 89, wherein X4] is NR42, and R42 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, wherein each R27 is independently -H or a lower alkyl.
95. The method of Claim 89, wherein X4i 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.
96. The method of Claim 89, wherein R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
97. The method of Claim 89, 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.
98. The method of Claim 97, wherein R43 and R44 together with the carbon atoms to which they are attached form a Cs-C8 cycloalkenyl or a C5-Cg aryl.
99. The method of Claim 97, wherein R45 or CR45 is selected from the group consisting of -H, -ORA, -SRB, -N(RC)2, a lower alkoxy, and a lower dialkyl amino.
100. The method of Claim 99, wherein R45 is selected from the group consisting of -H, -ORA, methoxy and ethoxy.
101. The method of claim 97, wherein X4i is O.
102. The method of Claims 13-18, wherein ring A is represented by the following Stuctural Formula:
Figure imgf000223_0001
R5 is represented by the following Structural Formula:
Figure imgf000223_0002
wherein: X41 is O, S, OrNR42;
X42 is CR44 or N;
Y40 is N or CR43;
Y4I is N or CR45;
Y42i for each occurrence, is independently N, C or CR46; R4, is -H, -ORpl, -NHRp3, -N(R^)2, -O(CH2)mORplf or -(CH2)mORp,; 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, -NR]0Rn, -OR7, -O(CH2)mNR7RP3, -C(O)R7, -C(O)OR7; -C(O)NR10R11; -OC(O)R7, -OC(O)OR7, -OC(O)NR10R11; -NR8C(O)R7, -NR7C(O)NR10RH, -NR7C(O)OR7; -S(O)PR7,
-OS(O)PR7, -OS(O)POR7, -OS(O)11NR10R11, -S(O)POR7, -S(O)pNR10Ri ,, -NR8S(O)11R7, -NR7S(O)13NR10R11, or -NR7S(O)POR7;
R42 is -H5 -ORpl, -NHRp3, -N(Rp3)2, -O(CH2)mORpl, or -(CHz)1nORp1; 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, -NRi0R, u -OR7, -O(CH2)mNR7Rp3, -C(O)R7, -C(O)OR7;
-C(O)NR10R11; -OC(O)R7, -OC(O)OR7, -OC(O)NR10R, ,; -NR8C(O)R7, -NR7C(O)NR10R11, -NR7C(O)OR7; -S(O)PR7, -OS(O)PR7, -OS(O)POR7, -OS(O)pNR10R,,, -S(O)POR7, -S(O)pNR10Rn, -NR8S(O)PR7, -NR7S(O)11NR1OR11, or -NR7S(O)POR7; R43 and R44 are, independently, -H, -ORp,, -NHRp3, -N(Rp3)2,
-O(CH2)mORpi, or -(CH2)mORp,; an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloaJkyl, 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, -NR10R1,, -OR7, -0(CH2)H1NR7Rp3, -C(O)R7, -C(O)OR7; -C(O)NR10Rn; -OC(O)R7, -OC(O)OR7, -OC(O)NRj0R11; -NR5C(O)R7, -NR7C(O)NR10R11, -NR7C(O)OR7; -S(O)PR7, -OS(O)PR7, -OS(O)POR7, -OS(O)PNR10R1 ,, -S(O)POR7, -S(O)pNR10R,,, -NRgS(O)pR7, -NR7S(O)11NR10R11, 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, -ORp1, -NHRp3, -N(Rp3)2, -O(CH2)mORpl, or -(CH2)mORpI; 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, -NRi0Rn, -OR7, -O(CH2)mNR7Rp3, -C(O)R7, -C(O)OR7; -C(O)NR10Rn; -OC(O)R7, -OC(O)OR7, -OC(O)NR]0Rn; -NR8C(O)R7, -NR7C(O)NR10R, ,, -NR7C(O)OR7; -S(O)PR7, -OS(O)PR7, -OS(O)POR7,
-OS(O)pNRi0R,,, -S(O)POR7, -S(O)pNR,0Rn, -NR8S(O)11R7, -NR7S(O)pNR,0Riis 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;
Ri7, for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R7, -C(O)OR7, or -C(O)NRi0Ri i; and p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
103. The method of Claim 102, wherein X4, is NR42 and X42 is CR44.
104. The method of Claim 102, wherein X4, is NR42 and X42 is N.
105. The method of Claim 102, wherein Rn is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
106. The method of Claim 102, wherein R41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
107. The method of Claim 102, wherein X41 is NR42, and R42 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, -C(O)N(R27)2, and -R0 , wherein R0 is a protected carboxyl group, and each R27 is independently -H or a lower alkyl.
108. The compound of Claim 102, 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, -R0, -(CH2)mRc, -CH2OCH3, -CH2CH2OCH3, and -C(O)N(CH3)2, wherein R0 is a protected carboxyl group and m is 1 or 2.
109. The method of Claim 102, wherein R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
110. The method of Claim 102, 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.
1 1 1. The method of Claim 110, wherein R43 and R44 together with the carbon atoms to which they are attached form a C5-C8 cycloalkenyl or a C3-C8 aryl.
112. The method of Claim 110, wherein R45 or CR45 is selected from the group consisting of -H, -ORpi, -SRp2, -NHRp3, -N(Rp3)2, a lower alkoxy, -(CH2)m- NHRp3, and -(CH2)m-N(Rp3)2, wherein m is an integer from 1 to 6.
113. The method of Claim 1 10, wherein R45 is selected from the group consisting of -H, -ORpi, methoxy and ethoxy.
114. The method of claim 110, wherein X4] is O. The method of any one Claims 19-26, wherein ring A is represented by the following Structural Formula:
Figure imgf000227_0001
R.5 is represented by the following Structural Formula:
Figure imgf000227_0002
wherein:
X4] is O5 S, Or NR42;
X42 is CR44 or N;
Y40 is N or CR43; Y41 Js N Or CR45;
Y42, for each occurrence, is independently N, C or CR^;
R4I is selected from the group consisting of -H5 a lower alkyl, a lower alkoxy, a lower cycloalkyl and a lower cycloalkoxy;
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, protected hydroxyalkyl that is optionally substituted, an optionally substituted alkoxyalkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, and -C(O)R7;
R43 and R44 are, independently, -H, -ORJOO, -N(RiO2)2> 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, protected hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -C(O)R7, or -SRioi; 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 -H5 -OR1OO1 -SR1O1, -N(R102) 2, -O(CH2)mORI00, -O(CH2)mSR101, -O(CH2)mN(RI02)2, -NR10R11, S(CH2)mOR100, -S(CH2)mSR101, -S(CH2)roN(R102)2, -OCH2C(O)R7, -SCH2C(O)R7, or -NR7CH2C(O)R7; and
R46, for each occurrence, is independently, selected from the group consisting 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, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10Rn, -OR10O, -C(O)R7, and -SR101; and or two R46 groups taken together with the carbon atoms to which they are attached form a fused ring.
116. The method of Claim 115, wherein X41 is NR42 and X42 is CR44 or N.
117. The method of Claim 1 16, wherein X41 is NR42, and R42 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, and an optionally substituted alkyl.
118. The method of Claim 116, 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, heteroaryl ring.
119. The method of Claim 118, R45 is selected from the group consisting of -H, -OR1Oo, -SRi01, and -N(RiO2) 2, a lower alkoxy and a protected lower alkyl amino.
120. The method of Claim 89, wherein R5 is represented by the following Structural Formula:
Figure imgf000228_0001
121. The method of Claim 120, wherein X42 is CR44.
122. The method of Claim 121, wherein R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propy, isopropyl, cyclopropyl, methooxy, ethoxy, propoxy, and cyclopropoxy.
123. The method of Claim 121 , wherein R43 and R44 taken together with the carbon atoms to which they are attached, form a cycloalkyenyl, aryl, heterocyclyl, or heteroaryl ring.
124. The method of Claim 123, wherein R43 and R44, taken together with the carbon atoms to which they are attached, form a Cs-Cg cycloalkyenyl or a Cs-Cg aryl.
125. The method of Claim 120, wherein X42 is N.
126. The method of Claim 120, wherein:
Figure imgf000229_0001
N;
R41 is selected from the group consisting of — H, methyl, ethyl, isopropyl, and cyclopropyl; R42 is selected selected from the group consisting of -H, methyl, ethyl, n- propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CH2)2OCH3;
R43 and R44 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 R45 is selected from the group consisting of -H, -OCH35-OCH2CH3 and -
ORA.
127. The method of Claim 102, wherein R5 is represented by the following Structural Formula:
Figure imgf000229_0002
128. The method of Claim 127, wherein X42 is CR44, and R43 and R44 are, independently,1 selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
129. The method of Claim 128, 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.
130. The method of Claim 127, wherein R43 and R44, taken together with the carbon atoms to which they are attached, form a C5-C8 cycloalkenyl or a Cs-Ce aryl.
131. The method of Claim 127, wherein X42 is CR44.
132. The method of Claim 127, wherein X42 is N.
133. The method of Claims 115, wherein R5 is represented by the following Structural Formula:
Figure imgf000230_0001
134. The method of Claim 133, wherein X42 is CR44, and R43 and R44 are, independently, -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, cyclopropoxy, or, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring.
135. The method of Claim 134, wherein R^ is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl.
136. A method of preparing a triazole compound represented by the following Structural Formula:
Figure imgf000231_0001
or a tautomer, a pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, comprising the steps of reacting in a reaction mixture an amide represented by the following Structural Formula:
Figure imgf000231_0002
with a thionation reagent to form a thioamide represented by the following Structural Formula:
Figure imgf000231_0003
wherein RA is a hydroxyl protecting group.
137. The method of Claim 136, wherein the thionation reagent is Lawesson's reagent.
138. The method of Claim 137, further comprising the step of washing the reaction mixture with a water soluble amine after completion of the reaction.
139. The method of Claim 138, wherein the water soluble amine is aqueous ammonium hydroxide.
140. The method of Claim 136, further comprising the steps of: a) reacting the thioamide with hydrazine to form a hydrazonamide represented by the following structural formula:
Figure imgf000232_0001
b) reacting the hydrazonamide of step a) with a carbonylation reagent to form the triazole compound.
141. A method of preparing a triazole compound of Structural Formula (XXA), or a tautomer, a pharmaceutically acceptable salt, solvate, or clathrate or a prodrug thereof, comprising reacting a compound of Structural Formula (XXIA):
Figure imgf000232_0002
(XXIA) with an oxidizing agent, thereby producing a compound of Structural Formula (XXA):
Figure imgf000232_0003
(XXA) wherein Rpi, for each occurrence, is independently selected from groups suitable for protecting hydroxyl.
142. The method of Claim 141, wherein Rp] is a benzyl group.
143. The method of Claim 141, wherein the oxidizing agent is K3Fe(CN)6, MnO2, Br2, N-bromosuccinimide or N-chlorosuccinimide.
144. ' The method of Claim 141, wherein the compound of Structural Formula (XXIA) is prepared by reacting a compound of Structural Formula (XXIIA)
Figure imgf000233_0001
(XXIIA) with a compound of Structural Formula (XXIIIA)
Figure imgf000233_0002
(XXΠIA) in the presence of an acid catalyst.
145. The method of Claim 141, further comprising a step of deprotection of a compound of formula (XXA)
(XXA) thereby producing a compound of formula (XXIVA):
Figure imgf000233_0004
(XXlVA)
146. A method of preparing a triazole compound represented by the following Structural Formula:
Figure imgf000234_0001
or a tautomer, a pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein the method comprises the step of reacting a first starting compound represented by the following Structural Formula:
Figure imgf000234_0002
with a second starting compound represented by the following structural formula
Figure imgf000234_0003
wherein each Rioo, independently, is a hydroxyl protecting group; and R50 is an alkyl.
147. The method of Claim 146, further comprising the step of deprotecting the compound, thereby forming a triazole compound represented by the following ' Structural Formula:
Figure imgf000235_0001
148. The method of Claim 146, wherein the second starting compound is prepared by reacting a thionation reagent with a compound represented by the following Structural Formula:
Figure imgf000235_0002
149. The method of Claim 148, wherein the thionation reagent is Lawesson's Reagent, tetraphosphorus pentasulfide, Scheeren's reagent, P4Si0-N(ethyl)3, Davy's Reagent or Heimgarner's reagent.
150. The method of Claim 148, wherein the thionation reagent is Lawesson's Reagent.
151. A compound represented by the following Structural Formula:
Figure imgf000235_0003
wherein:
Z is S or N-NH2; ring A is an aryl or a heteroaryl optionally substituted with one or more substituents in addition to R3; R3 is -OR26, -SR26, -O(CH2)mORA, -O(CH2)mSRB, -O(CH2)mNR7Rc,
-S(CH2)mORA, -S(CH2)mSRB, -S(CH2)mNR7Rc, -OS(O)PR7, -SS(O)PR7, -S(O)POR7> -NR7S(COpR7, -OS(O)PNR1OR111 -SS(O)PNR1ORI I, -NR7S(O)pNR10Rπ5 -SS(O)POR7, -NR7S(O)POR7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRi0R11, -SC(S)NR10RI I, -NR7C(S)NR1ORU5 -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7,
-NR7C(NR8)OR7, -OC(NR8)NR10R1 I5 -SC(NR8)NR1ORI I5 -NR7C(NR8)NRI0R115 -OP(O)(OR7)2, or -SP(O)(OR7J2, -ORA, -SR05 NR7Rc, NR26Rc or N(Rc)2, wherein RA is a hydroxyl protecting group; RB is a thiol protecting group, Rc, for each occurrence, is H or an amine protecting group, provided at least one Rc is an amine protecting group;
R5 is an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted cycloaliphatic, or an optionally substituted alkyl;
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 R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a C1-C6 alkyl; p, for each occurrence, is, independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
152. A compound represented by the following Structural Formula (IIA):
Figure imgf000237_0001
(HA) 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;
R20 is -ORpi, -NHRp3 or -N(Rp3)2, wherein Rpi, for each occurrence, is independently selected from groups suitable for protecting hydroxyl, and Rp3, for each occurrence, is independently selected from groups suitable for protecting an amino group;
R2i is O, NH, or NR26, and R2ia is OH, NH2 or NHR26; and R26 is a Cl -C6 alkyl.
153. A method comprising the step of deprotecting a compound represented by the following Structural Formula:
Figure imgf000237_0002
thereby producing a deprotected product represented by the following Structural Formula:
Figure imgf000237_0003
wherein:
R, is -OH, -SH or -NHR7; ring A is an aryl or a heteroaryl optionally further substituted with one or more substituents in addition to R3; R3 is ORA, SRB, NR7R0, NR26RC or N(Rc)2, wherein RA is a hydroxy! protecting group; RB is a thiol protecting group, Rc, for each occurrence, is H or an amine protecting group, provided at least one Rc is an amine protecting group; 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;
R7 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, or an optionally substituted heteraralkyl;
R26 is a Cl -C6 alkyl; p, for each occurrence, is, independently, 0, 1 or 2; m, for each occurrence, is independently, 1, 2, 3, or 4; and X is a leaving group; and
R3' is -OH, -SH, NHR7, NHR25 or NH2.
154. The method of Claim 153, wherein R3 is -ORA, RA is a benzyl group and the step of deprotecting comprises reacting the compound of Structural Formula (I) with ammonium formate in the presence of a hydrogen catalyst.
155. A method comprising the step of deprotecting a compound represented by the following Structural Formula:
Figure imgf000238_0001
thereby producing a deprotected product represented by the following Structural Formula:
Figure imgf000239_0001
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;
R20 is -ORpi, -NHRp3 or -N(RP3)2, wherein Rpi, for each occurrence, is independently selected from groups suitable, for protecting hydroxyl, and Rp3, for each occurrence, is independently selected from groups suitable for protecting an amino group; R21 is O, NH, or NR26;
Figure imgf000239_0002
R22 is -OH, or -NH2; and R26 is a Cl-C6 alkyl.
156. The method of Claim 155, wherein R20 is -ORpi, Rpi is a benzyl group and the step of deprotecting comprises reacting the compound of Structural Formula (IA) with ammonium formate in the presence of a hydrogen catalyst.
157. A method comprising the step of deprotecting a compound represented by the following Structural Formula:
Figure imgf000239_0003
thereby producing a deprotected product represented by the following Structural Formula:
Figure imgf000240_0001
wherein:
Rib is -OH, -SH or -NHR60, wherein R^o is H, an optionally substituted alkyl group, or an optionally substituted cycloalkyl group; ring A is an aryl or a heteroaryl, wherein the aryl group and the heteroaryl group represented by ring A is optionally further substituted with one or more substituents in addition to R3;
R3 is -OR10O, -SRioi, -N(Ri02*., -NR7R102, or -NR26RiO2; each R10O, independently, is a hydroxyl protecting group; each R101, independently, is a thiol protecting group; each R1023 independently, is — H or an amino protecting group, provided that at least one group represented by R102 is a protecting group;
R5 is an optionally substituted aryl group, an optionally substituted heteroarylgroup, an optionally substituted cycloalkyl group, an optionally substituted cycloakenyl group, or a substituted alkyl group, wherein each of the aryl group, heteroaryl group, cycloaryl group, cycloalkyl group, cycloalkenyl group, and alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkyl group, an optionally substituted alkynyl, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted heteroaryl group, an optionally substituted aralyalkyl group, or an optionally substituted heteraralkyl group;
R7 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, or R7, taken together with the oxygen atom to which it is bonded, forms an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a C1-C6 alkyl group; R5O 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, or an optionally substituted heteraralky;
Figure imgf000241_0001
p, for each occurrence, is, independently, 0, 1 or 1; m, for each occurrence, is, independently, 1, 2, 3, or 4; and
R3b' is -OH, -SH, -NH2, -NHR7 Or-NHR26
158. The method of Claim 157, wherein R3b is -ORioo, Rioo is a benzyl group and the step of deprotecting comprises reacting the compound of Structural Formula (IB) with ammonium formate in the presence of a hydrogen catalyst.
159. The method of any one of Claims 154, 156 or 158, wherein the hydrogen catalyst is palladium on activated carbon.
160. The method of Claim 159, wherein the step of deprotecting is carried out at about 55 0C.
161. The method of Claim 160, wherein the compound of Structural Formula (I), (IA) or (IB) and the ammonium formate are reacted for about 1 hour in the presence of the palladium on activated carbon.
162. The method of any one of Claims 153, 155 or 157, wherein the purity of the deprotected product is 99.0 % or greater.
163. The method of Claim 162, wherein the purity is 99.5% or greater.
164. The method of Claim 162, wherein the purity is 99.8% or greater.
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