WO2024026359A1 - Composés et méthodes pour le traitement de maladies associées à des vers parasites - Google Patents

Composés et méthodes pour le traitement de maladies associées à des vers parasites Download PDF

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WO2024026359A1
WO2024026359A1 PCT/US2023/071043 US2023071043W WO2024026359A1 WO 2024026359 A1 WO2024026359 A1 WO 2024026359A1 US 2023071043 W US2023071043 W US 2023071043W WO 2024026359 A1 WO2024026359 A1 WO 2024026359A1
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Prior art keywords
substituted
compound
unsubstituted
alkyl
tgr
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PCT/US2023/071043
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English (en)
Inventor
Pavel Petukhov
Valentina PETUKHOV
David Williams
Francesco Angelucci
Samuel ABOAGYE
Matteo ARDINI
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The Board Of Trustees Of The University Of Illinois
University Of L’Aquila
Rush University Medical Center
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Application filed by The Board Of Trustees Of The University Of Illinois, University Of L’Aquila, Rush University Medical Center filed Critical The Board Of Trustees Of The University Of Illinois
Publication of WO2024026359A1 publication Critical patent/WO2024026359A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A61P33/12—Schistosomicides
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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    • C07C247/00—Compounds containing azido groups
    • C07C247/16—Compounds containing azido groups with azido groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C247/18—Compounds containing azido groups with azido groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members 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
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
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    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
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    • 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
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    • 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
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    • C07D401/14—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 three or more hetero rings
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    • 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
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • Schistosomiasis is a devastating but neglected tropical disease with more than 200 million people infected resulting in more than 200,000 deaths annually. 1, 2 In addition, almost everyone infected has a significant degree of disability. 3 Female genital schistosomiasis is a common complication, occurring in approximately 40 million girls and women, making it one of the most common gynecologic conditions in Africa, and schistosome infections have been implicated as cofactors in the acquisition and transmission of HIV and are a WHO-recognized risk factor for HIV infection. 4, 5 Schistosomiasis control strategies rely almost exclusively on mass drug administration (MDA) using praziquantel (PZQ) monotherapy.
  • MDA mass drug administration
  • PZQ praziquantel
  • the disclosure in one aspect, relates to compounds that are inhibitors for thioredoxin glutathione reductase (TGR), which is key for the survival of parasitic worms and that target TGR in a new regulatory site, named the doorstop pocket.
  • TGR thioredoxin glutathione reductase
  • the compounds described herein treat diseases produced by parasitic worms such as, for example, praziquantel- resistant worms.
  • FIGS.22A-22G show the functional characterization of the inhibitors.
  • Time-dependent activity (DTNB reduction) of TGR in the presence of 50 ⁇ M slow inhibitors 1 (purple), 3 (orange), 4 (black), 5 (blue) compared to TGR activity incubated in the absence of compounds. Average ⁇ standard deviation (n 3) shown.
  • (e) Compound effect on thermal stability of TGR. Melting temperature without (black) or with addition of 500 ⁇ M NADPH (red) of TGR alone or with 100 ⁇ M inhibitor 1, 3, 5, 7, 8, 9 or control compounds 11 or 12. Average ⁇ standard deviation (n 3) shown.
  • FIGS.23A-23D show the schistosomicidal efficacy in mice.
  • each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.
  • a further aspect includes from the one particular value and/or to the other particular value.
  • ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’.
  • the range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’.
  • the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’.
  • the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.
  • a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5%, but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.
  • any value can be a lower and upper endpoint of a range
  • any range is contemplated between 1% and 5% (e.g., 1% to 3%, 2% to 4%, etc.).
  • the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein.
  • IC 50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process.
  • IC 50 refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay.
  • a residue of a chemical species refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species.
  • an ethylene glycol residue in a polyester refers to one or more -OCH 2 CH 2 O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester.
  • a sebacic acid residue in a polyester refers to one or more - CO(CH 2 ) 8 CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.
  • the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described below.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms, such as nitrogen can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • substitution or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted). [0028] The position of a substituent can be defined relative to the positions of other substituents in an aromatic ring.
  • a second substituent can be “ortho,” “para,” or “meta” to the R group, meaning that the second substituent is bonded to a carbon labeled ortho, para, or meta as indicated below. Combinations of ortho, para, and meta substituents relative to a given group or substituent are also envisioned and should be considered to be disclosed.
  • “A 1 ,” “A 2 ,” “A 3 ,” and “A 4 ” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.
  • aliphatic or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • alkyl as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t- butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like.
  • the alkyl group can be cyclic or acyclic.
  • the alkyl group can be branched or unbranched.
  • the alkyl group can also be substituted or unsubstituted.
  • the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • a “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms.
  • alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.
  • alkyl is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group.
  • halogenated alkyl or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine.
  • halogenated alkyl specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine.
  • monohaloalkyl specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine.
  • polyhaloalkyl specifically refers to an alkyl group that is independently substituted with two or more halides, i.e.
  • alkoxyalkyl specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below.
  • aminoalkyl specifically refers to an alkyl group that is substituted with one or more amino groups.
  • hydroxyalkyl specifically refers to an alkyl group that is substituted with one or more hydroxy groups.
  • alkyl is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like. [0033] This practice is also used for other groups described herein.
  • cycloalkyl refers to both unsubstituted and substituted cycloalkyl moieties
  • the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.”
  • a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy”
  • a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like.
  • cycloalkyl is a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like.
  • heterocycloalkyl is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted.
  • the cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • alkanediyl refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen.
  • alkoxy and alkoxyl as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA 1 where A 1 is alkyl or cycloalkyl as defined above.
  • Alkoxy also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA 1 —OA 2 or —OA 1 —(OA 2 ) a —OA 3 , where “a” is an integer of from 1 to 200 and A 1 , A 2 , and A 3 are alkyl and/or cycloalkyl groups.
  • the alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like.
  • heterocycloalkenyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • alkynyl as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond.
  • the alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or
  • cycloalkynyl as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound.
  • cycloalkynyl groups include, but are not limited to, cyclooctynyl, cyclononynyl, and the like.
  • heterocycloalkynyl is a type of cycloalkenyl group as defined above and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted.
  • the cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • aromatic group refers to a ring structure having cyclic clouds of delocalized ⁇ electrons above and below the plane of the molecule, where the ⁇ clouds contain (4n+2) ⁇ electrons.
  • aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “ Aromaticity,” pages 477-497, incorporated herein by reference.
  • aromatic group is inclusive of both aryl and heteroaryl groups.
  • aryl as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like.
  • the aryl group can be substituted or unsubstituted.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, ⁇ NH 2 , carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • biasing is a specific type of aryl group and is included in the definition of “aryl.”
  • the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond.
  • biaryl to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.
  • Fused aryl groups including, but not limited to, indene and naphthalene groups are also contemplated.
  • aldehyde as used herein is represented by the formula -C(O)H.
  • amine or “amino” as used herein are represented by the formula —NA 1A2, where A 1 and A 2 can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a specific example of amino is ⁇ NH 2 .
  • alkylamino as used herein is represented by the formula —NH(-alkyl) and — N(-alkyl) 2 , where alkyl is a described herein.
  • Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group
  • carboxylic acid as used herein is represented by the formula —C(O)OH.
  • esteer as used herein is represented by the formula —OC(O)A 1 or —C(O)OA 1 , where A 1 can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • ether as used herein is represented by the formula A 1 OA 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein.
  • a 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein.
  • halo halogen or halide
  • pseudohalide pseudohalogen or “pseudohalo,” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides.
  • heteroalkyl refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.
  • heteroaryl refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group.
  • heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions.
  • the heteroaryl group can be substituted or unsubstituted.
  • the heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2- b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.
  • heterocycle or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon.
  • Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,
  • heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl.
  • a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like.
  • a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like.
  • bicyclic heterocycle or “bicyclic heterocyclyl” as used herein refers to a ring system in which at least one of the ring members is other than carbon.
  • Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring.
  • Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms.
  • Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro- 1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2- b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl.
  • heterocycloalkyl refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems.
  • the heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted.
  • heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • hydroxyl or “hydroxy” as used herein is represented by the formula —OH.
  • ketone as used herein is represented by the formula A 1 C(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • Azide or “azido” as used herein is represented by the formula —N 3 .
  • nitro as used herein is represented by the formula —NO2.
  • nitrile or “cyano” as used herein is represented by the formula —CN.
  • sil as used herein is represented by the formula —SiA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfo-oxo is represented by the formulas —S(O)A 1 , —S(O) 2 A 1 , —OS(O) 2 A 1 , or —OS(O) 2 OA 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfonyl is used herein to refer to the sulfo-oxo group represented by the formula —S(O) 2 A 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a 1 S(O) 2 A 2 is represented by the formula A 1 S(O) 2 A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfoxide as used herein is represented by the formula A 1 S(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • thiol as used herein is represented by the formula -SH.
  • R 1 ,” “R 2 ,” “R 3 ,”... “R n ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above.
  • R 1 is a straight chain alkyl group
  • one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like.
  • a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group.
  • an alkyl group comprising an amino group the amino group can be incorporated within the backbone of the alkyl group.
  • the amino group can be attached to the backbone of the alkyl group.
  • the nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
  • Suitable monovalent substituents on R° are independently halogen, -(Ci_ 4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci ⁇ aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR* 2 ) 2-3 O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R* include halogen, ( ) wherein each is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R ⁇ , –NR ⁇ 2 , –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH 2 C(O)R ⁇ , –S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2 , –C(S)NR ⁇ 2 , –C(NH)NR ⁇ 2 , or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, –R z , -(haloR z ), –OH, –OR z , –O(haloR z ), –CN, –C(O)OH, –C(O)OR z , –NH 2 , –NHR z , –NR z 2, or –NO 2 , wherein each R z is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons.
  • suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.
  • Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.
  • a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture.
  • Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included.
  • stereoisomers For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another.
  • a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture.
  • Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*).
  • bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula.
  • bonds to the chiral carbon when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane).
  • the Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
  • Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance.
  • the disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds further comprise prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • the compounds described in the invention can be present as a solvate.
  • the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate.
  • the compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution.
  • one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates.
  • the invention includes all such possible solvates.
  • certain compounds described herein can be present as an equilibrium of tautomers.
  • ketones with an ⁇ -hydrogen can exist in an equilibrium of the keto form and the enol form.
  • amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form.
  • the invention includes all such possible tautomers.
  • a structure of a compound can be represented by a formula: , [0082] which is understood to be equivalent to a formula: , [0083] wherein n is typically an integer.
  • R n is understood to represent five independent substituents, R n(a) , R n(b) , R n(c) , R n(d) , and R n(e) .
  • independent substituents it is meant that each R substituent can be independently defined. For example, if in one instance R n(a) is halogen, then R n(b) is not necessarily halogen in that instance.
  • administering can refer to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, intracavernous, intrathecal, intravireal, intracerebral, and intracerebroventricular, intratympanic, intracochlear, rectal, vaginal, by inhalation, by catheters, stents or via an implanted reservoir or other device that administers, either actively or passively (e.g.
  • a composition the perivascular space and adventitia can contain a composition or formulation disposed on its surface, which can then dissolve or be otherwise distributed to the surrounding tissue and cells.
  • parenteral can include subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques. Administration can be continuous or intermittent.
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.
  • a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
  • subject can refer to a vertebrate organism, such as a mammal (e.g. human).
  • Subject can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to human and constituents thereof.
  • the terms “treating” and “treatment” can refer generally to obtaining a desired pharmacological and/or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as a hematological malignancy, breast cancer, and/or another solid malignancy.
  • the effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder, or condition.
  • treatment can include any treatment of a hematological malignancy, breast cancer, and/or another solid tumor in a subject, particularly a human and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and/or its symptoms or conditions.
  • treatment can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment.
  • Those in need of treatment can include those already with the disorder and/or those in which the disorder is to be prevented.
  • the term “treating” can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition.
  • Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.
  • therapeutic can refer to treating, healing, and/or ameliorating a disease, disorder, condition, or side effect, or to decreasing in the rate of advancement of a disease, disorder, condition, or side effect.
  • an effective amount can refer to the amount of a disclosed compound or pharmaceutical composition provided herein that is sufficient to effect beneficial or desired biological, emotional, medical, or clinical response of a cell, tissue, system, animal, or human.
  • An effective amount can be administered in one or more administrations, applications, or dosages. The term can also include within its scope amounts effective to enhance or restore to substantially normal physiological function.
  • the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the invention (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.
  • a response to a therapeutically effective dose of a disclosed compound and/or pharmaceutical composition for example, can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following administration of the treatment or pharmacological agent.
  • the amount of a treatment may be varied for example by increasing or decreasing the amount of a disclosed compound and/or pharmaceutical composition, by changing the disclosed compound and/or pharmaceutical composition administered, by changing the route of administration, by changing the dosage timing and so on. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. [0091] As used herein, the term “prophylactically effective amount” refers to an amount effective for preventing onset or initiation of a disease or condition.
  • the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.
  • pharmaceutically acceptable describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.
  • pharmaceutically acceptable salts means salts of the active principal agents which are prepared with acids or bases that are tolerated by a biological system or tolerated by a subject or tolerated by a biological system and tolerated by a subject when administered in a therapeutically effective amount.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include, but are not limited to; sodium, potassium, calcium, ammonium, organic amino, magnesium salt, lithium salt, strontium salt or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include, but are not limited to; those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • prodrug represents those prodrugs of the compounds of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • Prodrugs of the present disclosure can be rapidly transformed in vivo to a parent compound having a structure of a disclosed compound, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V.
  • dose can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and/or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.
  • dose can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and/or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.
  • dose can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and/or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.
  • Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art.
  • the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St.
  • A-D a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention.
  • compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result. [0101] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
  • a compound having a structure according to structure I or the pharmaceutically acceptable salt thereof [0104] A compound of formula I or a pharmaceutically acceptable salt thereof wherein is substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, or substituted or unsubstituted alkenyl; is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted C1-C6 alkyl; R1 and R2 are independently absent, H, halide, azide, nitro, cyano, amino, hydroxyl, carboxy, amido, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 este
  • formula I is a unsubstituted heteroaryl, substituted or unsubstituted aryl selected from where L1 in formula I can be bonded to any position of the aryl or heteroaryl ring.
  • formula I is wherein R 1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, and R 7 is H or substituted or unsubstituted C 1 -C 6 alkyl.
  • R 1 in the structures above is substituted or unsubstituted phenyl.
  • R 7 in the structures above is H or methyl.
  • n is an integer from 1 to 4; and R 8 and R 9 are independently absent, H, halide, azide, nitro, cyano, amino, amido, hydroxy, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 ester, C 1 -C 4 alkenyl, or C 1 -C 6 alkynyl, C 1 -C 6 alkyl amino, C 1 -C 6 alkyl amido, C 1 -C 6 alkyl hydroxy, C 1 -C 6 alkyl ether, substituted or unsubstituted aryl, arylalkyl, substituted or unsubstituted heteroaryl, heteroarylalkyl, cycloalkyl,
  • L 1 is absent or is straight or branched C 1 -C 4 alkylene or C 1 -C 4 alkenyl.
  • L 1 -CH 2 - is optionally substituted with an amide group, an ester group, or a carbonyl group, heteroaryl, aryl, an amide, or an ester.
  • L 1 can be represented by the formula -(CH 2 ) m -X- or -X-(CH 2 ) m -, where m is from 1 to 4 and X is an amide group, an ester group, or a carbonyl group, heteroaryl, aryl, an amide, or an ester.
  • R 4 and R 5 in formula I are independently H, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, C 1 -C 4 alkyl, oxo, carboxyl, or phenyl.
  • R 1 in structure III is substituted or unsubstituted phenyl.
  • L 1 in structure III is -CH 2 -.
  • Z is NH or O in structure III.
  • R 2 is H.
  • the compound has the structure IVA, IVB, VA, or VB or the pharmaceutically acceptable salt thereof and any stereoisomer thereof
  • L 1 in structure IVA, IVB, VA, or VB is –(CH 2 ) n -, where n is 1, 2, or 3.
  • Z is NH, O, or C(O)NH in structure IVA, IVB, VA, or VB.
  • R 8 in structure IVA, IVB, VA, or VB is H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted cycloalkyl.
  • R 9 in structure IVA, IVB, VA, or VB is H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted cycloalkyl.
  • the compound has the following structure
  • compositions comprising a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof.
  • “pharmaceutically-acceptable carriers” means one or more of a pharmaceutically acceptable diluents, preservatives, antioxidants, solubilizers, emulsifiers, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, and adjuvants.
  • the disclosed pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy and pharmaceutical sciences. [0121]
  • the disclosed pharmaceutical compositions comprise a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutically acceptable carrier, optionally one or more other therapeutic agent, and optionally one or more adjuvant.
  • the disclosed pharmaceutical compositions include those suitable for oral, rectal, topical, pulmonary, nasal, and parenteral administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the disclosed pharmaceutical composition can be formulated to allow administration orally, nasally, via inhalation, parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitoneally, intraventricularly, intracranially and intratumorally.
  • parenteral administration includes administration by bolus injection or infusion, as well as administration by intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular subarachnoid, intraspinal, epidural and intrasternal injection and infusion.
  • the present disclosure also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof.
  • a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes.
  • the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, of the present disclosure can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • the pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
  • the compounds of the present disclosure, and/or pharmaceutically acceptable salt(s) thereof can also be administered by controlled release means and/or delivery devices.
  • the compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
  • compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both.
  • the product can then be conveniently shaped into the desired presentation.
  • unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • a “unit dosage form” is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person administering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages.
  • Typical examples of unit dosage forms are tablets (including scored or coated tablets), capsules or pills for oral administration; single dose vials for injectable solutions or suspension; suppositories for rectal administration; powder packets; wafers; and segregated multiples thereof. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.
  • compositions disclosed herein comprise a compound of the present disclosure (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents.
  • the disclosed pharmaceutical compositions can include a pharmaceutically acceptable carrier and a disclosed compound, or a pharmaceutically acceptable salt thereof.
  • a disclosed compound, or pharmaceutically acceptable salt thereof can also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds.
  • the instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • Techniques and compositions for making dosage forms useful for materials and methods described herein are described, for example, in the following references: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7.
  • the compounds described herein are typically to be administered in admixture with suitable pharmaceutical diluents, excipients, extenders, or carriers (termed herein as a pharmaceutically acceptable carrier, or a carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • suitable pharmaceutical diluents, excipients, extenders, or carriers suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • the deliverable compound will be in a form suitable for oral, rectal, topical, intravenous injection or parenteral administration.
  • Carriers include solids or liquids, and the type of carrier is chosen based on the type of administration being used.
  • the compounds may be administered as a dosage that has a known quantity of the compound.
  • oral administration can be a preferred dosage form, and tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed.
  • other dosage forms may be suitable depending upon clinical population (e.g., age and severity of clinical condition), solubility properties of the specific disclosed compound used, and the like.
  • the disclosed compounds can be used in oral dosage forms such as pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • any convenient pharmaceutical media can be employed.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets can be coated by standard aqueous or nonaqueous techniques.
  • the disclosed pharmaceutical compositions in an oral dosage form can comprise one or more pharmaceutical excipient and/or additive.
  • Non-limiting examples of suitable excipients and additives include gelatin, natural sugars such as raw sugar or lactose, lecithin, pectin, starches (for example corn starch or amylose), dextran, polyvinyl pyrrolidone, polyvinyl acetate, gum arabic, alginic acid, tylose, talcum, lycopodium, silica gel (for example colloidal), cellulose, cellulose derivatives (for example cellulose ethers in which the cellulose hydroxy groups are partially etherified with lower saturated aliphatic alcohols and/or lower saturated, aliphatic oxyalcohols, for example methyl oxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate), fatty acids as well as magnesium, calcium or aluminum salts of fatty acids with 12 to 22 carbon atoms, in particular saturated (for example stearates), emulsifiers, oils and fats
  • auxiliary substances useful in preparing an oral dosage form are those which cause disintegration (so-called disintegrants), such as: cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose or microcrystalline cellulose.
  • Conventional coating substances may also be used to produce the oral dosage form.
  • Plasticizing agents that may be considered as coating substances in the disclosed oral dosage forms are: citric and tartaric acid esters (acetyl-triethyl citrate, acetyl tributyl-, tributyl-, triethyl-citrate); glycerol and glycerol esters (glycerol diacetate, -triacetate, acetylated monoglycerides, castor oil); phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl- phthalate), di-(2-methoxy- or 2-ethoxyethyl)-phthalate, ethylphthalyl glycolate, butylphthalylethyl glycolate and butylglycolate; alcohols (propylene glycol, polyethylene glycol of various chain lengths), adipates (diethyladipate, di-(2-methoxy- or 2-ethoxye
  • suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents may be included as carriers.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include, but are not limited to, lactose, terra alba, sucrose, glucose, methylcellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol talc, starch, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • a binder can include, for example, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • a disintegrator can include, for example, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • an oral dosage form such as a solid dosage form, can comprise a disclosed compound that is attached to polymers as targetable drug carriers or as a prodrug.
  • Suitable biodegradable polymers useful in achieving controlled release of a drug include, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, caprolactones, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and hydrogels, preferably covalently crosslinked hydrogels.
  • Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a tablet containing a disclosed compound can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • a solid oral dosage form such as a tablet, can be coated with an enteric coating to prevent ready decomposition in the stomach.
  • enteric coating agents include, but are not limited to, hydroxypropylmethylcellulose phthalate, methacrylic acid- methacrylic acid ester copolymer, polyvinyl acetate-phthalate and cellulose acetate phthalate.
  • Akihiko Hasegawa “Application of solid dispersions of Nifedipine with enteric coating agent to prepare a sustained-release dosage form” Chem. Pharm. Bull. 33:1615-1619 (1985).
  • enteric coating materials may be selected on the basis of testing to achieve an enteric coated dosage form designed ab initio to have a preferable combination of dissolution time, coating thicknesses and diametral crushing strength (e.g., see S. C. Porter et al.
  • an oral dosage form can be a solid dispersion with a water soluble or a water insoluble carrier.
  • an oral dosage form can be in a liquid dosage form, including those that are ingested, or alternatively, administered as a mouth wash or gargle.
  • a liquid dosage form can include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients.
  • the pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents.
  • water particularly sterile water, or physiologically acceptable organic solvents, such as alcohols (ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols and their derivatives, fatty alcohols, partial esters of glycerol), oils (for example peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soya bean oil, castor oil, bovine hoof oil), paraffins, dimethyl sulfoxide, triglycerides and the like.
  • alcohols ethanol, propanol, isopropanol, 1,2-propylene glycol, polyglycols and their derivatives, fatty alcohols, partial esters of glycerol
  • oils for example peanut oil, olive oil, sesame oil, almond oil, sunflower oil, soya bean oil, castor oil, bovine hoof oil
  • paraffins dimethyl sulfoxide, triglycerides and the like.
  • a liquid dosage form such as a drinkable solutions
  • the following substances may be used as stabilizers or solubilizers: lower aliphatic mono- and multivalent alcohols with 2- 4 carbon atoms, such as ethanol, n-propanol, glycerol, polyethylene glycols with molecular weights between 200-600 (for example 1 to 40% aqueous solution), diethylene glycol monoethyl ether, 1,2-propylene glycol, organic amides, for example amides of aliphatic C1-C6-carboxylic acids with ammonia or primary, secondary or tertiary C1-C4-amines or C1-C4-hydroxy amines such as urea, urethane, acetamide, N-methyl acetamide, N,N-diethyl acetamide, N,N-dimethyl acetamide, lower aliphatic amines and diamines with 2-6 carbon atoms, such as
  • solubilizers and emulsifiers such as the following non-limiting examples can be used: polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolizated oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkylphenols or fatty acids or also 1- methyl-3-(2-hydroxyethyl)imidazolidone-(2).
  • solubilizers and emulsifiers such as the following non-limiting examples can be used: polyvinyl pyrrolidone, sorbitan fatty acid esters such as sorbitan trioleate, phosphatides
  • polyoxyethylated means that the substances in question contain polyoxyethylene chains, the degree of polymerization of which generally lies between 2 and 40 and in particular between 10 and 20.
  • Polyoxyethylated substances of this kind may for example be obtained by reaction of hydroxyl group-containing compounds (for example mono- or diglycerides or unsaturated compounds such as those containing oleic acid radicals) with ethylene oxide (for example 40 Mol ethylene oxide per 1 Mol glyceride).
  • hydroxyl group-containing compounds for example mono- or diglycerides or unsaturated compounds such as those containing oleic acid radicals
  • ethylene oxide for example 40 Mol ethylene oxide per 1 Mol glyceride.
  • oleotriglycerides are olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil. See also Dr. H. P.
  • a liquid dosage form can further comprise preservatives, stabilizers, buffer substances, flavor correcting agents, sweeteners, colorants, antioxidants and complex formers and the like.
  • Complex formers which may be for example be considered are: chelate formers such as ethylene diamine retrascetic acid, nitrilotriacetic acid, diethylene triamine pentacetic acid and their salts.
  • ⁇ -, ⁇ - or ⁇ -cyclodextrins or their derivatives in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl- ⁇ -cyclodextrin or sulfobutyl- ⁇ -cyclodextrin.
  • co-solvents such as alcohols may improve the solubility and/or the stability of the compounds according to the present disclosure in pharmaceutical compositions.
  • a disclosed liquid dosage form, a parenteral injection form, or an intravenous injectable form can further comprise liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • suitable injection such as parenteral administration, such as intravenous, intramuscular, or subcutaneous administration.
  • Pharmaceutical compositions for injection can be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • Pharmaceutical compositions of the present disclosure suitable for parenteral administration can include sterile aqueous or oleaginous solutions, suspensions, or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In some aspects, the final injectable form is sterile and must be effectively fluid for use in a syringe.
  • the pharmaceutical compositions should be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • injectable solutions for example, can be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • a disclosed parenteral formulation can comprise about 0.01-0.1 M, e.g. about 0.05 M, phosphate buffer. In a further aspect, a disclosed parenteral formulation can comprise about 0.9% saline.
  • a disclosed parenteral pharmaceutical composition can comprise pharmaceutically acceptable carriers such as aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include but not limited to water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles can include mannitol, normal serum albumin, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like.
  • Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, collating agents, inert gases and the like.
  • a disclosed parenteral pharmaceutical composition can comprise may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives.
  • injectable pharmaceutical compositions are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the subject or patient. [0152]
  • the disclosed compounds can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection.
  • compositions of the present disclosure can be in a form suitable for topical administration.
  • topical application means administration onto a biological surface, whereby the biological surface includes, for example, a skin area (e.g., hands, forearms, elbows, legs, face, nails, anus and genital areas) or a mucosal membrane.
  • compositions of the present invention may be formulated into any form typically employed for topical application.
  • a topical pharmaceutical composition can be in a form of a cream, an ointment, a paste, a gel, a lotion, milk, a suspension, an aerosol, a spray, foam, a dusting powder, a pad, and a patch.
  • the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the present disclosure, or pharmaceutically acceptable salts thereof, via conventional processing methods.
  • a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
  • Ointments are semisolid preparations, typically based on petrolatum or petroleum derivatives.
  • the specific ointment base to be used is one that provides for optimum delivery for the active agent chosen for a given formulation, and, preferably, provides for other desired characteristics as well (e.g., emollience).
  • an ointment base should be inert, stable, nonirritating and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, 19th Ed., Easton, Pa.: Mack Publishing Co. (1995), pp.
  • ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases.
  • Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum.
  • Emulsifiable ointment bases also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum.
  • Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid.
  • Preferred water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight.
  • Lotions are preparations that are to be applied to the skin surface without friction. Lotions are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are typically preferred for treating large body areas, due to the ease of applying a more fluid composition.
  • Lotions are typically suspensions of solids, and oftentimes comprise a liquid oily emulsion of the oil-in-water type. It is generally necessary that the insoluble matter in a lotion be finely divided. Lotions typically contain suspending agents to produce better dispersions as well as compounds useful for localizing and holding the active agent in contact with the skin, such as methylcellulose, sodium carboxymethyl-cellulose, and the like.
  • Creams are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase also called the “internal” phase, is generally comprised of petrolatum and/or a fatty alcohol such as cetyl or stearyl alcohol.
  • the aqueous phase typically, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. Reference may be made to Remington: The Science and Practice of Pharmacy, supra, for further information.
  • Pastes are semisolid dosage forms in which the bioactive agent is suspended in a suitable base. Depending on the nature of the base, pastes are divided between fatty pastes or those made from a single-phase aqueous gel.
  • the base in a fatty paste is generally petrolatum, hydrophilic petrolatum and the like.
  • the pastes made from single-phase aqueous gels generally incorporate carboxymethylcellulose or the like as a base. Additional reference may be made to Remington: The Science and Practice of Pharmacy, for further information. [0159] Gel formulations are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil.
  • Preferred organic macromolecules are crosslinked acrylic acid polymers such as the family of carbomer polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the trademark CarbopolTM.
  • carbomer polymers e.g., carboxypolyalkylenes that may be obtained commercially under the trademark CarbopolTM.
  • Other types of preferred polymers in this context are hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol; modified cellulose, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin.
  • Sprays generally provide the active agent in an aqueous and/or alcoholic solution which can be misted onto the skin for delivery.
  • Such sprays include those formulated to provide for concentration of the active agent solution at the site of administration following delivery, e.g., the spray solution can be primarily composed of alcohol or other like volatile liquid in which the active agent can be dissolved.
  • the carrier evaporates, leaving concentrated active agent at the site of administration.
  • Foam compositions are typically formulated in a single or multiple phase liquid form and housed in a suitable container, optionally together with a propellant which facilitates the expulsion of the composition from the container, thus transforming it into a foam upon application.
  • Other foam forming techniques include, for example the “Bag-in-a-can” formulation technique.
  • Compositions thus formulated typically contain a low-boiling hydrocarbon, e.g., isopropane. Application and agitation of such a composition at the body temperature cause the isopropane to vaporize and generate the foam, in a manner similar to a pressurized aerosol foaming system.
  • Foams can be water-based or aqueous alkanolic, but are typically formulated with high alcohol content which, upon application to the skin of a user, quickly evaporates, driving the active ingredient through the upper skin layers to the site of treatment.
  • Skin patches typically comprise a backing, to which a reservoir containing the active agent is attached.
  • the reservoir can be, for example, a pad in which the active agent or composition is dispersed or soaked, or a liquid reservoir.
  • Patches typically further include a frontal water permeable adhesive, which adheres and secures the device to the treated region. Silicone rubbers with self-adhesiveness can alternatively be used. In both cases, a protective permeable layer can be used to protect the adhesive side of the patch prior to its use.
  • Skin patches may further comprise a removable cover, which serves for protecting it upon storage.
  • patch configuration which can be utilized with the present invention include a single-layer or multi-layer drug-in-adhesive systems which are characterized by the inclusion of the drug directly within the skin-contacting adhesive.
  • the adhesive not only serves to affix the patch to the skin, but also serves as the formulation foundation, containing the drug and all the excipients under a single backing film.
  • a membrane is disposed between two distinct drug-in-adhesive layers or multiple drug-in-adhesive layers are incorporated under a single backing film.
  • Examples of pharmaceutically acceptable carriers that are suitable for pharmaceutical compositions for topical applications include carrier materials that are well-known for use in the cosmetic and medical arts as bases for e.g., emulsions, creams, aqueous solutions, oils, ointments, pastes, gels, lotions, milks, foams, suspensions, aerosols and the like, depending on the final form of the composition.
  • suitable carriers according to the present invention therefore include, without limitation, water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkylated protein hydrolysates, liquid lanolin and lanolin derivatives, and like materials commonly employed in cosmetic and medicinal compositions.
  • suitable carriers include, without limitation, alcohols, such as, for example, monohydric and polyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol, mannitol, and propylene glycol; ethers such as diethyl or dipropyl ether; polyethylene glycols and methoxypolyoxyethylenes (carbowaxes having molecular weight ranging from 200 to 20,000); polyoxyethylene glycerols, polyoxyethylene sorbitols, stearoyl diacetin, and the like.
  • alcohols such as, for example, monohydric and polyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol, mannito
  • Topical compositions of the present disclosure can, if desired, be presented in a pack or dispenser device, such as an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient.
  • the dispenser device may, for example, comprise a tube.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser device may also be accompanied by a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions for human or veterinary administration.
  • Such notice for example, may include labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
  • compositions comprising the topical composition of the invention formulated in a pharmaceutically acceptable carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Another patch system configuration which can be used by the present invention is a reservoir transdermal system design which is characterized by the inclusion of a liquid compartment containing a drug solution or suspension separated from the release liner by a semi- permeable membrane and adhesive.
  • the adhesive component of this patch system can either be incorporated as a continuous layer between the membrane and the release liner or in a concentric configuration around the membrane.
  • compositions of the present disclosure can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • compositions containing a compound of the present disclosure, and/or pharmaceutically acceptable salts thereof can also be prepared in powder or liquid concentrate form.
  • the pharmaceutical composition (or formulation) may be packaged in a variety of ways. Generally, an article for distribution includes a container that contains the pharmaceutical composition in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, foil blister packs, and the like. The container may also include a tamper proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container typically has deposited thereon a label that describes the contents of the container and any appropriate warnings or instructions.
  • the disclosed pharmaceutical compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • Such notice for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • compositions comprising a disclosed compound formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the exact dosage and frequency of administration depends on the particular disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, solvate, or polymorph thereof, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof; the particular condition being treated and the severity of the condition being treated; various factors specific to the medical history of the subject to whom the dosage is administered such as the age; weight, sex, extent of disorder and general physical condition of the particular subject, as well as other medication the individual may be taking; as is well known to those skilled in the art.
  • the pharmaceutical composition will comprise from 0.05 to 99 % by weight, preferably from 0.1 to 70 % by weight, more preferably from 0.1 to 50 % by weight of the active ingredient, and, from 1 to 99.95 % by weight, preferably from 30 to 99.9 % by weight, more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
  • an appropriate dosage level will generally be about 0.01 to 1000 mg of a compound described herein per kg patient body weight per day and can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 500 mg/kg per day, about 0.1 to 250 mg/kg per day, or about 0.5 to 100 mg/kg per day.
  • a suitable dosage level can be about 0.01 to 1000 mg/kg per day, about 0.01 to 500 mg/kg per day, about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5.0 or 5.0 to 50 mg/kg per day.
  • compositions are preferably provided in the form of tablets containing 1.0 to 1000 mg of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 and 1000 mg of the active ingredient for the symptomatic adjustment of the dosage of the patient to be treated.
  • the compound can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosing regimen can be adjusted to provide the optimal therapeutic response.
  • Such unit doses as described hereinabove and hereinafter can be administered more than once a day, for example, 2, 3, 4, 5 or 6 times a day.
  • such unit doses can be administered 1 or 2 times per day, so that the total dosage for a 70 kg adult is in the range of 0.001 to about 15 mg per kg weight of subject per administration. In a further aspect, dosage is 0.01 to about 1.5 mg per kg weight of subject per administration, and such therapy can extend for a number of weeks or months, and in some cases, years. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs that have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those of skill in the area.
  • a typical dosage can be one 1 mg to about 100 mg tablet or 1 mg to about 300 mg taken once a day, or, multiple times per day, or one time-release capsule or tablet taken once a day and containing a proportionally higher content of active ingredient.
  • the time-release effect can be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release.
  • the disclosed pharmaceutical compositions can further comprise other therapeutically active compounds, which are usually applied in the treatment of the above mentioned pathological or clinical conditions.
  • the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.
  • the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, and a pharmaceutically acceptable carrier.
  • the present disclosure relates to a process for preparing such a pharmaceutical composition, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound according to the present disclosure.
  • Methods of Use [0180] Only praziquantel is available for treating parasitic worm infections such as, for example, schistosomiasis, a disease affecting more than 200 million people. Praziquantel-resistant worms have been selected for in the lab and low cure rates from mass drug administration programs, which suggests that resistance is evolving in the field. Not wishing to be bound by theory, thioredoxin glutathione reductase (TGR) is essential for schistosome survival.
  • TGR thioredoxin glutathione reductase
  • TGR is a 130 kDa obligate homodimer as the functional stereochemistry of the FAD redox site in each subunit is generated by protein dimerization.
  • TGR inhibitors identified to date are irreversible and/or covalent inhibitors with unacceptable off-target effects.
  • the compound selectively interacts with the target TGR protein by non- covalent bonds.
  • TGR-based therapeutic approaches is impeded by the lack of non-covalent small molecule inhibitors of TGR. It has been discovered that the compounds described herein interact at the doorstop pocket of thioredoxin glutathione reductase in a non-covalent manner.
  • the compounds described herein bind at the doorstop pocket, which prevents NADPH oxidation steps.
  • the compounds described herein are effective TGR inhibitors and.
  • the compounds described herein have an IC 50 value for inhibiting TGR of less than about 5 ⁇ m, or 0.01 ⁇ m, 0.05 ⁇ m, 0.10 ⁇ m, 0.20 ⁇ m, 0.40 ⁇ m, 0.60 ⁇ m, 0.80 ⁇ m, 1.00 ⁇ m, 1.50 ⁇ m, 2.00 ⁇ m, 2.50 ⁇ m, 3.00 ⁇ m, 3.50 ⁇ m, 4.00 ⁇ m, 4.50 ⁇ m, or 5.00 ⁇ m, where any value can be a lower and upper endpoint of a range (e.g., 0.50 ⁇ m to 2.00 ⁇ m).
  • the compounds described herein are effective in treating diseases in a subject produced by parasitic worms.
  • the compounds can reduce worm burden (i.e., the number of living or viable worms), worm egg burden (i.e., the number of living or viable eggs), or a combination thereof in a subject when compared to the same infected subject prior to the administration of the compound.
  • worm burden i.e., the number of living or viable worms
  • worm egg burden i.e., the number of living or viable eggs
  • the compounds described herein are effective in killing both juvenile (e.g., 23 days old) and adult parasitic worms.
  • the compounds described herein have an LD 50 value for killing adult or juvenile parasitic worms of less than about 50 ⁇ m, or 0.5 ⁇ m, 0.10 ⁇ m, 0.50 ⁇ m, 1.0 ⁇ m, 2.0 ⁇ m, 3.0 ⁇ m, 4.0 ⁇ m, 5.0 ⁇ m, 6.0 ⁇ m, 7.0 ⁇ m, 8.0 ⁇ m, 9.0 ⁇ m, 10.0 ⁇ m, 15.0 ⁇ m, 20.0 ⁇ m, 25.0 ⁇ m, 30.0 ⁇ m, 35.0 ⁇ m, 40.0 ⁇ m, 45.0 ⁇ m, or 50.0 ⁇ m, where any value can be a lower and upper endpoint of a range (e.g., 1.0 ⁇ m to 5.0 ⁇ m).
  • the parasitic worm is a flatworm or trematode.
  • the parasitic worm is a blood fluke, a liver fluke, a lung fluke, an intestinal fluke, a pancreatic fluke, a cestode, or tapeworm.
  • the parasitic worm is a flatworm is from the order Platyhelminthes.
  • the flatworm is from the class Turbellaria, Trematoda, Monogenea and Cestoda.
  • the parasitic worm is from the genus Schistosoma, Clonorchis, Dicrocoelium, Fasciola, Opisthorchis, Fasciolopsis Metagonimus, Heterophyes, Metorchis, Paragonimus, Eurytrema, Echinostoma, Watsonius, Gastrodiscoides, Gastrodiscus, Heterobilharzia, Paramphistomum, Prosthogonimus, Alaria, Taenia, Hymenolepis, Diphyllobothrium, Echinococcus, Moniezia, Dipylidium, Spirometra, Calicophoron, Nanophytus, Apophallus Cryptocotyle, or Mesocestoides.
  • the parasitic worm is S. mansoni, S. haematobium, S. japonicum, S. guineensis, S. intercalatum, S. malayensis, S. mekongi, S. bovis, C. sinensis, D. dendriticum, D. hospes, F. gigantica, F. hepatica, O. felineus, O. berrine, M. conjunctus, F. buski, M. miyatai, M. takahashii, M. yokogawai, H. heterophyes, H. nocens, E. pancreaticum, E. coelomaticum, E.
  • the compounds described herein can treat or prevent numerous diseases associated with parasitic worm infection.
  • the compounds described herein can treat schistosomiasis, which is an acute and chronic parasitic disease that has effects millions of people.
  • the compounds described herein can be used to treat renal disease, kidney disease, bladder disease, liver disease, pancreatitis, cholecystitis, cholangiocarcinoma, fever, urticaria, abdominal pain, hepatosplenic disease with periportal fibrosis, glomerular disease (e.g., glomerular lesions are mesangioproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, mesangiocapillary glomerulonephritis, FSGS, and amyloidosis), and urinary tract disease caused by a parasitic worm infection.
  • the compound is administered orally to the subject.
  • the compound is administered at a dosage of from about 50 mg per day to about 1,000 mg per day, or about 50 mg per day, 50 mg per day, 100 mg per day, 150 mg per day, 200 mg per day, 250 mg per day, 300 mg per day, 350 mg per day, 400 mg per day, 450 mg per day, 500 mg per day, 550 mg per day, 600 mg per day, 650 mg per day, 700 mg per day, 750 mg per day, 800 mg per day, 850 mg per day, 900 mg per day, 950 mg per day, or 1,000 mg per day, where any value can be a lower and upper endpoint of a range (e.g., 100 mg per day to 300 mg per day).
  • Aspect 1 Aspect 1
  • R1 and R2 are independently absent, H, halide, azide, nitro, cyano, amino, hydroxyl, carboxy, amido, substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 perfluoroalkoxy, C1-C6 ester, C1-C4 alkenyl, or C1-C6 alkynyl, C1-C6 alkyl amino, substituted or unsubstituted aryl, arylalkyl, substituted or unsubstituted
  • Aspect 4 The compound of Aspect 1, wherein is wherein R 1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, and R 7 is H or substituted or unsubstituted C 1 -C 6 alkyl.
  • Aspect 5 The compound of Aspect 4, wherein R 1 is substituted or unsubstituted phenyl.
  • Aspect 6 The compound of Aspect 4 or 5, wherein R 7 is H or methyl.
  • n is an integer from 1 to 4; and R 8 and R 9 are independently absent, H, halide, azide, nitro, cyano, amino, amido, hydroxy, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 ester, C 1 -C 4 alkenyl, or C 1 -C 6 alkynyl, C 1 -C 6 alkyl amino, C 1 -C 6 alkyl amido, C 1 -C 6 alkyl hydroxy, C 1 -C 6 alkyl ether, substituted or unsubstituted aryl, arylalkyl, substituted or unsubstituted heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, or heterocycloalkyl.
  • Aspect 8 The compound of any one of Aspects 1-7, wherein L 1 –(CH 2 )n-, n is 1, 2, or 3.
  • Aspect 9 The compound of any one of Aspects 1-8, wherein Z is NH.
  • Aspect 10 The compound of any one of Aspects 1-8, wherein Z is O.
  • R 1 is substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl.
  • Aspect 14 The compound of Aspect 13, wherein R 1 is substituted or unsubstituted phenyl.
  • Aspect 16 The compound of any one of Aspects 13-15, wherein Z is NH.
  • Aspect 17 The compound of any one of Aspects 13-15, wherein Z is O.
  • Aspect 18 The compound of any one of Aspects 13-17, wherein R 7 is H, methyl, or ethyl.
  • Aspect 19 The compound Aspect 1 having formula III and any stereoisomer thereof
  • Aspect 20 The compound of Aspect 19, wherein R 1 is substituted or unsubstituted phenyl.
  • Aspect 21 The compound of Aspect 20 or 21, wherein L 1 is -CH 2 -.
  • Aspect 22 The compound of any one of Aspects 19-21, wherein Z is NH.
  • Aspect 23 The compound of any one of Aspects 19-21, wherein Z is O.
  • Aspect 24 The compound of any one of Aspects 19-23, wherein R 2 is H.
  • Aspect 25 The compound Aspect 1 having formula IVA, IVB, VA, or VB and any stereoisomer thereof
  • Aspect 26 The compound of Aspect 25, wherein L 1 –(CH 2 ) n -, where n is 1, 2, or 3.
  • Aspect 27 The compound of Aspect 25 or 26, wherein Z is NH or C(O)NH.
  • Aspect 28 The compound of Aspect 25 or 26, wherein Z is O.
  • Aspect 29 The compound of any one of Aspects 25-28, wherein R 8 is H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted cycloalkyl with an optional carbonyl group.
  • Aspect 30 The compound of any one of Aspects 25-28, wherein R 8 is H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsub
  • R 9 is H, halide, azide, nitro, cyano, amino, amido, hydroxy, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 ester, C 1 -C 4 alkenyl, or C 1 -C 6 alkynyl, C 1 -C 6 alkyl amino, C 1 -C 6 alkyl amido, C 1 -C 6 alkyl hydroxy, C 1 -C 6 alkyl ether, substituted or unsubstituted aryl, arylalkyl, substituted or unsubstituted heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, or heterocycloalkyl.
  • Aspect 31 The compound of Aspect 1 selected from
  • Aspect 32 A composition comprising a compound of any one of Aspects 1-31 and a pharmaceutically acceptable excipient.
  • Aspect 33. A method of treating a disease in a subject produced by a parasitic worm comprising administering to the subject an effective amount of a compound of any one of Aspects 1-31.
  • Aspect 34. The method of Aspect 33, wherein the disease is produced from a parasitic flatworm or trematode.
  • Aspect 35. The method of Aspect 33, wherein the disease is produced from a blood fluke, a liver fluke, a lung fluke, an intestinal fluke, a pancreatic fluke, a cestode, or tapeworm.
  • the parasitic worm is from the genus Schistosoma, Clonorchis, Dicrocoelium, Fasciola, Opisthorchis, Fasciolopsis Metagonimus, Heterophyes, Metorchis, Paragonimus, Eurytrema, Echinostoma, Watsonius, Gastrodiscoides, Gastrodiscus, Heterobilharzia, Paramphistomum, Prosthogonimus, Alaria, Taenia, Hymenolepis, Diphyllobothrium, Echinococcus, Moniezia, Dipylidium, Spirometra, Calicophoron, Nanophytus, Apophallus Cryptocotyle, or Mesocestoides.
  • Aspect 37 The method of Aspect 33, wherein the parasitic worm is S. mansoni, S. haematobium, S. japonicum, S. guineensis, S. intercalatum, S. malayensis, S. mekongi, S. bovis, C. sinensis, D. dendriticum, D. hospes, F. gigantica, F. hepatica, O. felineus, O. berrine, M. conjunctus, F. buski, M. miyatai, M. takahashii, M. yokogawai, H. heterophyes, H. nocens, E. pancreaticum, E. coelomaticum, E.
  • Aspect 38 The method of any one of Aspects 33-37, wherein the compound reduces worm burden, worm egg burden, or a combination thereof in a subject when compared to the same subject prior to the administration of the compound.
  • Aspect 39 The method of any one of Aspects 33-37, wherein the compound reduces worm burden, worm egg burden, or a combination thereof in a subject when compared to the same subject prior to the administration of the compound.
  • a method of inhibiting thioredoxin glutathione reductase (TGR) in a cell comprising administering to the cell an effective amount of a compound of any one of Aspects 1-31.
  • FIGS. 1-21 show exemplary reaction sequences and conditions for making the compounds described herein. All reactions were carried out under inert atmosphere of nitrogen and monitored by thin-layer chromatography with silica gel 60 F 254 precoated glass plates. Visualization of TLC plates was performed by UV light irradiation (254 nm) or staining with phosphomolybdic acid. All reagents were purchased from commercial suppliers and were used without further purification.
  • Chromatographic purifications were performed using an HPFC Biotage Isolera TM Four 3.0 system using prepacked flash chromatography cartridges in normal phase (irregular silica, 40-60 ⁇ m; hexanes/ethyl acetate gradient) or reverse phase (Biotage KP- C18-HS, water/methanol gradient) modes with UV detection at 254 and 280 nm.
  • 1 H NMR spectra were recorded on Bruker spectrometer at 400 MHz.
  • 13 C NMR spectra were recorded on Bruker spectrometer at 100 MHz. Chemical shifts were reported in parts per million (ppm) and calibrated with CDCl 3 residual peak.
  • compound 26 (186 mg; 0.533 mmol) in 5 mL methylene chloride was added 4M HCl in 1,4-dioxane (1.33 mL, 10 eq) and the resulting mixture was stirred at ambient temperature for 12 hrs. Reaction mixture was diluted with methylene chloride and water and pH of an aqueous layer was adjusted to 9 with aqueous ammonia.
  • the proteins were subjected to the Structure Preparation procedure followed by addition of hydrogen atoms using the Protonate 3D application 71 with all the default settings in MOE.
  • the energy of the resulting structure was minimized utilizing AMBER14:EHT forcefield in MOE 72, 73 with all the settings set default until the RMS gradient reached 0.001 kcal/mol/ ⁇ 2 .
  • the resulting ligand-proteins complexes were aligned to match the position of the co-crystallized small molecule fragments. At this step, the water molecules found in the X-ray structures were removed.
  • the co-crystallized fragments found in sub-pockets A-C and the protein were used as input for the SZMAP, Gameplan, and vBrood applications and visualization in MOE.
  • an artificial chimera molecule was built using the X-ray fragments found in subpockets A-C in PDB:6FP4 (https://www.rcsb.org/structure/6FP4) and PBD:6FTC (https://www.rcsb.org/structure/6FTC) and connected by a short CH 2 CH 2 linker.
  • the resulting complex was additionally minimized as described above.
  • the default settings for the SZMAP and Gameplan applications were used in all the calculations.
  • SZMAP was used for analysis of energetics of stabilizing and destabilizing effects of water.
  • the szmap command with keyword -stbl resulted in complex, apo, and ligand grids. Additional grids were generated using - results_set max keyword. To break-out the region displaced by the ligand, the grid_comp command was run on the results of the previous step. WaterColor and WaterOrientation VIDA extensions were applied to the results of SZMAP calculations to visualize the regions that favor polar and non-polar substituents. The water probes position, orientation, and energetics were determined for the chimera-TGR complex.
  • the -1.5 kcal/mol and 0.75 kcal/mol cutoffs were used for the lower and upper cutoffs in the “Exclude free energy range” settings, the water molecules were visualized by energy.
  • the grid point pruning was set to “more”.
  • the positions of the probes and the free energy values were exported in a PDB file and visualized in Pymol. 74 The S.
  • Gameplan was used to generate a set of hypotheses for polar and non-polar ligand modifications. All the settings in Gameplan were set default.
  • the fragment library for the vBrood application was prepared using the CHOMP application to fragment the ChEMBL database 77 version CHEMBL25. 78 In the CHOMP application, no additional parameters were used except for the minimal required to run it (i.e. -in and -out). The total number of fragments in the resulting database was 17,697,078.
  • vBrood was run to replace the piperazine portion of the molecule using the default settings in vBrood.
  • TGR (1 ⁇ M) or SmHDAC8 (1 ⁇ M) was incubated at concentrations of either 5 or 50 ⁇ M PRP with or without 100 ⁇ M NADPH totaling eight samples.
  • the photocrosslinking and CuAAC click biotinylation were performed as previously described by our group.
  • western blot normalization was performed with the Licor RevertTM 700 Total Protein Stain Kit as described in their protocol. Protein was finally imaged with the Licor IRDye® 800CW streptavidin on the Odyssey Sa imager.
  • Enzyme inhibition, kinetics, ex vivo and in vivo activity [0249] Enzyme preparation and activity determination: Recombinant TGR, human TrxR1, B. malayi (Bm)TrxR and human GR proteins were expressed and purified as described. 20, 69, 79 The codon optimized sequence for P. falciparum (PfTrxR, https://www.ncbi.nlm.nih.gov/protein/CAA60574.1/) with an N-terminal 6-His tag was synthesized and inserted into pET15b (GenScript) and expressed in BL21 (DE3) cells and purified as described for human GR.
  • TGR and TrxR enzyme inhibition assays were performed in triplicate at 25 °C as described 20 in 0.1 M potassium phosphate (pH 7.4), 10 mM EDTA, 100 ⁇ M NADPH and 0.01% Tween-20.
  • TGR, human TrxR1 and BmTrxR (all at 4 nM) and PfTrxR (50 nM) were preincubated with the compounds for 15 min. The reaction was started with addition of an equal volume of DTNB (6 mM) and NADPH (100 ⁇ M) and the increase in A 412 during the first 3 min was recorded.
  • GR 120 pM was added to an assay mixture (100 ⁇ M NADPH, 0.1 M potassium phosphate (pH 6.9), 200 mM KCl, and 1 mM EDTA). The reaction was preincubated for 15 min. Activity was initiated with the addition of 1 mM GSSG and 100 ⁇ M NADPH and initial rates of NADPH oxidation were monitored at 340 nm. The reactions were done in triplicate. The IC 50 was calculated in GraphPad Prism.
  • TSA Thermal Shift Assay
  • Inhibitors were added at a concentration dependent on the compound’s IC 50 , from 125-500 ⁇ M.
  • the mixtures containing inhibitors 1-5 were incubated for 6 h and for 30 min for treatments with 6-8 at room temperature. After the preincubation period, 20 ⁇ L samples were pipetted into a BioRad un-skirted PCR 96 well plate and sealed with MicroAmp TM Optical Adhesive film. The plate was then centrifuged for 5 min at 1000 u g. TSA was carried out using a BioRad CFX Connect qPCR instrument with a melt curve setting of 25 - 95 ⁇ , in increments of 0.5 ⁇ /10 seconds.
  • the SYBR green channel was used to detect fluorescence as the wavelength of flavin fluorescence overlaps with that of SYBR green.
  • BioRad CFX Maestro 5.2 was used to analyze TSA data.
  • NADPH Dependence of Inhibition TGR was incubated at room temperature with inhibitor in the presence or absence of 100 ⁇ M NADPH for 15 min. DTNB (3 mM) and NADPH (100 ⁇ M) were added, and the reaction was monitored at A 412 for 5 min to determine reaction rate. The assay was done in triplicate.
  • TGR Time Dependence of Inhibition: TGR was incubated at room temperature (up to 6 h) and at 4 ⁇ for 6 to 24 h with 50 ⁇ M inhibitor and 100 ⁇ M NADPH for the indicated times. Then DTNB (3 mM) and NADPH (100 ⁇ M) were added, and the reaction was monitored at A 412 for 5 min. The assay was done in triplicate.
  • Reversibility by jump dilution A reaction of 370 nM TGR, 100 ⁇ M NADPH, and 250 ⁇ M inhibitor was incubated for 15 min at room temperature. A 100x dilution of the reaction was made and the activity was determined immediately and after 60 min.
  • NADPH Competition Master mixes with varying concentrations of NADPH were made, each with 2 nM TGR in reaction buffer. Inhibitor (2 ⁇ l) was added to a 96 well microplate in triplicate for each NADPH and inhibitor concentration, and 192 ⁇ l of the master buffer was added to each well. The reaction incubated for 15 minutes and 6 ⁇ l of 50 mM DTNB was added to each well. The kinetic rate was measured at A 412 for 5 min.
  • NADPH Consumption TRi-1, Stattic (both at 50 ⁇ M) and AF (20 ⁇ M) were incubated with 1 ml of 500 nM TGR and 100 ⁇ M NADPH in TGR reaction buffer for 30 min. The samples were desalted using a Zeba spin desalting column (Thermo Fisher Scientific) and 100 ⁇ l of the desalted sample was combined with 100 ⁇ l of 100 ⁇ M NADPH. NADPH consumption was monitored at 340 nm in triplicate.
  • cercariae were mechanically transformed to schistosomula. 54 Briefly, cercariae were placed on ice for 30 min and then centrifuged at 350 u g for 10 mins. The supernatant was decanted and 2 ml of serum-free M199 medium was added to cercarial pellets and vortexed for 1 min until cercarial tails were detached.
  • NTS were purified by layering on 4 °C Percoll gradient suspension containing Eagle’s minimum essential medium, penicillin- streptomycin (10,000 U per ml penicillin/10,000 U per ml streptomycin), and 1 M HEPES in 0.85% NaCl with cercariae suspension and centrifuged at 500 u g for 15 min. Cercarial pellets were resuspended and washed thrice in serum-free M199 medium and collected at 100 u g for 5 min.
  • NTS (240) were transferred to U-bottom 96 well assay plates containing 200 ⁇ l of M199 medium supplemented with 5.5 mM D-glucose, penicillin-streptomycin and 5% heat inactivated fetal bovine serum and incubated at 37 °C in a 5% CO 2 incubator overnight.
  • All animal studies at Rush University Medical Center were approved by the Institutional Animal Care and Use Committee of the Rush University Medical Center (Department of Health and Human Services animal welfare assurance number A-3120 ⁇ 01) with protocol ID: 20-069. Three-week old, female Swiss-Webster mice obtained from the Charles River were housed in the Comparative Research Center of Rush University Medical Center.
  • mice were infected by percutaneous tail exposure to about 200 S. mansoni or 50 S. japonicum cercaria for adult worms and about 1000 cercaria for juvenile S. mansoni worms through natural transdermal penetration of the cercariae for 1 h.
  • 81 Mice were euthanized three-and seven-weeks post infection for juvenile and adult worms, respectively, using a lethal dose of 0.018 ml of Euthasol and 5.85 mg/ml heparin to prevent blood coagulation (injection volume of 400 ⁇ l).
  • Perfusion was performed by flushing pre-warmed RPMI containing phenol red and L-glutamine through a 25- and 3/8-gauge needle placed into the aorta attached to Tygon tubing aided by the Masterflex L/S perfusion pump as described. 81 Juvenile and adult worms were carefully washed in phenol red free RPMI medium and subsequently incubated in phenol red free RPMI medium supplemented with 5.5 mM D- glucose, penicillin-streptomycin and 5% heat inactivated fetal bovine serum and at 37 °C in a 5% CO 2 incubator overnight.
  • DMSO formulated compounds were diluted with phenol red free M199 medium or RPMI medium for NTS or juvenile and adult worms, respectively, at ⁇ 1% DMSO final concentrations. NTS, juvenile and adult worms from overnight cultures were tested against compounds in triplicate. Controls were treated with DMSO alone or 5 ⁇ M AF as a positive control in appropriate medium. 18 Worm viability was assessed at 24 or 72 h by measuring ATP content of worms using Cell Titer Glo Assay (Promega) as described.
  • % Viability Averages of Test / Averages of DMSO Control x 100.
  • Channel blockers enhanced schistosomicidal activity of compounds.
  • Vero cells African Green Monkey Kidney cells, ATCC CCL-81 were grown in Dulbecco's modified Eagle's medium (DMEM) containing glucose, L-glutamine and sodium pyruvate and supplemented with 10% fetal bovine serum and 1X penicillin–streptomycin (Sigma) at 37 °C in culture flasks (TPT-90025) until confluent growth was attained. Vero cells were detached from the flasks by treatment with trypsin (0.5 mg/ml)/EDTA (0.2 mg/ml) in PBS for 5 min at 37 °C.
  • DMEM Dulbecco's modified Eagle's medium
  • fetal bovine serum 1X penicillin–streptomycin
  • Detached cells were suspended in the modified DMEM medium and seeded at 10 4 cells/well in 96-well microtiter plates (Costar, Corning) and incubated in the presence of 5% CO 2 at 37 °C for 24 ⁇ h. Following overnight incubation, formulated DMSO-compound stock solutions were diluted with DMEM at ⁇ 1% DMSO final concentrations. Vero cells were treated with different concentrations of compounds with DMSO as control and incubated in the presence of 5% CO 2 at 37 °C for 24 ⁇ h. Vero cells treated similarly with different concentrations of PZQ, MZM and AF (Cayman Chemicals) were used as positive controls.
  • mice treated three weeks post infection for juvenile worms were euthanized three weeks post treatment and mice treated six weeks post infection were euthanized one week post treatment with 0.018 ml of Euthasol and 5.85 mg/ml heparin and perfused.
  • the mesenteric and hepatic portal veins of the mice were carefully scanned under the microscope to extract any remaining S. mansoni adult worms and worm burdens were determined.
  • Egg burden was determined by weighing 50 mg of liver tissue from each of treated and control mice. The liver tissues were digested with 5% KOH at 37 °C overnight and washed twice with PBS. The number of eggs per 50 mg of liver tissue was determined using a Keyence BZ-X800 microscope using the egg autofluorescence.
  • TGR inhibition in worms TRFS-Green fluorescence quantification and GSH/GSSG determination
  • TGR inhibition in NTS was assessed using a fluorescent probe TRFS-Green. 43 NTS prepared as previously described and cultured in M199 supplemented with 5.5 mM D-glucose, penicillin-streptomycin and 5% heat inactivated fetal bovine serum were incubated at 37 °C in a clear bottom flat well plate in a 5% CO 2 incubator overnight. To inhibit TGR activity, NTS were treated with compounds (30 ⁇ M) or auranofin (5 ⁇ M) for 2 h.
  • NTS were further treated with TRFS- Green (10 ⁇ M) for additional 4 h and rinsed with M199 medium to remove residual TRFS-Green. Fluorescence images were obtained using Keyence BZ-X800. The quantification of fluorescence intensity upon the uptake of TRFS-Green by NTS was performed by a fluorescent microplate imager (BioTek Cytation3) (excitation, 438 nm; emission, 538 nm) hourly for 5 h and after 24 h. [0274]
  • GSH/GSSG levels experimentally by treating S. mansoni adult worms with 50 ⁇ M of compounds, or respective controls 5 ⁇ M Auranofin, 50 ⁇ M PZQ or 50 ⁇ M MZM and 0.01% DMSO for 3 h.
  • Worm homogenate was prepared by washing three times with PBS to remove residual compounds and ten volumes of ice cold 5% sulfosalicylic acid was added. Worms were manually homogenized on ice using VWR Pellet Mixer Adaptor. The worm suspension was centrifuged at 14000 u g, 4 °C for 10 min and the acid supernatants transferred. An equal volume of ice-cold neutralization buffer (500 mM HEPES, pH 8.0) was added to the acid supernatants. [0275] GSH/GSSG assay was performed by diluting the acid supernatant (5-fold) with ice-cold dilution buffer (250 mM HEPES, pH 7.5).
  • Luciferin detection reagent (100 ⁇ l) was added to all wells, briefly shaken and incubated for 15 min at room temperature and the luminescence measured using microplate imager (BioTek Cytation3).
  • GSH/GSSH ratio for DMSO control and compounds were calculated using (Net DMSO total glutathione RFU) – (Net DMSO GSSG RFU)/ (Net DMSO GSSG RFU)/2 and (Net inhibitor total glutathione RFU) – (Net inhibitor GSSG RFU)/ (Net inhibitor GSSG RFU)/2 respectively.
  • mice were housed in plastic cages and received standard chow (AIN-76) and water ad libitum prior to experiment maintained on a 12 h/12 h light/dark cycle. All the mice were weighed and dosed intraperitoneally accordingly at 100 mg/kg body weight with freshly prepared 1 or 2. [0279] Blood was collected by submandibular puncture into 1mL Eppendorf tubes, the plasma was separated and stored in -80 °C until used. A 25 ⁇ l of mouse plasma was transferred into 1.5 ml centrifuge tube which was spiked with 2.5 ⁇ l of internal standard (IS) working standard solution (100 ⁇ g/ml) to get final IS contraction of 250 ng/ml and the solution was vortexed.
  • IS internal standard
  • LC-MS/MS Conditions The analyte molecules were eluted on Zorbax XDB-C18 column (3.5 ⁇ m, 2.1x20 mm) with the mobile phase composed of water/0.1% formic acid and methanol/0.1% formic acid in the ratio of 70:30 V/V with the flow rate of 0.2 ml/min. The total run time of 2 min with an injection volume of 3 Pl at column temperature 40 qC were efficient to achieve accepted results.
  • a Shimadzu LC20AD, Ultra Performance Liquid Chromatography (UPLC) system (Shimadzu Corporation, Kyoto, Japan) equipped with Shimadzu 8040 triple quadrupole (QqQ) mass analyzer (Shimadzu Corporation, Kyoto, Japan) with an electrospray ionization source (ESI) operated in the positive charge mode for the quantification of 1 and 2.
  • UPLC Ultra Performance Liquid Chromatography
  • QqQ triple quadrupole
  • ESI electrospray ionization source
  • Instrument control and data acquisition was achieved via LabSolutioFns software (Shimadzu Corporation, Kyoto, Japan).
  • Pharmacokinetics of 2 in vivo Oral Gavage
  • Chemicals and Reagents HPLC-grade water was prepared by an in-house PURELAB Option filtration system (Elga lab water solution, UK).
  • mice were housed in plastic cages and received standard chow (AIN-76) and water ad libitum prior to experiment maintained on a 12 h/12 h light/dark cycle. All the mice were weighed and gavaged orally at 200 mg/kg body weight with freshly prepared 2. Blood was collected by submandibular puncture at 0, 0.25, 0.5, 1, and 2 h.
  • Animal experiments were performed according to the policies and guidelines of the Institutional Animal Care and Use Committee (IACUC) of the University of Illinois at Chicago (Protocol 19-049).
  • IACUC Institutional Animal Care and Use Committee
  • Analytical standard preparation The multiplexed working standards were prepared by dilution from stock solutions in methanol at concentrations from 2.5 ng/ml – 2000 ng/ml. The working internal standards were also diluted from stock solutions in methanol with 0.1% formic acid. The working concentration of internal standard compound 1 was 750 ng/ml.
  • Sample Preparation Calibration curve for 2 was prepared by spiking 40 ⁇ l of blank mouse plasma with 10 ⁇ l of working standard solution to get final concentration ranging from 2.5 ng/ml – 2000 ng/ml. Samples were deproteinized with 150 ⁇ l of internal standard solution. This mixture was vortexed to mix properly and centrifuged at 13000 u g for 30 min.
  • the analyte molecules were separated on Phenomenex kinetex C18 column 100 ⁇ (2.6 ⁇ m, 50 u 3 mm) with the mobile phase composed of Water/0.1% formic acid (A) and Acetonitrile (B) at the flow rate of 0.5 ml/min with the column temperature maintained at 40 °C and the sample of injection was 5 ⁇ l.
  • the gradient program was set as follows: 0.1 min, 5% B; 0.1-0.5 min, 5%-95% B; 0.5-2.5 min, 95% B; 2.5-3.5 min, 95%-5%; 3.5-4 min and stop at 5 min.
  • Quantification was performed using electrospray in the positive mode with the spray voltage of 3500 V.
  • the ion transfer tube has a temperature of 325 °C and vaporizer temperature of 350 °C.
  • a Shimadzu LC20AD, Ultra Performance Liquid Chromatography (UPLC) system (Shimadzu Corporation, Kyoto, Japan) equipped with Shimadzu 8040 triple quadrupole (QqQ) mass analyzer (Shimadzu Corporation, Kyoto, Japan) with an electrospray ionization source (ESI) operated in the positive charge mode for the quantification of 2.
  • UPLC Ultra Performance Liquid Chromatography
  • QqQ triple quadrupole
  • ESI electrospray ionization source
  • TGR assay solutions (1 ml each) were prepared as described in the main manuscript.
  • Compound 2, NADPH, and incubation time was varied as following: 1) TGR and 2, no preincubation, 2) TGR, 2, and NADPH, no preincubation, 3) TGR and 2, 15 min preincubation, 4) TGR, 2, and NADPH, 15 min preincubation, 5) TGR and NADPH followed by 15 min preincubation, 2 was added after 15 min preincubation, 6) TGR and 2 followed by 15 min preincubation, NADPH was added after 15 min preincubation.
  • reaction mixtures were terminated by the addition of 250 ⁇ l of ethyl acetate, extracted with 1 ml of methyl tert-butyl ether. The organic layer was evaporated in vacuo, and the residue was redissolved in 0.5 mL of 50% MeOH before injection onto LC column.
  • LC-MS analysis was done on a Waters SYNAPT quadrupole/time-of-flight mass spectrometer operated in positive ion electrospray mode. The column was Waters XBridge C8 column and gradient was from 20-90% MeCN/0.1% formic acid over 12 minutes. No additional ions except for those corresponding to 2 were detected.
  • Covalent TGR inhibitor TRi-1 was used as a positive control for the reaction with (N-tert- butoxycarbonyl)-L-selenocysteine methyl ester. The reactivity of TRi-1 was tested similarly as described above for compound 2. An adduct between TRi-1 was detected by TLC and LCMS analysis. [0300] Cryo-Em Methods [0301] Negative staining Transmission electron microscopy: The homogeneity of the protein before structural determination was assessed by negative staining electron microscopy.
  • Cryogenic Electron Microscopy The specimens for cryogenic electron microscopy (Cryo-EM) have been prepared onto 300 mesh Ultrafoil Au R1.2/1.3 grids (Quantifoil Micro Tools GmbH, Germany). First, 0.4 mg/ml TGR protein was mixed with 5 mM of inhibitor (9VP128-2) in buffer solution containing 0.15% DMSO and incubated 30 min at room temperature (20 °C). Then, 3.5 ⁇ l of the sample was applied onto 45 s glow-discharged quantifoil grids and vitrified in liquid ethane using a Vitrobot Mark IV (ThermoFisher Scientific) at 100% humidity, 7 s blotting time and 10 s waiting time.
  • Cho-EM cryogenic electron microscopy
  • Single-particle structure determination has been carried out with Relion v3.1.2 88 after motion-correction using 5 ⁇ 5 patches 89 and CTF estimation.
  • the crystal structure of TGR (PDB ID: 2V6O [https://www.rcsb.org/structure/2V6O]) 32 was docked manually in the cryo-EM map using COOT 91 .
  • 90 Map local anisotropic sharpening and real space refinement was carried out with Phenix, 92 while manual model building was done with COOT. After several cycles of refinement and model building, the inhibitor was placed into the cryo-EM map.
  • Data Availability Source data are provided with this paper.
  • cryo-EM data generated in this study have been deposited in the PDB and in the EM data bank under accession codes 8A1R [https://www.rcsb.org/structure/8A1R] and EMD-15084 [https://www.ebi.ac.uk/emdb/EMD- 15084], respectively.
  • the cryo-EM data will be released immediately upon publication.
  • ChEMBL25 data used in this study are available in the ChEMBL25 database under accession code [http://doi.org/10.6019/CHEMBL.database.25] RESULTS [0306] Fragment-based drug design and chemistry: [0307] Utilizing “actives” identified in a quantitative high-throughput screen against Schistosoma mansoni TGR, 20,35 92 commercially available low molecular weight (MW) compounds/fragments were tested by X-ray crystallography. 33, 34, 36 Some of the fragments, for which X-ray structures were obtained, were found in the doorstop pocket expected to be critical for TGR inhibition and adjacent to the NADPH binding site.
  • subpocket A binds 2- carboxynaphthyridine and subpockets B and C bind 4-(2-hydroxyethyl)-1-piperazineethane (HEPE).
  • TGR IC 50 s for these low MW fragments varied from 0.76 mM to 4.4 mM. Considering their low MW and non-covalent nature of inhibition of TGR, these compounds were deemed appropriate for fragment-based design. [0308] Further structure-based iterative optimization resulting in inhibitors was driven by bioisosteric replacement of the fragments bound to subpockets A-C, scaffold-hopping, de novo design, and medicinal chemistry and was facilitated by SZMAP/GamePlan, 37 vBrood, 38 and MOE software.
  • subpockets B and C are rather large, subpocket A is narrow and restricted in depth by FAD at the bottom of the pocket, limiting the choice of modifications of the inhibitor in subpocket A.
  • SZMAP and GamePlan analyses suggested placement of polar and non-polar substituents in multiple locations, including those that were relatively remote, we intentionally limited the modifications to those in proximity or to the putative chimera molecule itself to maximize the potential for further improvements during structure-activity relationship (SAR) studies.
  • SAR structure-activity relationship
  • TGR is inhibited in S. mansoni worms
  • a predicted outcome of TGR inhibition in worms is the accumulation of oxidized GSH (GSSG) because of attenuated reduction to GSH by TGR, leading to decreases in the GSH/GSSG ratio.
  • GSSG oxidized GSH
  • TRFS-Green a TrxR-selective fluorescent probe, 43, 44 TRFS-Green.
  • the fluorescence of TRFS-Green is induced by the TGR (or TrxR)-mediated disulfide cleavage followed by intramolecular cyclization to liberate the masked naphthalimide fluorophore.
  • Treatment of NTS with inhibitors 1, 2, 4, 7, and 8, positive control AF, or negative control 12 for 2 h was followed by addition of TRFS-Green.
  • TGR inhibitors do not react covalently with GSH, selenocysteine, or TGR, and inhibition of TGR is reversible
  • compound 2 and a known covalent inhibitor of TGR TRi-1, 20, 45 were incubated with GSH or the N-Boc protected methyl ester of selenocysteine, and the reaction mixtures were analyzed by LCMS. Unlike TRi-1, no reaction of 2 with either thiol or selenol groups in GSH or protected selenocysteine was observed.
  • TGR inhibitors were tested in the jump dilution assay. 46, 47 In the jump dilution assay, after incubation of enzyme, NADPH, and inhibitor, the reactions are diluted to well below the IC 50 for the inhibitor allowing its release from the enzyme and activity is determined. We find that our inhibitors are reversible, while known covalent TGR inhibitors, 20, 45 including AF, Stattic, and TRi- 1, are irreversible (FIG.22a).
  • TGR inhibitors target a reduced form of TGR
  • Inhibitors 6-8 were incubated with TGR with and without NADPH, and the inhibition of TGR activity was determined after adding a second aliquot of NADPH and 5,5’-dithiobis (2- nitrobenzoic acid) (DTNB). Incubation of these inhibitors with TGR in the absence of NADPH led to significantly attenuated enzyme inhibition compared to inhibition resulting from incubation in the presence of NADPH (FIG.22b).
  • Typical TGR inhibitor studies utilize a 15-minute preincubation step of enzyme, NADPH, and inhibitor.
  • reaction is started by the addition of substrate, DTNB or GSSG, and a second aliquot of NADPH. While compounds 6-8 caused maximal inhibition of TGR within 15 minutes (referred to here as fast inhibitors; Table 3, FIG. 22c), compounds 1-5 were found to be slow inhibitors as they displayed little to no inhibition after 15 minutes, but time-dependent inhibition of TGR over 25 h (FIG.22d and Table 3).
  • both uncompetitive and noncompetitive inhibitors exert their action through the binding of the ES complex and/or downstream catalytic species, with the difference that noncompetitive ones bind also to free enzyme.
  • TGR and more generally in TrxRs, electron transfer from NADPH to the enzyme is fast and practically irreversible and so an actual ES complex (NADPH-TGR) is not significantly populated during the catalytic cycle. 17
  • NADP + -TGR(H) reduced complexes indicating that electrons are inside the polypeptide chain of the enzyme giving rise to the EH 2 and the EH 4 species.
  • Inhibitors do not convert TGR into an NADPH oxidase
  • Several covalent inhibitors of TGR are electrophilic compounds reacting with the Sec residue at the C-terminus, which induce a transition in the enzyme from an antioxidant to a pro- oxidant with increased NADPH consumption. 20, 45
  • Stattic and TRi-1 converted TGR to a pro-oxidant enzyme, whereas our non-covalent inhibitors did not increase NADPH consumption or superoxide production (FIG.22f,g), indicating again the lack of involvement of the Sec-containing C-terminus in the mechanism of action of the newly described TGR inhibitors.
  • TGR inhibitors bind to the doorstop pocket [0322]
  • Our attempts to obtain X-ray co-crystal structures of TGR and inhibitors resulted in structures with no detectable density of the inhibitors, possibly owing to the limited solubility of the compounds in the crystallization conditions.
  • the cycloheptyl substituent in TGR uncompetitive inhibitor 8 was replaced with a sugar moiety, resulting in compound 9, a noncompetitive inhibitor and thus capable of binding the enzyme in absence of NADPH.
  • co-crystallization trials failed again.
  • the pinane ring of the compound interacts with F324, V469, T471, A481 and L484 in subpocket C
  • the indole interacts with F324, G325, P439 and L441 present in subpocket B
  • the sugar moiety through its hydroxyl groups, is close to the main chain carbonyls of G323 and R322 in one conformation and with the analogous groups of G437 and Q440 occupying the hydrophilic portion of subpocket A in the other conformation.
  • 17 inhibitor 9 does not sterically interfere with NADPH binding.
  • TGR inhibitors can achieve selectivity over mammalian enzymes
  • Compounds 1-8 affected viability of Vero cells (EC 50 ) mostly at concentrations >50 ⁇ M (Table 4). An analysis of the raw data shows that for 1, 4-7, and 9, EC 50 against Vero cells is likely to be >200 ⁇ M.
  • TrxR1 cytoplasmic TrxR1
  • TrxR1 IC 50 values varied from 4.9 to >50 ⁇ M (Table 3).
  • Compound 6 is at least 25 times more potent against TGR than human TrxR1 indicating that selective enzyme inhibition is possible.
  • Table 4 Ex vivo characterization of 1-10, controls 11, 12, auranofin (AF), praziquantel (PZQ), and meclonazepam (MZM).
  • TGR inhibitors are potent schistosomicidal agents ex vivo
  • Compounds in Table 3 were tested for schistosomicidal activity against S. mansoni and S. japonicum adult worms and S.
  • the PZQ LD 50 for NTS was determined after just 24 h exposure using both the Cell TiterGlo (27.1 ⁇ 2.27 ⁇ M, Table 4) and the phenotypic analysis (42.9 ⁇ 0.83 ⁇ M), which is also used by others 54 . If incubation with compounds is prolonged, superior efficacies can be reached: after 72 h exposure of NTS to compounds 1 and 6 had LD 50 s of 2.2 ⁇ 0.19 and 7.8 ⁇ 2.36 ⁇ M respectively, whereas 2 had 0.18 ⁇ 0.007 ⁇ M. In the assay with juvenile S.
  • TGR inhibitors 1- 5 displayed potency comparable to that against adult worms and superior to PZQ and MZM, whereas LD 50 for 6-8, PZQ and MZM were all >30 ⁇ M. Potency of inhibitors 1-4, 7, and 8 against S. mansoni and S. japonicum adult worms was generally comparable. [0327] Efflux may affect efficacy of TGR inhibitors ex vivo [0328] Compounds 7-9 were found to have significant NTS killing activity, but the decrease in GSH/GSSG ratio was attenuated and less adult schistosomicidal activity was observed.
  • mice 42 days post infection (d.p.i.) with 1 (100 mg/kg i.p.) resulted in a 44% decrease in worm and a 40% reduction in egg burdens, respectively.
  • Administration, at 42 d.p.i., of two doses of 1 (100 mg/kg i.p. bid) resulted in 54% and 48% decrease in worm and egg burdens, respectively.
  • a single dose of 2 (100 mg/kg i.p.) at 42 d.p.i. resulted in a 85% decrease in worm burden and 73% decrease in egg burden. Decreased efficacy was observed when this dose was spread over two administrations (50 mg/kg i.p. at 42 d.p.i.
  • a single dose of 6 (100 mg/kg i.p.) at 42 d.p.i. resulted in a 34% decrease in worm and 3% decrease in egg burdens, respectively, while two doses (100 mg/kg i.p. at 42 d.p.i. and 100 mg/kg i.p. at 45 d.p.i.), did not result in increased efficacy (38% decrease in worm and 18% reduction in egg burdens, respectively).
  • Plasma exposure of mice to both 1 and 2 is compatible with observed efficacy and no overt toxicity was observed. Based on the time points available, the half-lives of 1 and 2 can be estimated at 90 min.
  • the TGR inhibitor demonstrating greatest efficacy in treating infected mice, 2 was also studied after oral administration: 2 (200 mg/kg p.o.) gave plasma concentrations of 0.71, 0.77, and 0.40 ⁇ M at 30, 60, and 120 min, respectively.
  • Non-covalent inhibitors of TrxR class of redox proteins may have broad application
  • cryo-EM single particle cryo-EM can be applied to a member of the pyridine nucleotide-disulfide oxidoreductase protein family, which includes crucial drug targets for several human diseases.
  • the cryo-EM data show inhibitor 9 bound in the doorstop pocket, indicating that the design strategy, based on the initial fragments found in X-ray co-crystal structures, is successful.
  • this class of inhibitors trap the NADP + -TGR(H) species, preventing NADP + release.
  • the evidence is provided by: (i) the inhibitors are found in the secondary site known to interact with outgoing NADP + in related pyridine nucleotide–disulfide oxidoreductases; 53 (ii) inhibition is reversible; and (iii) inhibition is exerted by binding to the NADP + -TGR(H) reduced species.
  • One advantage of noncompetitive and uncompetitive inhibitors over competitive inhibitors in disruption of metabolic pathways, is the lack of competition with endogenous substrates that may be present at high cellular concentrations as a result of enzyme inhibition, making uncompetitive inhibitors, in particular, ideal for drug development.
  • TrxR and TGR proteins appear to be sufficiently different, as evidenced by the differential activity of our inhibitors against TGR and human, B. malayi, and P. falciparum TrxRs, and inhibitors selective for individual enzymes could be developed.
  • Human TrxR1 (the cytosolic isoform) displays 74% sequence identity in the doorstop pocket residues with respect to TGR.
  • TrxR1 in this site is different with respect to TGR 33 due to the presence of charged and bulky residues, i.e., E337, D338, E341, E368 and K389 in human TrxR1 in place of A436, G437, Q440, S467 and D488 in TGR.
  • E337, D338, E341, E368 and K389 in human TrxR1 in place of A436, G437, Q440, S467 and D488 in TGR.
  • TGR inhibitors are schistosomicidal both ex vivo and in vivo. These inhibitors outperform PZQ, the drug of choice to fight schistosomiasis.
  • the LD 50 of compound 1 was similar to that of PZQ, whereas 2 was 5-fold more potent than PZQ.
  • the LD 50 for PZQ against adult worms has been reported as 1.5 ⁇ M and 5.1 ⁇ M for male and female worms, respectively; 61 however, these LD 50 s were determined after overnight exposure to PZQ followed by 8 days culture.
  • Our comparison of PZQ activity against NTS in the phenotypic and Cell Titer Glo assays found similar LD 50 s immediately after 24 h exposure.
  • the compounds presented herein have similar activities against both S. mansoni and S. japonicum adult worms and show no differences between male and female parasites. The similar effect observed against S.
  • japonicum can be rationalized by the 100% homology of the residues in the doorstop pocket of TGR from the two species.
  • the complete reliance of all schistosome species 15 on TGR for regulation of the redox defense network, and our previous results with several covalent TGR inhibitors, 19, 20 are compatible with species and sex concordance.
  • some inhibitors (7-9) on the basis of adult schistosomicidal activity in combination with efflux transport blockers, appear to be substrates for efflux pumps, this does not cause species nor sex differences.
  • administration of inhibitors 1, 2, and 6 resulted in significant reductions in both worm and egg burdens.
  • the PZQ plasma exposure measured by C max , is substantially lower than the LD 50 against adult worms and NTS reported by others, 61, 62 and substantially below the LD 50 for NTS killing measured herein (27-43 ⁇ M).
  • the half-life of PZQ in healthy volunteers (1.6 h) 64 is also much shorter than the 3-8 days assays used by others to determine LD 50 for worms and NTS ex vivo. Discordance between ex vivo potency and in vivo PK/PD has many potential causes, one of which, in the case of schistosomicidal agents, is the involvement of the host immune response.
  • the schistosomicidal activities of PZQ and of potassium antimonial tartrate, a drug used in the past for schistosomiasis and a TGR inhibitor, are reduced in immunosuppressed mice, 65 indicating a crucial role of the host immune system in the mechanism of action of schistosomicidal agents in vivo.
  • the efficacy observed for compounds 1 and 2 in vivo incorporates a similar role for the host immune response as seen for other schistosomicidal agents.
  • TrxR Given the mechanism of enzyme inhibition, our non-covalent inhibitors can be targeted to TrxR and can be applicable to development of therapeutics for a broad range of diseases. All TrxR enzymes require an NADPH-dependent reduction step to exert their function in vivo and TrxR is a therapeutic target for cancer and infectious diseases. 21, 67 Several currently used cancer drugs exert their anticancer activity in part through covalent inhibition of TrxR 21 and two covalent TrxR inhibitors are currently in clinical trials. 68 TrxRs from filarial nematodes and malaria parasites have been validated as druggable 56, 57 and have structures available.
  • Praziquantel a new board-spectrum antischistosomal agent.
  • ODTs orally disintegrating tablets
  • Copeland RA Evaluation of enzyme inhibitors in drug discovery. A guide for medicinal chemists and pharmacologists. Methods Biochem. Anal.46, 1-265 (2005). 48. Bartee D, Morris F, Al-Khouja A, Freel Meyers CL. Hydroxybenzaldoximes Are D-GAP- Competitive Inhibitors of E. coli 1-Deoxy-D-Xylulose-5-Phosphate Synthase. ChemBioChem 16, 1771-1781 (2015). 49. Kumar S, et al. Structure based development of phenylimidazole-derived inhibitors of indoleamine 2,3-dioxygenase. J. Med. Chem.51, 4968-4977 (2008). 50.
  • Thioredoxin reductase is essential for the survival of Plasmodium falciparum erythrocytic stages. J. Biol. Chem. 277, 25970-25975 (2002). 58. Holdgate GA, Meek TD, Grimley RL. Mechanistic enzymology in drug discovery: a fresh perspective. Nat. Rev. Drug. Discov.17, 115-132 (2016). 59. Saccoccia F, et al. Thioredoxin reductase and its inhibitors. Current Protein & Peptide Science 15, 621-646 (2014). 60. Benhar M, Shytaj IL, Stamler JS, Savarino A.
  • Schistosoma mansoni eggshell formation is regulated by pH and calcium. Exp. Parasitol.73, 295-310 (1991). 85. Stocking EM, Schwarz JN, Senn H, Salzmann M, Silks LA. Synthesis of L-selenocystine, L-[77Se]selenocystine and L-tellurocystine. J. Chem. Soc. Perkin 1, 2443-2448 (1997). 86. Reddy KM, Mugesh G. Modelling the Inhibition of Selenoproteins by Small Molecules Using Cysteine and Selenocysteine Derivatives. Chem. Eur. J.25, 8875-8883 (2019). 87. Mastronarde DN.

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Abstract

Conformément au(x) objectif(s) de la présente invention, tels que mis en oeuvre et largement décrits ici, l'invention, selon un aspect, concerne des composés qui sont des inhibiteurs de la thiorédoxine glutathione réductase (TGR), qui est une clé pour la survie de vers parasites. Selon un aspect, les composés décrits ici traitent des maladies produites par des vers parasites tels que, par exemple, des vers résistants au praziquantel.
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