WO2010018458A2 - Phenol derivatives and methods of use thereof - Google Patents

Phenol derivatives and methods of use thereof Download PDF

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Publication number
WO2010018458A2
WO2010018458A2 PCT/IB2009/006751 IB2009006751W WO2010018458A2 WO 2010018458 A2 WO2010018458 A2 WO 2010018458A2 IB 2009006751 W IB2009006751 W IB 2009006751W WO 2010018458 A2 WO2010018458 A2 WO 2010018458A2
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Prior art keywords
hydroxy
pyridin
optionally substituted
thiazol
cyano
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PCT/IB2009/006751
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French (fr)
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WO2010018458A3 (en
Inventor
Yong Rae Hong
Dongkyu Shin
Seonggu Ro
Joong Myung Cho
Hyun Tae Kim
Jun Hee Lee
Jeong Mi Kim
Whee Seong Lee
Jong-Ryoo Choi
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Crystalgenomics, Inc.
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Publication of WO2010018458A2 publication Critical patent/WO2010018458A2/en
Publication of WO2010018458A3 publication Critical patent/WO2010018458A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/60—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 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/60—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 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/22—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D277/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention is in the field of pharmaceutical chemistry, and particularly in the field of compounds that affect the stability of hypoxia inducible factor- ⁇ (HIF- ⁇ ) and the expression of HIF-regulated genes, and methods of using the same for the treatment of disease.
  • HIF- ⁇ hypoxia inducible factor- ⁇
  • hypoxia-inducible factor (HIF) family of transcription factors play a central regulatory role in the control of the intracellular response to hypoxia, throughout the body.
  • HIF itself is primarily regulated by prolyl hydroxylases (PHDs), as well as asparaginyl hydroxylases.
  • PHDs prolyl hydroxylases
  • these PHDs site specifically hydroxylate the alpha subunit of HIF, which ultimately results in its degradation.
  • the body continually expresses and degrades the HIF alpha protein.
  • Modulation of PHD via the compounds disclosed herein will alter the regulation of cellular oxygen homeostasis. This has utility in any disease state where ischemia, hypoxia, and/or anemia plays a role
  • X 1 -X 4 is each independently carbon or nitrogen, provided that at least one of X 1 -X 4 is carbon;
  • R 1 is selected from the group consisting of hydrogen, optionally substituted alkyl, and cationic counterion;
  • Xi and X 2 are carbon and R 2 and R3 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; or
  • X 2 and X 3 are carbon and R 3 and R 4 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring;
  • A is a moiety of Formula II, Formula HA, or Formula III:
  • Yi is selected from the group consisting of nitrogen, oxygen, and sulfur, as valence allows;
  • Y 2 and Y 3 is each independently selected from the group consisting of carbon, CH, oxygen, nitrogen, and sulfur;
  • Y 4 is carbon or nitrogen
  • Y 2 and Y 3 are carbon and R 7 and Rs taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; bond a is single bond or double bond, such that Y 2 and Y3 have a complete octet along with R 7 and R 8 ; Zi-Z 5 is each independently carbon or nitrogen, provided that at least two of Zi-Z 5 are carbon;
  • Ri 5 is independently selected as it appears from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and R 16 and R 17 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; or Z3 and Z 4 are carbon and R 12 and Rn taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring.
  • compositions comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, and a physiologically acceptable carrier, diluent, or excipient.
  • a subject in addition, disclosed are methods of controlling HIF levels in a subject, inhibiting hydroxylation of HIF ⁇ in a subject, inhibiting prolyl hydroxylases in a subject, modulating expression of HIF-controlled genes in a subject, treating an HIF -related disorder in a subject, treating diseases associated with ischemia, hypoxia and/or anemia, treating conditions in a subject associated with angiogenesis and/or erythropoietin levels, or treating a disorder in a subject, the method comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
  • pharmaceutically acceptable salt means those salts of compounds of the invention that are safe and effective for use in a subject and that possess the desired biological activity.
  • Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the invention.
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1,1 '
  • Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.
  • the term "ester” refers to a chemical moiety with formula -(R) n -COOR', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.
  • An "amide” is a chemical moiety with formula -(R) n -C(O)NHR' or -(R) n -NHC(O)R', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.
  • An amide may be an amino acid or a peptide molecule attached to a molecule of the present invention, thereby forming a prodrug.
  • Any amine, hydroxy, or carboxyl side chain on the compounds of the present invention can be esterif ⁇ ed or amidif ⁇ ed.
  • the procedures and specific groups to be used to achieve this end is known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York, N. Y., 1999, which is incorporated herein in its entirety.
  • a “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • a group of this invention is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the substituents described for that group.
  • the substituent may be selected from the same group of substituents.
  • substituent is a group that may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (hetereoalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sul
  • C m -C n in which "m” and “n” are integers refers to the number of carbon atoms in an alkyl, alkenyl or alkynyl group or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, or aryl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, or of the aryl can contain from “m” to "n", inclusive, carbon atoms.
  • a "C 1 -C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, CH 3 CH(CH 3 )-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )-, and (CH 3 ) 3 CH-. If no "m” and "n” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group, the broadest range described in these definitions is to be assumed.
  • alkyl refers to a straight or branched chain fully saturated (no double or triple bonds) hydrocarbon (all carbon) group.
  • alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, amyl, tert-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
  • an alkyl group of this invention may be substituted or unsubstituted.
  • the substituent group(s) may be one or more group(s) independently selected from cycloalkyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, oxo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR a R b , protected hydroxyl, protected amino,
  • substituted alkyl groups include, without limitation, 2-oxo-prop-l-yl, 3- oxo-but-1-yl, cyanomethyl, nitromethyl, chloromethyl, hydroxymethyl, tetrahydropyranyloxymethyl, m-trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylaminomethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichlorobutyl, 2-aminopropyl, 1-chloroethyl, 2-chloroethyl, 1-bromoethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroethyl, 1-iodoethyl, 2-iodo
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
  • alkenyl group of this invention may be unsubstituted or substituted.
  • the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.
  • substituted alkenyl groups include, without limitation, styrenyl, 3-chloro-propen-l-yl, 3-chloro-buten-l-yl, 3-methoxy-propen-2-yl, 3-phenyl-buten-2-yl and l-cyano-buten-3-yl.
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
  • alkynyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.
  • cycloalkyl refers to a completely saturated (no double bonds) hydrocarbon ring. Cycloalkyl groups of this invention may range from C 3 to C 8 . A cycloalkyl group may be unsubstituted or substituted. If substituted, the substituent(s) may be selected from those indicated above with regard to substitution of an alkyl group.
  • the "cycloalkyl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms).
  • the ring that is connected to the rest of the molecule is a cycloalkyl as defined above.
  • the other ring(s) in the fused ring system may be a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, or a heteroalicyclic.
  • cycloalkenyl refers to a cycloalkyl group that contains one or more double bonds in the ring although, if there is more than one, they cannot form a fully delocalized pi-electron system in the ring (otherwise the group would be "aryl,” as defined herein).
  • a cycloalkenyl group of this invention may unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.
  • the "cycloalkenyl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms).
  • the ring that is connected to the rest of the molecule is a cycloalkenyl as defined above.
  • the other ring(s) in the fused ring system may be a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, or a heteroalicyclic.
  • alkylene refers to an alkyl group, as defined here, which is a biradical and is connected to two other moieties.
  • methylene -CH 2 -
  • ethylene -CH 2 CH 2 -
  • proylene - CH 2 CH 2 CH 2 -
  • isopropylene -CH 2 -CH(CH 3 )-
  • isobutylene -CH 2 -CH(CH 3 )-CH 2 -
  • cycloalkylene refers to a cycloalkyl group, as defined here, which binds in an analogous way to two other moieties. If the alkyl and cycloalkyl groups contain unsaturated carbons, the terms "alkenylene” and "cycloalkenylene” are used.
  • An acyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.
  • Example of substituted acyl groups include, without limitation, 4- phenylbutyroyl, 3-phenylbutyroyl, 3-phenylpropanoyl, 2-cyclohexanylacetyl, cyclohexanecarbonyl, 2-furanoyl and 3-dimethylaminobenzoyl.
  • aryl refers to a carbocyclic (all carbon) ring that has a fully delocalized pi-electron system.
  • the "aryl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the aryl is a fused ring system, then the ring that is connected to the rest of the molecule has a fully delocalized pi-electron system. The other ring(s) in the fused ring system may or may not have a fully delocalized pi-electron system.
  • aryl groups include, but are not limited to, benzene, naphthalene and azulene.
  • heteroaryl rings include, but are not limited to, furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyran, pyridine, pyridazine, pyrimidine, pyrazine, indole, isoindole, isoquinoline and triazine.
  • heterocycloalkyl refers to a ring having in the ring system one or more heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • the ring may also contain one or more double bonds provided that they do not form a fully delocalized pi-electron system in the rings.
  • Heteroalicyclyl groups of this invention may be unsubstituted or substituted.
  • the substituent(s) may be one or more groups independently selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, amino, protected amino, carboxamide, protected carboxamide, alkylsulfonamido and trifluoromethanesulfonamido.
  • the "heterocycloalkyl” group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the heterocycloalkyl is a fused ring system, then the ring that is connected to the rest of the molecule is a heterocycloalkyl as defined above.
  • the other ring(s) in the fused ring system may be a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, or a heteroalicyclic.
  • substituted phenylalkyl groups include, without limitation, 2-phenyl-l-chloroethyl, 2-(4-methoxyphenyl)ethyl, 4-(2,6-dihydroxy phenyl)hexyl, 2-(5-cyano-3-methoxyphenyl)pentyl, 3-(2,6-dimethylphenyl)propyl, 4-chloro-3- aminobenzyl, 6-(4-methoxyphenyl)-3 -carboxy(n-hexyl), 5 -(4-aminomethylphenyl)-3 -
  • heteroarylalkyl and “heteroalicyclylalkyl” refer to a heteroaryl or a heteroalicyclyl group covalently bonded to an alkyl group, as defined herein.
  • examples of such groups include, without limitation, 2-pyridylethyl, 3-pyridylpropyl, 4-furylhexyl, 3- piperazylamyl and 3-morpholinylbutyl.
  • Presently preferred heteroarylalkyl and heteroalicyclylalkyl groups are those in which a presently preferred heteroaryl or heteroalicyclyl group is covalently bonded to a presently preferred alkyl group as disclosed herein.
  • phenyl refers to a 6-member aryl group.
  • a phenyl group may be unsubstituted or substituted.
  • the substituent(s) is/are one or more, preferably one or two, group(s) independently selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, -NR a R b wherein R a and R b are as defined above but in addition R a may be an amino protecting group as defined herein, carboxamide, protected carboxamide, N-alkylcarboxamide, protected N- alkylcarboxamide, N,N-dialkylcarboxamide, trifluoromethyl, N-alkylsulfonylamino, N- (phenylsulfonyl)amino and pheny
  • substituted phenyl groups include, without limitation, 2, 3 or A- chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2, 3 or A- bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2, 3 and 4-fluorophenyl, 2, 3 or A- hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof, 2, 3 or A- nitrophenyl; 2, 3 or 4-cyanophenyl; 2, 3 or 4-methylphenyl, 2,4-dimethylphenyl, 2, 3 or 4-(iso- propyl)phenyl, 2, 3 or 4-ethylphenyl, 2, 3 or 4-(n-propyl)phenyl, 2,6-dimethoxyphenyl, 2, 3 or A- methoxyphenyl, 2, 3 or 4-ethoxyphenyl
  • phenylalkoxy refers to a “phenylalkyl-O-" group with “phenyl” and “alkyl” as defined herein.
  • a phenylalkoxy group of this invention may be substituted or unsubstituted on the phenyl ring, in the alkyl group or both.
  • phenylalkoxy groups include, without limitation, 2-(4-hydroxyphenyl)ethoxy, 4-(4-methoxyphenyl)butoxy, (2R)-3- phenyl-2-amino-propoxy, (2S)-3-phenyl-2-amino-propoxy, 2-indanoxy, 6-phenyl-l-hexanoxy, cinnamyloxy, 2-phenyl-l-propoxy and 2,2-dimethyl-3-phenyl-l-propoxy.
  • halo and halogen refer to the fluoro, chloro, bromo or iodo atoms. Preferred halogens are chloro and fluoro.
  • amino protecting group refers to a group commonly employed to keep (i.e., to "block” or “protect”) an amino group from reacting with a reagent while it reacts with an intended target functional group of a molecule.
  • a "protected carboxamide” refers to a carboxamide in which the nitrogen is substituted with an amino protecting group.
  • amino protecting groups include, without limitation, formyl ("For"), trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl groups, t-butoxycarbonyl ("Boc”), 2-(4-biphenylyl)propyl-2-oxycarbonyl ("Bpoc”), 2-phenylpropyl-2-oxycarbonyl ("Poc”), 2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenylethyl-l-oxycarbonyl, 1,1-diphenylpropyl- 1-oxycarbonyl, 2-(3,5-dimethoxyphenyl)propyl-2-oxycarbonyl (“Ddz”), 2-(p-toluyl)propyl-2- oxycarbonyl, cyclopentanyloxycarbonyl, 1 -methyl cyclopentanyloxycarbonyl, cyclopentanyl
  • amino-protecting group employed is not critical so long as the derivatized amino group is stable to the conditions of the subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule.
  • amino- protecting groups are Boc, Cbz and Fmoc. Descriptions of these and other amino-protecting groups may be found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, N. Y., 1991, Chapter 7, M.
  • the ester employed is not critical so long as it is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule.
  • carboxy-protecting groups are found in E. Haslam, "Protective Groups in Organic Chemistry,” J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, N.Y., 1991, Chapter 5.
  • a "hydroxyl protecting group” refers to a readily cleavable group that replaces the hydrogen of the hydroxyl group, such as, without limitation, tetrahydropyranyl, 2- methoxypropyl, 1 -ethoxyethyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, t- butyl, t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, benzyl, allyl, trimethylsilyl, (t-butyl)dimethylsilyl, and 2,2,2-trichloroethoxycarbonyl.
  • hydroxyl protecting groups is not critical so long as the derivatized hydroxyl group is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of hydroxy-protecting groups are described by C. B. Reese and E. Haslam, "Protective Groups in Organic Chemistry," J. G. W.
  • alkylthio refers to an “alkyl-S-” group, with alkyl as defined above.
  • alkylthio group examples include, without limitation, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio and t-butylthio.
  • alkylsulfmyl refers to an "alkyl-SO-" group, with alkyl as defined above.
  • alkylsulfinyl groups include, without limitation, methylsulfmyl, ethylsulfmyl, n-propylsulfmyl, isopropylsulfmyl, n-butylsulfmyl and sec-butylsulfinyl.
  • alkylsulfonyl refers to an "alkyl-SO2-" group.
  • alkylsulfonyl groups include, without limitation, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, and t-butylsulfonyl.
  • phenylthio As used herein, "phenylthio,” “phenylsulfmyl,” and “phenylsulfonyl” refer to a
  • substituted alkylaminocarbonyl examples include, without limitation, methoxymethyl- aminocarbonyl, 2-chloroethylaminocarbonyl, 2-oxopropylaminocarbonyl and A- phenylbutylaminocarbonyl .
  • alkylaminothio- carbonyl groups include, without limitation, methylaminothiocarbonyl, ethylaminothiocarbonyl, propylaminothiocarbonyl and butylaminothiocarbonyl .
  • alkyl-substituted alkylaminothiocarbonyl groups include, without limitation, methoxymethylaminothiocarbonyl, 2-chloroethylaminothiocarbonyl, 2- oxopropylaminothiocarbonyl and 4-phenylbutylaminothiocarbonyl.
  • hydroxyl refers to an “-OH” group.
  • cyano refers to a "-C ⁇ N” group.
  • nitro refers to an "-NO 2 " group.
  • a "trihalomethanesulfonyl” group refers to an "XsCSO 2 -" group wherein X is a halogen.
  • a "thiocyanato" group refers to a "-CNS” group.
  • An "isothiocyanato" group refers to an " -NCS” group.
  • S-sulfonamido refers to a "-SO 2 NR" group with R as defined above.
  • N-sulfonamido refers to a "RSO 2 NH-” group with R as defined above.
  • a "trihalomethanesulfonamido” group refers to an "X 3 CSO 2 NR-" group with X as halogen and R as defined above.
  • perhaloalkyl it is meant an alkyl moiety where all of the hydrogen atoms normally present on the alkyl are replaced by a halogen.
  • a perchloroalkyl is an alkyl moiety where all of the carbon atoms not connected to the rest of the molecule are connected to chlorine atoms.
  • an “ester” refers to a “-C(O)OR a " group with R a as defined herein.
  • an “amide” refers to a "-C(O)NR a R b " group with R a and R b as defined herein.
  • Any unsubstituted or monosubstituted amine group on a compound herein can be converted to an amide, any hydroxyl group can be converted to an ester and any carboxyl group can be converted to either an amide or ester using techniques well-known to those skilled in the art (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John
  • an “ether” refers to an "-C-O-C-" group wherein either or both carbons may independently be part of an alkyl, alkenyl, alkynyl, aryl, heteroaryl or heteroalicyclyl group.
  • halogenated ether refers to an ether in which the groups to either side of the oxygen are both alkyl substituted with halogen.
  • amino acid refers to any one of the twenty naturally-occurring L- amino acids, to their non-natural D-enantiomers, to non-naturally occurring amino acids such as, without limitation, norleucine ("NIe”), norvaline (“Nva”), L- or D-naphthalanine, ornithine
  • Amino acids are referred to herein by their full chemical names, by their three letter codes, or by their one letter code, which are well-known to those skilled in the art. Unless the chirality of an amino acid is specifically designated or the amino acid is expressly stated to be a naturally occurring (i.e., L-) amino acid, the amino acid may be D or L or a racemic mixture of the two.
  • a “functionalized resin” refers to any resin to which functional groups have been appended. Such functionalized resins are well-known to those skilled in the art and include, without limitation, resins functionalized with amino, alkylhalo, formyl or hydroxy groups.
  • Examples of functionalized resins which can serve as solid supports for immobilized solid phase synthesis are well-known in the art and include, without limitation, 4- methylbenzhydrylamine-copoly(styrene-l% divinylbenzene) (MBHA), 4- hydroxymethylphenoxymethyl-copoly(styrene- 1 % divinylbenzene), 4-oxymethyl-phenyl- acetamido-copoly(stryene-l% divinylbenzene) (Wang), 4-(oxymethyl)-phenylacetamido methyl (Pam), and TentagelTM, from Rapp Polymere Gmbh, trialkoxy-diphenyl-methyl ester- copoly(styrene-l% divinylbenzene)(RINK) all of which are commercially available.
  • Other functionalized resins useful in the synthesis of the compounds of this invention will become apparent to those skilled in the art based on the disclosures herein. All such resins are within the scope
  • compositions comprising the racemic mixture of the two enantiomers, as well as compositions comprising each enantiomer individually substantially free of the other enantiomer.
  • contemplated herein is a composition comprising the S enantiomer substantially free of the R enantiomer, or a composition comprising the R enantiomer substantially free of the S enantiomer.
  • substantially free it is meant that the composition comprises less than 10%, or less than 8%, or less than 5%, or less than 3%, or less than 1% of the minor enantiomer.
  • compositions comprising a mixture of the various diastereomers, as well as compositions comprising each diastereomer substantially free of the other diastereomers.
  • the recitation of a compound, without reference to any of its particular diastereomers, includes compositions comprising all four diastereomers, compositions comprising the racemic mixture of R,R and S, S isomers, compositions comprising the racemic mixture of R,S and S,R isomers, compositions comprising the R,R enantiomer substantially free of the other diastereomers, compositions comprising the S, S enantiomer substantially free of the other diastereomers, compositions comprising the R,S enantiomer substantially free of the other diastereomers, and compositions comprising the S,R enantiomer substantially free of the other diastereomers.
  • the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically drawn or stated otherwise
  • the disclosure and claims of the present invention are based on the known general principles of chemical bonding. It is understood that the claims do not encompass structures known to be unstable or not able to exist based on the literature.
  • X 1 -X 4 is each independently carbon or nitrogen, provided that at least one of X 1 -X 4 is carbon;
  • R 1 is selected from the group consisting of hydrogen optionally substituted alkyl, and cationic counterion;
  • X 1 and X 2 are carbon and R 2 and R3 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; or
  • X 2 and X 3 are carbon and R 3 and R 4 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring;
  • A is a moiety of Formula II, Formula HA, or Formula III: where
  • Y 1 is selected from the group consisting of nitrogen, oxygen, and sulfur, as valence allows; Y 2 and Y3 is each independently selected from the group consisting of carbon, CH, oxygen, nitrogen and sulfur; Y 4 is carbon or nitrogen; R 6 -Rg is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -OR 1S , -NO 2 ,
  • R 6 does not exist when Yi is oxygen or sulfur, and provided that R 9 does not exist when Y 4 is nitrogen; or Y 2 and Y 3 are carbon and R 7 and R 8 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; bond a is single bond or double bond, such that Y 2 and Y3 have a complete octet along with R 7 and R 8 ;
  • Zi-Z 5 is each independently carbon or nitrogen, provided that at least two of Zi-Z 5 are carbon;
  • R 15 is independently selected as it appears from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and
  • Ri6 and R 17 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl.
  • Z 3 and Z 4 are carbon and R 12 and R 13 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring.
  • X 1 -X 4 is each independently carbon or nitrogen, provided that at least one of X 1 -X 4 is carbon;
  • R 1 is selected from the group consisting of hydrogen optionally substituted alkyl, and cationic counterion;
  • Xi and X 2 are carbon and R 2 and R3 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; or
  • X 2 and X 3 are carbon and R 3 and R 4 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring;
  • A is a moiety of Formula II or Formula III:
  • Yi is selected from the group consisting of nitrogen, oxygen, and sulfur
  • Y 2 and Y 3 is each independently selected from the group consisting of carbon, CH, oxygen, and sulfur;
  • Y 4 is carbon or nitrogen
  • Y 2 and Y 3 are carbon and R 7 and R 8 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; bond a is single bond or double bond, such that Y 2 and Y3 have a complete octet along with R 7 and R 8 ; Z 1 -Z 5 is each independently carbon or nitrogen, provided that at least two of Z 1 -Z 5 are carbon;
  • R 15 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R 16 and R 17 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl.
  • R 1 is an optionally substituted alkyl.
  • the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • R 1 is hydrogen.
  • R 1 is a cationic counterion.
  • Cationic counterions are well- known in the art. Some cationic counterions comprise metal ions, whereas others, such as the ammonium ion (NH 4 + ), dialkylammonium ion, dialkanolammonium ion, protonated piperazine, protonated betaine, protonated meglumine, protonated tromethamine, protonated L-lysine, protonated L-arginine, and other protonated amino acids, are non-metallic.
  • the interaction between the two groups is electrostatic.
  • the cation is an ionic form of a metal.
  • the metal is selected from the group consisting of alkali metal, alkali earth metal, and transition metal.
  • alkali metals include lithium, sodium, and potassium.
  • alkali earth metals include magnesium and calcium.
  • the metal ion is complexed in a crown ether.
  • R 2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • the aryl is phenyl, while in other embodiments, the heteroaryl is pyridyl.
  • R 2 is hydrogen.
  • R 3 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -OR 1 S, and -NO 2 , where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • the aryl is phenyl, while in other embodiments, the heteroaryl is pyridyl.
  • the halo is selected from the group consisting of fluoro, chloro, bromo, and iodo. In some embodiments, R3 is chloro or bromo.
  • R3 is -OR 1 S.
  • R 15 is hydrogen or an optionally substituted alkyl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • the alkyl is substituted with an aryl.
  • the aryl is a phenyl.
  • R 3 is -OH or -OCH 2 CeH 5 .
  • R 3 is selected from the group consisting of hydrogen, bromo, phenyl, -NO 2 , -OH, and -OCH 2 CeH 5 .
  • R 15 is hydrogen.
  • R 15 is an optionally substituted alkyl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • R3 is selected from -CH 2 NH(SO 2 )R 15 . In some embodiments,
  • R 15 is selected from optionally substituted aryl or optionally substituted arylalkyl.
  • the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • the aryl is phenyl, while in other embodiments, the heteroaryl is pyridyl.
  • the halo is selected from the group consisting of fluoro, chloro, bromo, and iodo.
  • R 4 is selected from the group consisting of hydrogen, acetyl, chloro, bromo, and phenyl.
  • R 5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • the aryl is phenyl, while in other embodiments, the heteroaryl is pyridyl.
  • R 5 is hydrogen.
  • X 1 and X 2 are carbon and R 2 and
  • R 3 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring.
  • the six-membered ring from by R 2 and R3 is phenyl, while in other embodiments, the six-membered ring is pyridyl.
  • X 1 and X 2 are carbon and R 3 and
  • R 4 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring.
  • the six-membered ring from by R 3 and R 4 is phenyl, while in other embodiments, the six-membered ring is pyridyl.
  • X 1 -X 4 are carbon. In other embodiments, X 1 -X 3 are carbon and
  • X 4 is nitrogen.
  • A is a moiety of Formula II.
  • A is a moiety of Formula IIA
  • R5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • the aryl is phenyl, while in other embodiments, the heteroaryl is pyridyl.
  • R5 is hydrogen.
  • the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, and tert-butyl.
  • R 1S is hydrogen or an optionally substituted alkyl.
  • the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • Some of these embodiments include those in which the alkyl is substituted with an aryl.
  • the aryl can be a phenyl.
  • R 7 is -OH or -OCH 2 CeH 5 .
  • (CRi 6 Rn) n -C(O)Ri 5 R 1S is hydrogen or an optionally substituted alkyl.
  • the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • Some of these embodiments include those in which the alkyl is substituted with an aryl.
  • the aryl can be a phenyl.
  • R 16 and R 17 is each independently hydrogen or an optionally substituted alkyl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • n is 0, 1, 2, or 3.
  • Ri 5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroalicyclyl, optionally substituted arylalkyl.
  • the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • the heteroalicyclyl is selected from pyrrolidine.
  • Ri 6 and Rn is each independently hydrogen or an optionally substituted alkyl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • n is O, 1, 2, or 3.
  • Rs is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, - C(Ri 6 Rn) n N(Ri 5 ),, -CH 2 NH-C(O)ORi 5 , - (CRi 6 Rn) n -C(O)Ri 5 , —
  • Rg is hydrogen, methyl, or -CH 2 C(O)OH.
  • Ri 5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl.
  • the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, and tert-butyl.
  • the alkyl is substituted with an optionally substituted aryl, optionally substituted heteroaryl, dialkylamino, or hydroxy.
  • the aryl can be a phenyl.
  • the cycloalkyl is cyclopropyl.
  • the heteroalicyclyl is selected from pyrrolidine, piperdine, piperazine, morpholine, aziridine, and azetedine.
  • the heteroaryl is selected from pyridine, imidazol, indole, isoindole, oxadiazol and isoquinoline.
  • Ri 6 and Rn is each independently hydrogen or an optionally substituted alkyl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • n is O, 1, 2, or 3
  • Ri 5 is an optionally substituted arylalkyl where the arylalkyl can be selected from phenylmethyl and phenylethyl or heteroarylalkyl where the heteroarylalkyl can be selected from pyridinemethyl and pyridineethyl.
  • Y 2 and Y 3 are carbon and R 7 and R 8 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring.
  • the six-membered ring from R 2 and R 3 is phenyl, while in other embodiments, the six-membered ring is pyridyl.
  • Yi is sulfur; Y 2 is carbon; Y 3 is carbon; Y 4 is nitrogen, and bond a is a double bond.
  • Yi is oxygen; Y 2 is CH; Y 3 is CH; Y 4 is nitrogen, and bond a is a single bond.
  • Y 1 is sulfur;
  • Y 2 is CH; Y 3 is CH; Y 4 is nitrogen, and bond a is a single bond.
  • Y 1 is nitrogen; Y 2 is CH; Y 3 is CH; Y 4 is nitrogen, and bond a is a single bond.
  • Y 3 is carbon and Y 4 is nitrogen, and bond a is a double bond.
  • Y 1 is oxygen
  • Y 2 is nitrogen
  • Y 3 is carbon
  • Y4 is nitrogen and bond a is double bond.
  • Y 1 is sulfur
  • Y 2 is nitrogen
  • Y 3 is carbon and Y 4 is nitrogen
  • bond a is a double bond.
  • Rio is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • R 1 O is hydrogen.
  • R 15 is hydrogen or an optionally substituted alkyl.
  • the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • Some of these embodiments include those in which the alkyl is substituted with an aryl.
  • the aryl can be a phenyl.
  • Ri 6 and Rn is each independently hydrogen or an optionally substituted alkyl, where the alkyl can be selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • n is 0, 1, 2, or 3.
  • R 12 is selected from the group consisting of hydrogen, optionally substituted alkyl, and halo, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • the halo is selected from the group consisting of fluoro, chloro, bromo, and iodo.
  • R 12 is hydrogen or bromo.
  • R 12 is selected from the group consisting of , -
  • R 15 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl,
  • the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • Some of these embodiments include those in which the alkyl is substituted with an aryl or hydroxy.
  • the aryl can be a phenyl.
  • the cycloalkyl is cyclopropyl.
  • the heteroalicyclyl is selected from pyrrolidine, piperdine, or indole.
  • the heteroaryl is selected from pyridine.
  • Ri 6 and Rn is each independently hydrogen or an optionally substituted alkyl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • n is O, 1, 2, or 3.
  • R 13 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.
  • the alkyl can be selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • R13 is hydrogen.
  • Z 3 and Z 4 are carbon and Ri 2 and R 13 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or six-membered optionally substituted heteroaryl.
  • the aryl ring formed by Ri 2 and R13 is phenyl.
  • the compounds of Formula I are those selected from the group consisting of
  • A is selected from the group consisting of
  • A is selected from the group consisting of
  • A is a moiety selected from the group consisting of
  • Ri is selected from the group consisting of hydrogen optionally substituted alkyl, and cationic counterion;
  • X is selected from the group consisting of oxygen, NH, and sulfur;
  • R 1S and R 1 Q is each independently selected from the group consisting of hydrogen, - (CR 16 Rn) n -S(O)R 20 , and -(CR 16 Rn) n -S(O) 2 R 20 , n is an integer between 0 and 10, inclusive;
  • R 16 and R 17 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl;
  • R 20 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR 1 S, and -N(R 1 S) 2 ; where R 15 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and bond a is a single bond or a double bond.
  • the compounds disclosed herein have increased or decreased potency at HIF prolyl hydroxylases, bind the open or closed conformations of HIF pyrolyl hydroxylases, have more optimal pharmacokinetics, improved dosing schedules, less toxicity, have higher selectivity for HIF PH2 (less off-target activity), increase or decrease expression of HIF- regulated genes to a greater or lesser extent, or combinations of the preceding as compared to other HIF prolyl hydroxylase modulators.
  • the compounds disclosed herein have greater potency at HIF PHD3 as compared to HIF-PHD2.
  • aryl carboxylic acid derivatives may be prepared according to a variety of the known synthetic methods. Some of these compounds are also commercially available from manufacturers and suppliers of reagents, such as Aldrich, Sigma,
  • Fluoroarylnitrile and acetohydroxamic acid may react in the presence of a base to form isoxazolo[4,5-b]pyridin-3-ylamine.
  • the resulting compound may be subject to a reduction reaction to obtain 3-Hydroxy-pyridine-2-carboxamidine.
  • a pyrimidine group may be introduced through the reaction of diethyl ethoxymethylenemalonate with carboxamidine, and the pyrimidine-grafted compounds may be modified into their various derivatives using well-known methods.
  • Oxazoline or thiazoline may be synthesized from hydroxybenznitrile through the reaction with isoserine or isocysteine (Synth. Commun., 1991, 21, 265-270) (reaction a), and imidazoline may be synthesized through the reaction of 1,2-diamine with nitrile or ester (reaction b).
  • the oxazoline and thiazoline may be also synthesized through the intramolecular cyclization of amide produced by the coupling reaction of acid with homoalanine (reaction c).
  • compositions comprising a therapeutically effective amount of at least one compound of Formula I and a physiologically acceptable carrier, diluent, or excipient.
  • composition refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to a subject. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration.
  • Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like.
  • carrier defines a chemical compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • carrier facilitates the uptake of many organic compounds into the cells or tissues of a subject.
  • diot defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art.
  • One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.
  • physiologically acceptable defines a carrier or diluent that does not abrogate the biological activity and properties of the compound and/or is not harmful to the subject to which it is administered.
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.
  • compositions for use in accordance with the present disclosure thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.
  • the agents disclosed herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • compositions for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination disclosed herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present disclosure are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly, concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for the hydrophobic compounds disclosed herein is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • a common cosolvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant
  • Polysorbate 80TM and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of
  • POLYSORBATE 80TM the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may be used.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for stabilization may be employed.
  • salts may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acids or base forms.
  • compositions suitable for use in the methods disclosed herein include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the exact formulation, route of administration and dosage for the pharmaceutical compositions disclosed herein can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1).
  • the dose about the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight, or 1 to 500 mg/kg, or 10 to 500 mg/kg, or 50 to 100 mg/kg of the patient's body weight.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient.
  • human dosages for treatment of at least some condition have been established.
  • the methods disclosed herein will use those same dosages, or dosages that are between about 0.1% and 500%, or between about 25% and 250%, or between 50% and 100% of the established human dosage.
  • a suitable human dosage can be inferred from ED 50 or ID 50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg of each ingredient, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of each ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical compositions disclosed herein or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day.
  • compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day.
  • the total daily dosage by oral administration of each ingredient will typically be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will typically be in the range 0.1 to 400 mg.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety, which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen, which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • 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 compound disclosed herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • compound of Formula I includes in its scope those compounds as described herein, including any pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
  • HIF in a cell comprising administering to the cell an amount of at least one compound of Formula I sufficient to modulate the expression level of HIF in the cell.
  • methods of controlling the expression level of HIF in a cell comprising contacting the cell with an amount of at least one compound of Formula I sufficient to modulate the expression level of HIF in the cell.
  • administering in the context of administering a compound refers to preparing a formulation, as discussed herein, containing the compound being administered, and administering the formulation by any known method to the subject or to the cell.
  • a solution containing the compound can be injected to the subject or be added to the medium containing the cells, or the subject can orally ingest a formulation containing the compound.
  • the term “contacting” refers to bringing the subject or the cell into contact with the compound.
  • a formulation of a prodrug can be administered to a subject, whereupon the prodrug undergoes metabolism. The metabolite is then either in the systemic circulation or within the cytoplasm. In this situation, the prodrug is "administered" to the subject, but both the subject and the cells are “contacted” with the metabolite.
  • a subject in another aspect, disclosed herein are methods of controlling the expression level of HIF in a subject comprising identifying a subject in need thereof and administering to the subject an amount of at least one compound of Formula I sufficient to modulate the expression level of HIF in the subject.
  • methods of controlling the expression level of HIF in a subject comprising identifying a subject in need thereof and contacting the subject with an amount of at least one compound of Formula I sufficient to modulate the expression level of HIF in the subject.
  • the modulator lowers the levels or concentration of HIF in the cell. Preferably, the modulator increases the levels or concentration of HIF in the cell.
  • methods of inhibiting hydroxylation of HIF ⁇ in a cell comprising administering to the cell an amount of at least one compound of Formula I sufficient to inhibit the hydroxylation of HIF ⁇ in the cell.
  • methods of inhibiting hydroxylation of HIF ⁇ in a cell comprising contacting the cell with an amount of at least one compound of Formula I sufficient to inhibit the hydroxylation of HIF ⁇ in the cell.
  • hydroxylation of HIF ⁇ in a subject comprising identifying a subject in need thereof and administering to the subject an amount of at least one compound of Formula I sufficient to inhibit the hydroxylation of HIF ⁇ in the subject.
  • methods of inhibiting hydroxylation of HIF ⁇ in a cell comprising identifying a subject in need thereof and contacting the subject with an amount of at least one compound of Formula I sufficient to inhibit the hydroxylation of HIF ⁇ in the subject.
  • a cell comprising administering to the cell an amount of at least one compound of Formula I sufficient to modulate expression of HIF- regulated genes in the cell.
  • methods of modulate expression of HIF-regulated genes in a cell comprising contacting the cell with an amount of at least one compound of Formula I sufficient to modulate expression of HIF-regulated genes in the cell.
  • a subject in another aspect, disclosed herein are methods of modulating expression of HIF- regulated genes in a subject comprising identifying a subject in need thereof and administering to the subject an amount of at least one compound of Formula I sufficient to modulate expression of HIF-regulated genes in the subject.
  • methods of modulating expression of HIF-regulated genes in a subject comprising identifying a subject in need thereof and contacting the subject with an amount of at least one compound of Formula I sufficient to modulate expression of HIF-regulated genes in the subject.
  • disclosed herein are methods for increasing HIF levels or HIF activity in a cell comprising administering to the cell an amount of at least one compound of Formula I sufficient to increase HIF levels or HIF activity in the cell.
  • methods for increasing HIF levels or HIF activity in a cell comprising contacting the cell with an amount of at least one compound of Formula I sufficient to increase HIF levels or HIF activity in the cell.
  • disclosed herein are methods for increasing HIF levels or HIF activity in a subject comprising identifying a subject in need thereof and administering to the subject an amount of at least one compound of Formula I sufficient to increase HIF levels or HIF activity in the subject.
  • methods for increasing HIF levels or HIF activity in a subject comprising identifying a subject in need thereof and contacting the subject with an amount of at least one compound of Formula I sufficient to increase HIF levels or HIF activity in the subject.
  • HIF-related disorder in another aspect, disclosed herein are methods of treating a disorder in a subject where it is desired to modulate HIF levels or activity, the method comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of at least one compound of Formula I.
  • methods of treating an HIF -related disorder in a subject comprising identifying a subject in need thereof and contacting the subject with a therapeutically effective amount of at least one compound of Formula I.
  • HIF-related disorder is meant a disorder in which the modulation of HIF levels or activity provides a therapeutic effect.
  • the HIF-related disorder is selected from the group consisting of ischemic disorders, hypoxic disorders, anemic disorders (including, but not limited to, anemia associated with autoimmune diseases, rheumatoid arthritis, systemic lupus, chronic infections such as, without limitation, HCV, and HIV, inflammatory bowel disease, chemotherapy-induced, chronic heart disease, chronic kidney disease, chronic obstructive pulmonary disease (COPD), end stage renal disease, prematurity, hypothyroidism, malnutrition, blood disorders, including but not limited to, sickle cell anemia, and ⁇ -thalassemia, malignancies), stenocardia, neurological disorders, stroke, epilepsy, neurodegenerative disease, myocardial infarction, liver ischemia, renal ischemia, chronic kidney disease, peripheral vascular disorders, ulcers, burns, chronic wounds, pulmonary embolism, ischemic-reperfusion injury, ischemic-reperfusion injuries associated with surgeries and organ transplantations, respiratory distress syndrome,
  • ischemic disorders including,
  • treatment does not necessarily mean total cure. Any alleviation of any undesired signs or symptoms of the disease to any extent or the slowing down of the progress of the disease can be considered treatment. Furthermore, treatment may include acts that may worsen the patient's overall feeling of well being or appearance. Treatment may also include lengthening the life of the patient, even if the symptoms are not alleviated, the disease conditions are not ameliorated, or the patient's overall feeling of well being is not improved.
  • ischemic disorders including, but not limited to, anemia associated with autoimmune diseases, rheumatoid arthritis, systemic lupus, chronic infections such as, without limitation, HCV, and HIV, inflammatory bowel disease, chemotherapy-induced, chronic heart disease, chronic kidney disease, chronic obstructive pulmonary disease (COPD), end stage renal disease, prematurity, hypothyroidism, malnutrition, blood disorders, including but not limited to, sickle cell anemia, and ⁇ -thalassemia, malignancies), stenocardia, neurological disorders, stroke, epilepsy, neurodegenerative disease, myocardial infarction, liver ischemia, renal ischemia, chronic kidney disease, peripheral vascular disorders, ulcers,
  • a disorder in a subject comprising identifying a subject in need thereof and contacting the subject with a therapeutically effective amount of at least one compound of Formula I, wherein the disorder is selected from the group consisting of anemic disorders, neurological disorders, stroke, trauma, epilepsy, neurodegenerative disease, myocardial infarction, liver ischemia, renal ischemia, peripheral vascular disorders, ulcers, burns, chronic wounds, pulmonary embolism, and ischemic-reperfusion injury.
  • a method of modulating the expression level of HIF and/or EPO by inhibiting the hydroxylation of HIF ⁇ , and thus stabilizing HIF and/or modulating expression of HIF -regulated genes may be useful to prevent, remedy and treat conditions associated with HIF and/or EPO including anemia, ischemia and hypoxia.
  • Ischemia, anemia, and hypoxia are three conditions associated with HIF, and include, but are not limited to, of ischemic disorders, hypoxic disorders, anemic disorders (including, but not limited to, anemia associated with autoimmune diseases, rheumatoid arthritis, systemic lupus, chronic infections such as, without limitation, HCV, and HIV, inflammatory bowel disease, chemotherapy-induced, chronic heart disease, chronic kidney disease, chronic obstructive pulmonary disease (COPD), end stage renal disease, prematurity, hypothyroidism, malnutrition, blood disorders, including but not limited to, sickle cell anemia, and ⁇ -thalassemia, malignancies), stenocardia, neurological disorders, stroke, epilepsy, neurodegenerative disease, myocardial infarction, liver ischemia, renal ischemia, chronic kidney disease, peripheral vascular disorders, ulcers, burns, chronic wounds, pulmonary embolism, ischemic-reperfusion injury, ischemic-reperfusion injuries associated with surgeries
  • the methods disclosed herein provide for stabilizing HIF ⁇ before/after the advent of the ischemia or hypoxia or in ischemia or hypoxia when the ischemia or hypoxia is associated with myocardial infarctions, strokes, or renal ischemia-reperfusion injuries.
  • ischemic- and/or hypoxic-related disorders using the compounds of Formula I.
  • the methods disclosed herein are advantageous for the treatment when the compounds are administered before or after the advent of ischemia or hypoxia.
  • the methods disclosed herein may reduce mortality rates and improve cardiac structure and performance after the advent of the myocardial infarction.
  • liver disorders comprising administering the compounds of Formula I before or after exposure to conditions and/or agents that are associated with liver disease.
  • hypoxia is associated with liver disease, particularly chronic liver disease that is associated with compounds toxic to the liver, such as ethanol.
  • the expression of genes known to be regulated by HIF ⁇ for example nitric oxide synthase and glucose transporter- 1, is increased in alcoholic liver diseases.
  • methods for treating conditions associated with ischemia or hypoxia where the method includes administrating to subjects a therapeutically effective amount of at least one compound of Formula I.
  • the compounds of Formula I are administered to patients after the onset of conditions such as acute ischemia, for example myocardial infarction, pulmonary embolism, bowel infarction, ischemic strokes, and renal ischemia-reperfusion injuries.
  • the compounds of Formula I are administered to patients after the patients are diagnosed with conditions associated with chronic ischemia, for example, without limitation, cardiachepatopathy, macular degeneration, pulmonary embolism, acute respiratory dysfunction, neonatal respiratory distress syndrome, and congestive heart failure.
  • the compounds of Formula I are administered to patients after trauma or injuries.
  • disclosed herein are methods for treating with the compounds disclosed herein patients at risk of developing ischemic or hypoxic conditions.
  • High risk individuals include, but are not limited to, atherosclerotic patients.
  • Risk factors in atherosclerosis include, for example without limitation, hyperlipidemia, smoking, hypertension, diabetes, hyperinsulinemia, and visceral obesity.
  • disclosed herein are methods for preventing or mitigating ischemic tissue injuries, where the method includes administrating to subjects in need thereof a therapeutically effective amount of a compound of Formula I.
  • the compounds disclosed herein may be administered to treat conditions, such as, hypertension, diabetes, obliterative artery disease, chronic venous insufficiency, Raynaud's disease, chronic ulcer of skin, hepatopathy, congestive heart failure, and systemic sclerosis.
  • the methods disclosed herein are used to stimulate angiogenesis and/or formation of granulation tissue in injured tissues, and ulcers.
  • the compounds disclosed herein are effective in stimulating the formation of granulation tissue in the wound healing processes. Secretion of growth factors from inflammatory cells, blood platelets, and activated endothelia stimulates the translocation of fibroblast and endothelial cells and the growth in the granulation tissues.
  • the methods disclosed herein are effective in stimulating the formation of granulation tissues. Accordingly, disclosed herein are methods for treating, for example, patients suffering from tissue injuries due to infarctions, patients suffering from injuries induced by trauma, or patients suffering from chronic injuries or ulcers caused by disorders, such as, diabetes.
  • the methods disclosed herein include administering to subjects in need thereof a therapeutically effective amount of a compound of Formula I.
  • disclosed herein are methods for pre-treating subjects to reduce or prevent the development of tissue injuries associated with ischemia or hypoxia, by employing the compounds disclosed herein.
  • the methods disclosed herein have advantages for the treatment when the compounds are administered before the advent of the ischemia or hypoxia.
  • the methods disclosed herein reduce mortality rates and significantly improve cardiac structure and performance when the compounds disclosed herein are administered before the induction of myocardial infarction.
  • the methods disclosed herein provide a therapeutic effect associated with renal failure when the compounds disclosed herein are administered before and/or during the advent of ischemia-reperfusion injuries.
  • ischemic disorders for example, those having a history of myocardial infarction, or patients suffering from symptoms of serious ischemia, for example stenocardia.
  • the compounds disclosed herein may be administered to humans who are under conditions that are associated with possible ischemia, for example general anesthesia, or who work temporarily at high altitudes.
  • the compounds disclosed herein may be used in organ transplant procedures by previously treating organ donors with the compounds disclosed herein to maintain the organs that have been removed from the donors before the organs are transplanted into recipients.
  • a subject in need thereof comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of at least one compound of Formula I.
  • methods for regulating angiogenesis in a subject comprising identifying a subject in need thereof and contacting the subject with a therapeutically effective amount of at least one compound of Formula I.
  • vascularizing ischemic tissue in a subject comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of at least one compound of Formula I.
  • methods for vascularizing ischemic tissue in a subject comprising identifying a subject in need thereof and contacting the subject with a therapeutically effective amount of at least one compound of Formula I.
  • a method for promoting the growth of skin graft replacements comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of at least one compound of Formula I.
  • methods for promoting the growth of skin graft replacements comprising identifying a subject in need thereof and contacting the subject with a therapeutically effective amount of at least one compound of Formula I.
  • GTR guided tissue regeneration
  • methods for promoting tissue repair in the context of guided tissue regeneration (GTR) procedures comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of at least one compound of Formula I.
  • methods for promoting tissue repair in the context of guided tissue regeneration (GTR) procedures comprising identifying a subject in need thereof and contacting the subject with a therapeutically effective amount of at least one compound of Formula I.
  • a subject in need thereof comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of at least one compound of Formula I.
  • methods for regulating anemia in a subject comprising identifying a subject in need thereof and contacting the subject with a therapeutically effective amount of at least one compound of Formula I.
  • EPO endogenous erythropoietin
  • these methods may be used in vivo or in vitro, for example in cell culture-controlled media.
  • methods for increasing the level of endogenous EPO to prevent, remedy or treat conditions associated with deficient EPO levels or where increased EPO would be beneficial, such as in stroke patients, conditions associated with anemia and neurological disorders, e.g., Parkinson's disease.
  • Increased EPO may be beneficial as a neuroprotectant and neurotrophic agent useful for treating cognitive disorders and depression and other disorders associated with structural problems and/or regeneration of nerve cells.
  • the methods disclosed herein may be used to increase endogenous EPO levels in subjects undergoing prevention or certain treatment procedures. Examples include HIV-infected anemic subjects being treated with azidothymidine (zidovudin) or other reverse transcriptase inhibitors, patients receiving cyclic cisplatin- or non-cisplatin-containing chemotherapy, or anemic or non-anemic patients scheduled for surgical operations.
  • the methods of increasing endogenous EPO levels may be used to prevent, pre-treat or treat EPO-related conditions that are associated with nerve injuries or degeneracy of nerve tissues, including, but not limited to, stroke, trauma, epilepsy, spinal cord injury, and neurodegenerative disorders.
  • the methods disclosed herein may be used to reduce the need for allogenic blood transfusions in anemic or non-anemic patients scheduled for surgery, such as joint replacement, or to facilitate autologous blood collection prior to surgery by increasing endogenous EPO levels. These methods would reduce the risk associated with non-autologous blood transfusions such as, without limitation, transmission of infectious disease.
  • the methods disclosed herein may also be used to enhance physical performance, improve exercise abilities, and facilitate or strengthen aerobic conditioning. These methods may, for example, be used for athletes to facilitate their training, and for military personnel to improve energy and stamina.

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Abstract

Disclosed herein are hydroxyaryl or hydroxyheteroaryl derivative compounds, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, pharmaceutical compositions comprising the same, and methods of modulating the level or activity of HIF in a subject, inhibiting hydroxylation of HIFα in a subject, modulating expression of HIF-regulated genes in a subject, treating an HIF -related disorder in a subject, increasing levels of endogenous EPO in a subject, or treating a disorder in a subject, using the disclosed compounds.

Description

PHENOL DERIVATIVES AND METHODS OF USE THEREOF
FIELD OF THE INVENTION
[0001] The present invention is in the field of pharmaceutical chemistry, and particularly in the field of compounds that affect the stability of hypoxia inducible factor-α (HIF- α) and the expression of HIF-regulated genes, and methods of using the same for the treatment of disease.
BACKGROUND OF THE DISCLOSURE
[0002] The hypoxia-inducible factor (HIF) family of transcription factors play a central regulatory role in the control of the intracellular response to hypoxia, throughout the body. HIF itself is primarily regulated by prolyl hydroxylases (PHDs), as well as asparaginyl hydroxylases. Under normoxic conditions, these PHDs site specifically hydroxylate the alpha subunit of HIF, which ultimately results in its degradation. Thus, under adequate oxygenation levels, the body continually expresses and degrades the HIF alpha protein. [0003] Modulation of PHD via the compounds disclosed herein will alter the regulation of cellular oxygen homeostasis. This has utility in any disease state where ischemia, hypoxia, and/or anemia plays a role
SUMMARY OF THE INVENTION [0004] Disclosed herein are compounds of Formula I:
Figure imgf000002_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, where
X1-X4 is each independently carbon or nitrogen, provided that at least one of X1-X4 is carbon;
R1 is selected from the group consisting of hydrogen, optionally substituted alkyl, and cationic counterion; R2-R5 is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -OR1S, -NO2, -N(RiS)2, -(CRi6Ri7)n-NHC(=O)Ris, -CH2NHR15, -NH(SO2)Ri5, - CH2NH(SO2)Ri5, - (CRi6Ri7)n-C(=O)Ri5, and -(CRi6Ri7)n-C(=O)ORi5, , where n is an integer between 0 and 10, inclusive, provided that R2 does not exist when Xi is nitrogen, provided that R3 does not exist when X2 is nitrogen, provided that R4 does not exist when X3 is nitrogen, and provided that R5 does not exist when X4 is nitrogen; or
Xi and X2 are carbon and R2 and R3 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; or
X2 and X3 are carbon and R3 and R4 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; A is a moiety of Formula II, Formula HA, or Formula III:
(«)
Figure imgf000003_0001
where
Yi is selected from the group consisting of nitrogen, oxygen, and sulfur, as valence allows;
Y2 and Y3 is each independently selected from the group consisting of carbon, CH, oxygen, nitrogen, and sulfur;
Y4 is carbon or nitrogen;
R6-R9 is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -ORi5, -NO2, -N(Ri5)2, -NHC(=0)R15, -NHC(=0)0Ri5, -NH(SO2)Ri5,-(CRi6Ri7)n-C(=O)ORi5, -(CRi6Rn)n-SRi5, - (CRi6Ri7)nC(=O)N(Ri5)2, - (CRi6Ri7)n-C(=O)NH-(CRi6Ri7)n-C(=O)ORi5, - (CRi6Ri7)n-C(=O)NH-(CRi6Ri7)n-C(=O)Ri5
Figure imgf000004_0001
- (CRi6Ri7)n-C(=O)Ri5, and -(CRi6Ri7)n-S(=O)2Ri5, where n is an integer between 0 and 10, inclusive, provided that R6 does not exist when Yi is oxygen or sulfur, and provided that R9 does not exist when Y4 is nitrogen; or
Y2 and Y3 are carbon and R7 and Rs taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; bond a is single bond or double bond, such that Y2 and Y3 have a complete octet along with R7 and R8; Zi-Z5 is each independently carbon or nitrogen, provided that at least two of Zi-Z5 are carbon;
R10-R14 is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -ORi5, -NO2, -N(Ri5)2, -NHC(=0)Ri5, -NH(SO2)Ar, - (CRi6Rn)n-C(O)Ri5, -(CRi6Rn)n-C(=O)NH-(CRi6Rn)n-C(=O)ORi5, (CRi6Rn)nC(=O)N(Ri5)2 -(CRi6Rn)n-S(O)2Ri5, and -(CRi6Rn)n-C(=O)ORi5, where Ar is an optionally substituted aryl, and where n is an integer between O and 10, inclusive, provided that R1O does not exist when Zi is nitrogen, provided that Rn does not exist when Z2 is nitrogen, provided that Ri2 does not exist when Z3 is nitrogen, provided that Ri 3 does not exist when Z4 is nitrogen, and provided that Ri4 does not exist when Z5 is nitrogen;
Ri5 is independently selected as it appears from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and R16 and R17 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; or Z3 and Z4 are carbon and R12 and Rn taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring.
[0005] Also disclosed are pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, and a physiologically acceptable carrier, diluent, or excipient. [0006] In addition, disclosed are methods of controlling HIF levels in a subject, inhibiting hydroxylation of HIFα in a subject, inhibiting prolyl hydroxylases in a subject, modulating expression of HIF-controlled genes in a subject, treating an HIF -related disorder in a subject, treating diseases associated with ischemia, hypoxia and/or anemia, treating conditions in a subject associated with angiogenesis and/or erythropoietin levels, or treating a disorder in a subject, the method comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0007] The term "pharmaceutically acceptable salt" means those salts of compounds of the invention that are safe and effective for use in a subject and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the invention. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1,1 ' -methyl ene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds of the invention can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. For a review on pharmaceutically acceptable salts see BERGE ET AL., 66 J. PHARM. SCI. 1-19 (1977), incorporated herein by reference. [0008] The term "ester" refers to a chemical moiety with formula -(R)n-COOR', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.
[0009] An "amide" is a chemical moiety with formula -(R)n-C(O)NHR' or -(R)n-NHC(O)R', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1. An amide may be an amino acid or a peptide molecule attached to a molecule of the present invention, thereby forming a prodrug.
[0010] Any amine, hydroxy, or carboxyl side chain on the compounds of the present invention can be esterifϊed or amidifϊed. The procedures and specific groups to be used to achieve this end is known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York, N. Y., 1999, which is incorporated herein in its entirety.
[0011] A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety. [0012] Whenever a group of this invention is described as being "optionally substituted" that group may be unsubstituted or substituted with one or more of the substituents described for that group. Likewise, when a group is described as being "unsubstituted or substituted," if substituted, the substituent may be selected from the same group of substituents. Unless otherwise indicated, when a substituent is deemed to be "optionally substituted," or "substituted" it is meant that the substituent is a group that may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (hetereoalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfmyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. The protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, which is hereby incorporated by reference in its entirety.
[0013] As used herein, "Cm-Cn" in which "m" and "n" are integers refers to the number of carbon atoms in an alkyl, alkenyl or alkynyl group or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, or aryl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, or of the aryl can contain from "m" to "n", inclusive, carbon atoms. Thus, for example, a "C1-C4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, CH3CH(CH3)-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3CH-. If no "m" and "n" are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group, the broadest range described in these definitions is to be assumed.
[0014] As used herein, "alkyl" refers to a straight or branched chain fully saturated (no double or triple bonds) hydrocarbon (all carbon) group. An alkyl group of this invention may comprise from 1 - 20 carbon atoms, that is, "m" = 1 and "n" = 20, designated as a "C1 to C2o alkyl." It is presently preferred that "m" = 1 and "n":= 12 (C1 to C12 alkyl). It is presently more preferred that "m" = 1 and "n" = 6 (C1 to Ce alkyl). Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, amyl, tert-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
[0015] An alkyl group of this invention may be substituted or unsubstituted. When substituted, the substituent group(s) may be one or more group(s) independently selected from cycloalkyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, oxo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NRaRb, protected hydroxyl, protected amino, protected carboxy and protected amido groups.
[0016] Examples of substituted alkyl groups include, without limitation, 2-oxo-prop-l-yl, 3- oxo-but-1-yl, cyanomethyl, nitromethyl, chloromethyl, hydroxymethyl, tetrahydropyranyloxymethyl, m-trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylaminomethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichlorobutyl, 2-aminopropyl, 1-chloroethyl, 2-chloroethyl, 1-bromoethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroethyl, 1-iodoethyl, 2-iodoethyl, 1- chloropropyl, 2-chloropropyl, 3-chloropropyl, 1-bromopropyl, 2-bromopropyl, 3-bromopropyl, 1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 1-iodopropyl, 2-iodopropyl, 3-iodopropyl, 2- aminoethyl, 1-aminoethyl, N-benzoyl-2-aminoethyl, N-acetyl-2-aminoethyl, N-benzoyl-1- aminoethyl and N-acetyl- 1-aminoethyl.
[0017] As used herein, "alkenyl" refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. Examples of alkenyl groups include, without limitation, vinyl (CH2=CH-), allyl (CHsCH=CH2-), 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl; 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3 -methyl- 1-butenyl, and the various isomers of hexenyl, heptenyl, octenyl, nonenyl, decenyl undecenyl and dodecenyl. [0018] An alkenyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution. Examples of substituted alkenyl groups include, without limitation, styrenyl, 3-chloro-propen-l-yl, 3-chloro-buten-l-yl, 3-methoxy-propen-2-yl, 3-phenyl-buten-2-yl and l-cyano-buten-3-yl.
[0019] As used herein, "alkynyl" refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
[0020] An alkynyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution. [0021] As used herein, "cycloalkyl" refers to a completely saturated (no double bonds) hydrocarbon ring. Cycloalkyl groups of this invention may range from C3 to C8. A cycloalkyl group may be unsubstituted or substituted. If substituted, the substituent(s) may be selected from those indicated above with regard to substitution of an alkyl group. The "cycloalkyl" group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the cycloalkyl is a fused ring system, then the ring that is connected to the rest of the molecule is a cycloalkyl as defined above. The other ring(s) in the fused ring system may be a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, or a heteroalicyclic.
[0022] As used herein, "cycloalkenyl" refers to a cycloalkyl group that contains one or more double bonds in the ring although, if there is more than one, they cannot form a fully delocalized pi-electron system in the ring (otherwise the group would be "aryl," as defined herein). A cycloalkenyl group of this invention may unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution. The "cycloalkenyl" group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the cycloalkenyl is a fused ring system, then the ring that is connected to the rest of the molecule is a cycloalkenyl as defined above. The other ring(s) in the fused ring system may be a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, or a heteroalicyclic.
[0023] The term "alkylene" refers to an alkyl group, as defined here, which is a biradical and is connected to two other moieties. Thus, methylene (-CH2-), ethylene (-CH2CH2-), proylene (- CH2CH2CH2-), isopropylene (-CH2-CH(CH3)-), and isobutylene (-CH2-CH(CH3)-CH2-) are examples, without limitation, of an alkylene group. Similarly, the term "cycloalkylene" refers to a cycloalkyl group, as defined here, which binds in an analogous way to two other moieties. If the alkyl and cycloalkyl groups contain unsaturated carbons, the terms "alkenylene" and "cycloalkenylene" are used.
[0024] As used herein, "acyl" refers to an "RC(=O)O-" Examples of acyl groups include, without limitation, formyl, acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl and benzoyl. Presently preferred acyl groups are acetyl and benzoyl.
[0025] An acyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution. Example of substituted acyl groups include, without limitation, 4- phenylbutyroyl, 3-phenylbutyroyl, 3-phenylpropanoyl, 2-cyclohexanylacetyl, cyclohexanecarbonyl, 2-furanoyl and 3-dimethylaminobenzoyl.
[0026] As used herein, "aryl" refers to a carbocyclic (all carbon) ring that has a fully delocalized pi-electron system. The "aryl" group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the aryl is a fused ring system, then the ring that is connected to the rest of the molecule has a fully delocalized pi-electron system. The other ring(s) in the fused ring system may or may not have a fully delocalized pi-electron system. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. [0027] As used herein, "heteroaryl" refers to a ring that contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur in the ring and that has a fully delocalized pi-electron system. The "heteroaryl" group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the heteroaryl is a fused ring system, then the ring that is connected to the rest of the molecule has a fully delocalized pi-electron system. The other ring(s) in the fused ring system may or may not have a fully delocalized pi- electron system. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyran, pyridine, pyridazine, pyrimidine, pyrazine, indole, isoindole, isoquinoline and triazine.
[0028] As used herein, "heterocycloalkyl," "heteroalicyclic," or "heteroalicyclyl" refers to a ring having in the ring system one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. The ring may also contain one or more double bonds provided that they do not form a fully delocalized pi-electron system in the rings. Heteroalicyclyl groups of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be one or more groups independently selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, amino, protected amino, carboxamide, protected carboxamide, alkylsulfonamido and trifluoromethanesulfonamido. The "heterocycloalkyl" group can be made up of two or more fused rings (rings that share two adjacent carbon atoms). When the heterocycloalkyl is a fused ring system, then the ring that is connected to the rest of the molecule is a heterocycloalkyl as defined above. The other ring(s) in the fused ring system may be a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, or a heteroalicyclic.
[0029] As used herein, "phenylalkyl" refers to a phenyl ring covalently bonded to an alkyl group as defined herein. Examples, without limitation, of phenylalkyl groups include, without limitation, benzyl, 2-phenylethyl, 1-phenylpropyl, 4-phenylhexyl, 3-phenylamyl and 3-phenyl-2- methylpropyl. Presently preferred phenylalkyl groups are those wherein the phenyl group is covalently bonded to one of the presently preferred alkyl groups. A phenyl alkyl group of this invention may be unsubstituted or substituted. Examples of substituted phenylalkyl groups include, without limitation, 2-phenyl-l-chloroethyl, 2-(4-methoxyphenyl)ethyl, 4-(2,6-dihydroxy phenyl)hexyl, 2-(5-cyano-3-methoxyphenyl)pentyl, 3-(2,6-dimethylphenyl)propyl, 4-chloro-3- aminobenzyl, 6-(4-methoxyphenyl)-3 -carboxy(n-hexyl), 5 -(4-aminomethylphenyl)-3 -
(aminomethyl)pentyl and 5-phenyl-3-oxo-pent-l-yl.
[0030] As used herein, "heteroarylalkyl" and "heteroalicyclylalkyl" refer to a heteroaryl or a heteroalicyclyl group covalently bonded to an alkyl group, as defined herein. Examples of such groups include, without limitation, 2-pyridylethyl, 3-pyridylpropyl, 4-furylhexyl, 3- piperazylamyl and 3-morpholinylbutyl. Presently preferred heteroarylalkyl and heteroalicyclylalkyl groups are those in which a presently preferred heteroaryl or heteroalicyclyl group is covalently bonded to a presently preferred alkyl group as disclosed herein. [0031] As used herein, "phenyl" refers to a 6-member aryl group. A phenyl group may be unsubstituted or substituted. When substituted the substituent(s) is/are one or more, preferably one or two, group(s) independently selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, -NRaRb wherein Ra and Rb are as defined above but in addition Ra may be an amino protecting group as defined herein, carboxamide, protected carboxamide, N-alkylcarboxamide, protected N- alkylcarboxamide, N,N-dialkylcarboxamide, trifluoromethyl, N-alkylsulfonylamino, N- (phenylsulfonyl)amino and phenyl (resulting in the formation of a biphenyl group). [0032] Examples of substituted phenyl groups include, without limitation, 2, 3 or A- chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2, 3 or A- bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2, 3 and 4-fluorophenyl, 2, 3 or A- hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof, 2, 3 or A- nitrophenyl; 2, 3 or 4-cyanophenyl; 2, 3 or 4-methylphenyl, 2,4-dimethylphenyl, 2, 3 or 4-(iso- propyl)phenyl, 2, 3 or 4-ethylphenyl, 2, 3 or 4-(n-propyl)phenyl, 2,6-dimethoxyphenyl, 2, 3 or A- methoxyphenyl, 2, 3 or 4-ethoxyphenyl, 2, 3 or 4-(isopropoxy)phenyl, 2, 3 or 4-(t- butoxy)phenyl, 3-ethoxy-4-methoxyphenyl; 2, 3 or 4-trifluoromethylphenyl; 2, 3 or A- carboxyphenyl or 2,4-di(protected carboxy)phenyl; 2, 3, or 4-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; 2, 3 or 4-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; and 2, 3 or 4-(N-(methylsulfonylamino))phenyl.
[0033] As used herein, "phenylalkoxy" refers to a "phenylalkyl-O-" group with "phenyl" and "alkyl" as defined herein. A phenylalkoxy group of this invention may be substituted or unsubstituted on the phenyl ring, in the alkyl group or both. Examples of phenylalkoxy groups include, without limitation, 2-(4-hydroxyphenyl)ethoxy, 4-(4-methoxyphenyl)butoxy, (2R)-3- phenyl-2-amino-propoxy, (2S)-3-phenyl-2-amino-propoxy, 2-indanoxy, 6-phenyl-l-hexanoxy, cinnamyloxy, 2-phenyl-l-propoxy and 2,2-dimethyl-3-phenyl-l-propoxy.
[0034] As used herein, "halo" and "halogen" refer to the fluoro, chloro, bromo or iodo atoms. Preferred halogens are chloro and fluoro.
[0035] As used herein, "amino protecting group" refers to a group commonly employed to keep (i.e., to "block" or "protect") an amino group from reacting with a reagent while it reacts with an intended target functional group of a molecule.
[0036] As used herein, a "protected carboxamide" refers to a carboxamide in which the nitrogen is substituted with an amino protecting group.
[0037] Examples of amino protecting groups include, without limitation, formyl ("For"), trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl groups, t-butoxycarbonyl ("Boc"), 2-(4-biphenylyl)propyl-2-oxycarbonyl ("Bpoc"), 2-phenylpropyl-2-oxycarbonyl ("Poc"), 2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenylethyl-l-oxycarbonyl, 1,1-diphenylpropyl- 1-oxycarbonyl, 2-(3,5-dimethoxyphenyl)propyl-2-oxycarbonyl ("Ddz"), 2-(p-toluyl)propyl-2- oxycarbonyl, cyclopentanyloxycarbonyl, 1 -methyl cyclopentanyloxycarbonyl, cyclohexanyloxy- carbonyl, 1 -methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4- toluylsulfonyl)-ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)- ethoxycarbonyl, 9-fluorenylmethoxycarbonyl ("Fmoc"), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1 -(trimethylsilylmethyl)prop- 1 -enyloxycarbonyl, 5 - benzisoxalylmethoxycarbonyl, 4-acetoxybenzyl-oxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2- ethynyl-2-propoxycarbonyl, cyclopropyl-methoxycarbonyl, isobornyloxycarbonyl, 1- piperidyloxycarbonyl, benzyloxycarbonyl ("Cbz"), 4-phenylbenzyloxycarbonyl, 2- methylbenzyloxy-carbonyl, -2,4,5, -tetramethylbenzyloxycarbonyl ("Tmz"), A- methoxybenzyloxy- carbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3- chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyl-oxycarbonyl, A- bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxy-carbonyl, A- cyanobenzyloxycarbonyl, 4-(decyloxy) benzyloxycarbonyl, benzoylmethylsulfonyl, dithiasuccinoyl ("Dts"),2-(nitro)phenylsulfenyl ("Nps"), and diphenyl-phosphine oxide. The species of amino-protecting group employed is not critical so long as the derivatized amino group is stable to the conditions of the subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Presently preferred amino- protecting groups are Boc, Cbz and Fmoc. Descriptions of these and other amino-protecting groups may be found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, N. Y., 1991, Chapter 7, M. Bodanzsky, "Principles of Peptide Synthesis," 1st and 2nd revised ed., Springer- Verlag, New York, N.Y., 1984 and 1993, and Stewart and Young, "Solid Phase Peptide Synthesis," 2nd ed., Pierce Chemical Co., Rockford, III, 1984.
[0038] As used herein, the term "carboxy protecting group" refers to a labile ester commonly used to block or protect a carboxylic acid while reactions are carried out on other functional groups on the compound. Examples of carboxy protecting groups include, without limitation, t- butyl, 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6- trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylpropyl, trimethylsilyl, t- butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, -(trimethylsilyl)ethyl, -(di(n- butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, and l-(trimethylsilylmethyl)-propenyl. The ester employed is not critical so long as it is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of carboxy-protecting groups are found in E. Haslam, "Protective Groups in Organic Chemistry," J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and Sons, New York, N.Y., 1991, Chapter 5. [0039] As used herein, a "hydroxyl protecting group" refers to a readily cleavable group that replaces the hydrogen of the hydroxyl group, such as, without limitation, tetrahydropyranyl, 2- methoxypropyl, 1 -ethoxyethyl, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, t- butyl, t-amyl, trityl, 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, benzyl, allyl, trimethylsilyl, (t-butyl)dimethylsilyl, and 2,2,2-trichloroethoxycarbonyl. The species of hydroxyl protecting groups is not critical so long as the derivatized hydroxyl group is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of hydroxy-protecting groups are described by C. B. Reese and E. Haslam, "Protective Groups in Organic Chemistry," J. G. W.
McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapters 3 and 4, respectively, and T. W.
Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis," 2nd ed., John Wiley and
Sons, New York, N. Y., 1991, Chapters 2 and 3.
[0040] As used herein, "alkylthio" refers to an "alkyl-S-" group, with alkyl as defined above.
Examples of alkylthio group include, without limitation, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio and t-butylthio.
[0041] As used herein, "alkylsulfmyl" refers to an "alkyl-SO-" group, with alkyl as defined above. Examples of alkylsulfinyl groups include, without limitation, methylsulfmyl, ethylsulfmyl, n-propylsulfmyl, isopropylsulfmyl, n-butylsulfmyl and sec-butylsulfinyl.
[0042] As used herein, "alkylsulfonyl" refers to an "alkyl-SO2-" group. Examples of alkylsulfonyl groups include, without limitation, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, and t-butylsulfonyl.
[0043] As used herein, "phenylthio," "phenylsulfmyl," and "phenylsulfonyl" refer to a
"phenyl-S-," "phenyl-SO-," and "phenyl-SO2-" group, with phenyl as defined herein.
[0044] As used herein, "alkylaminocarbonyl" refers to an "alkylNHC(=O)-" group, with alkyl as defined herein. Examples of alkylaminocarbonyl groups include, without limitation, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl and butylaminocarbonyl.
Examples of substituted alkylaminocarbonyl include, without limitation, methoxymethyl- aminocarbonyl, 2-chloroethylaminocarbonyl, 2-oxopropylaminocarbonyl and A- phenylbutylaminocarbonyl .
[0045] As used herein, "alkoxycarbonyl" refers to an "alkyl-OC(=O)-" group, with alkyl as defined above. [0046] As used herein, "phenylaminocarbonyl" refers to a "phenyl-NHC(=O)-" group, with phenyl as defined above. Examples of substituted phenylaminocarbonyl groups include, without limitation, 2-chlorophenyl-aminocarbonyl, 3-chlorophenylaminocarbonyl, 2- nitorphenylaminocarbonyl, 4-biphenylaminocarbonyl, and 4-methoxyphenylaminocarbonyl.
[0047] As used herein, "alkylaminothiocarbonyl" refers to an "alkyl-NHC(=O)-" group, with alkyl as defined above. Examples of alkylaminothio- carbonyl groups include, without limitation, methylaminothiocarbonyl, ethylaminothiocarbonyl, propylaminothiocarbonyl and butylaminothiocarbonyl .
[0048] Examples of alkyl-substituted alkylaminothiocarbonyl groups include, without limitation, methoxymethylaminothiocarbonyl, 2-chloroethylaminothiocarbonyl, 2- oxopropylaminothiocarbonyl and 4-phenylbutylaminothiocarbonyl.
[0049] As used herein, "phenylaminothiocarbonyl" refers to a "phenyl-NHC(=S)-" group, with phenyl as defined above. Examples of phenylaminothiocarbonyl groups include, without limitation, 2-chlorophenylaminothiocarbonyl, 3-chlorophenyl-aminothiocarbonyl, 2- nitrophenylaminothiocarbonyl, 4-biphenylaminothiocarbonyl and 4- methoxyphenylaminothiocarbonyl .
[0050] As used herein, "carbamoyl" refers to an "-NCO-" group.
[0051] As used herein, "hydroxyl" refers to an "-OH" group.
[0052] As used herein, "cyano" refers to a "-C≡N" group.
[0053] As used herein, "nitro" refers to an "-NO2" group.
[0054] An "O-carboxy" group refers to a "RC(=O)O-" group with R as defined above.
[0055] A "C-carboxy" group refers to a "-C(=O)OR" group with R as defined above.
[0056] An "acetyl" group refers to a CH3C(=O)- group.
[0057] A "trihalomethanesulfonyl" group refers to an "XsCSO2-" group wherein X is a halogen.
[0058] An "isocyanato" group refers to an "-NCO" group.
[0059] A "thiocyanato" group refers to a "-CNS" group.
[0060] An "isothiocyanato" group refers to an " -NCS" group.
[0061] A "sulfmyl" group refers to an "-S(=O)-R" group with R as defined above.
[0062] An "S-sulfonamido" group refers to a "-SO2NR" group with R as defined above.
[0063] An "N-sulfonamido" group refers to a "RSO2NH-" group with R as defined above. [0064] A "trihalomethanesulfonamido" group refers to an "X3CSO2NR-" group with X as halogen and R as defined above.
[0065] An "O-carbamyl" group refers to a "-OC(=O)-NR" group with R as defined above.
[0066] An "N-carbamyl" group refers to an "ROC(=O)NH-" group with R as defined above.
[0067] An "O-thiocarbamyl" group refers to a "-OC(=S)-NR" group with R as defined above.
[0068] "N-thiocarbamyl" group refers to an "ROC(=S)NH-" group with R as defined above.
[0069] A "C-amido" group refers to a "-C(=O)-NRaRb group with Ra and Rb as defined above.
[0070] An "N-amido" group refers to a RC(=O)NH- group with R as defined above.
[0071] By "perhaloalkyl" it is meant an alkyl moiety where all of the hydrogen atoms normally present on the alkyl are replaced by a halogen. Thus, for example, a perchloroalkyl is an alkyl moiety where all of the carbon atoms not connected to the rest of the molecule are connected to chlorine atoms.
[0072] As used herein, an "ester" refers to a "-C(O)ORa" group with Ra as defined herein.
[0073] As used herein, an "amide" refers to a "-C(O)NRaRb" group with Ra and Rb as defined herein.
[0074] Any unsubstituted or monosubstituted amine group on a compound herein can be converted to an amide, any hydroxyl group can be converted to an ester and any carboxyl group can be converted to either an amide or ester using techniques well-known to those skilled in the art (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John
Wiley & Sons, New York, NY, 1999). Compounds containing any such converted hydroxyl, amino and/or carboxylic acid groups are within the scope of this invention.
[0075] As used herein, an "ether" refers to an "-C-O-C-" group wherein either or both carbons may independently be part of an alkyl, alkenyl, alkynyl, aryl, heteroaryl or heteroalicyclyl group.
[0076] As used herein, a "halogenated ether" refers to an ether in which the groups to either side of the oxygen are both alkyl substituted with halogen.
[0077] As used herein, "amino acid" refers to any one of the twenty naturally-occurring L- amino acids, to their non-natural D-enantiomers, to non-naturally occurring amino acids such as, without limitation, norleucine ("NIe"), norvaline ("Nva"), L- or D-naphthalanine, ornithine
("Orn"), homoarginine (homoArg) and to other amino acids well-known in the peptide art such as those described in M. Bodanzsky, "Principles of Peptide Synthesis," 1st and 2nd revised ed., Springer- Verlag, New York, N. Y., 1984 and 1993, and Stewart and Young, "Solid Phase Peptide Synthesis," 2nd ed., Pierce Chemical Co., Rockford, 111.
[0078] Amino acids are referred to herein by their full chemical names, by their three letter codes, or by their one letter code, which are well-known to those skilled in the art. Unless the chirality of an amino acid is specifically designated or the amino acid is expressly stated to be a naturally occurring (i.e., L-) amino acid, the amino acid may be D or L or a racemic mixture of the two.
[0079] As used herein, a "functionalized resin" refers to any resin to which functional groups have been appended. Such functionalized resins are well-known to those skilled in the art and include, without limitation, resins functionalized with amino, alkylhalo, formyl or hydroxy groups. Examples of functionalized resins which can serve as solid supports for immobilized solid phase synthesis are well-known in the art and include, without limitation, 4- methylbenzhydrylamine-copoly(styrene-l% divinylbenzene) (MBHA), 4- hydroxymethylphenoxymethyl-copoly(styrene- 1 % divinylbenzene), 4-oxymethyl-phenyl- acetamido-copoly(stryene-l% divinylbenzene) (Wang), 4-(oxymethyl)-phenylacetamido methyl (Pam), and Tentagel™, from Rapp Polymere Gmbh, trialkoxy-diphenyl-methyl ester- copoly(styrene-l% divinylbenzene)(RINK) all of which are commercially available. Other functionalized resins useful in the synthesis of the compounds of this invention will become apparent to those skilled in the art based on the disclosures herein. All such resins are within the scope of this invention.
[0080] When two substituents taken together along with the carbon atoms to which they are attached form a five- or six-membered optionally substituted carbocyclic ring or optionally substituted heterocyclic ring, or form a six-membered optionally substituted aryl, optionally substituted heteroaryl, it is meant that the following structure:
Figure imgf000017_0001
can be representative of, for example, the following structures:
Figure imgf000017_0002
Figure imgf000018_0001
where X is a heteroatom.
[0081] Throughout the present disclosure, when a particular compound comprises a chiral center, the scope of the present disclosure also includes compositions comprising the racemic mixture of the two enantiomers, as well as compositions comprising each enantiomer individually substantially free of the other enantiomer. Thus, for example, contemplated herein is a composition comprising the S enantiomer substantially free of the R enantiomer, or a composition comprising the R enantiomer substantially free of the S enantiomer. By "substantially free" it is meant that the composition comprises less than 10%, or less than 8%, or less than 5%, or less than 3%, or less than 1% of the minor enantiomer. If the particular compound comprises more than one chiral center, the scope of the present disclosure also includes compositions comprising a mixture of the various diastereomers, as well as compositions comprising each diastereomer substantially free of the other diastereomers. The recitation of a compound, without reference to any of its particular diastereomers, includes compositions comprising all four diastereomers, compositions comprising the racemic mixture of R,R and S, S isomers, compositions comprising the racemic mixture of R,S and S,R isomers, compositions comprising the R,R enantiomer substantially free of the other diastereomers, compositions comprising the S, S enantiomer substantially free of the other diastereomers, compositions comprising the R,S enantiomer substantially free of the other diastereomers, and compositions comprising the S,R enantiomer substantially free of the other diastereomers. [0082] When a tautomer of the compound of the Formula I exists, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically drawn or stated otherwise The disclosure and claims of the present invention are based on the known general principles of chemical bonding. It is understood that the claims do not encompass structures known to be unstable or not able to exist based on the literature.
COMPOUNDS
[0083] In one aspect, disclosed herein are compounds of Formula I:
Figure imgf000019_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, where
X1-X4 is each independently carbon or nitrogen, provided that at least one of X1-X4 is carbon; R1 is selected from the group consisting of hydrogen optionally substituted alkyl, and cationic counterion;
R2-R5 is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -OR15, -NO2, -N(R15)2, -(CR16R17)n-NHC(=O)R15, -NH(SO2)R15, -CH2NHR15, - CH2NH(SO2)R15, -(CR16R17)n-C(=O)R15, and -(CR16Rn)n-C(O)OR15, where n is an integer between O and 10, inclusive, provided that R2 does not exist when X1 is nitrogen, provided that R3 does not exist when X2 is nitrogen, provided that R4 does not exist when X3 is nitrogen, and provided that R5 does not exist when X4 is nitrogen; or
X1 and X2 are carbon and R2 and R3 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; or
X2 and X3 are carbon and R3 and R4 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; A is a moiety of Formula II, Formula HA, or Formula III:
Figure imgf000020_0001
where
Y1 is selected from the group consisting of nitrogen, oxygen, and sulfur, as valence allows; Y2 and Y3 is each independently selected from the group consisting of carbon, CH, oxygen, nitrogen and sulfur; Y4 is carbon or nitrogen; R6-Rg is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -OR1S, -NO2,
-N(R15)2, -NHC(=0)R15, -NHC(=0)0R15, -NH(SO2)R15, -(CR16Rn)n-C(O)OR15,
-(CRi6Rn)n-SRi5, - (CRi6Rn)nC(=O)N(Ri5)2, -
(CRi6Rn)n-C(=O)N-(CRi6Ri7)n-C(=O)ORi5,
(CRi6Rn)n-C(=O)N-(CRi6Ri7)n-C(=O)Ri5, -(CRi6Rn)n-S(O)Ri5,-
(CRi6Rn)n-C(O)Ri5, and -(CRi6Rn)n-S(O)2Ri5, where n is an integer between
O and 10, inclusive, provided that R6 does not exist when Yi is oxygen or sulfur, and provided that R9 does not exist when Y4 is nitrogen; or Y2 and Y3 are carbon and R7 and R8 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; bond a is single bond or double bond, such that Y2 and Y3 have a complete octet along with R7 and R8; Zi-Z5 is each independently carbon or nitrogen, provided that at least two of Zi-Z5 are carbon; RiO-Ri4 is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, O, -ORi5, -NO2, -N(R15)2, -NHC(=O)R15, -NH(SO2)Ar, - (CR16R17)n-C(=O)R15, -(CR16R17)n-C(=O)N-(CR16R17)n-C(=O)OR15, (CR16R17)nC(=O)N(R15)2 -(CR16Ri7)n-S(=O)2R15, and -(CR16Ri7)n-C(=O)OR15, where Ar is an optionally substituted aryl, and where n is an integer between 0 and 10, inclusive, provided that R1O does not exist when Z1 is nitrogen, provided that R11 does not exist when Z2 is nitrogen, provided that R12 does not exist when Z3 is nitrogen, provided that R13 does not exist when Z4 is nitrogen, and provided that R14 does not exist when Z5 is nitrogen;
R15 is independently selected as it appears from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and
Ri6 and R17 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl.
Z3 and Z4 are carbon and R12 and R13 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring. [0084] In another aspect, disclosed herein are compounds of Formula I:
Figure imgf000021_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, where
X1-X4 is each independently carbon or nitrogen, provided that at least one of X1-X4 is carbon;
R1 is selected from the group consisting of hydrogen optionally substituted alkyl, and cationic counterion; R2-R5 is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -OR1S, -NO2, -N(RiS)2, -NHC(=0)R15, -NH(SO2)Ar, and -(CRi6Rn)n-C(O)ORiS, where Ar is an optionally substituted aryl, and where n is an integer between O and 10, inclusive, provided that R2 does not exist when Xi is nitrogen, provided that R3 does not exist when X2 is nitrogen, provided that R4 does not exist when X3 is nitrogen, and provided that R5 does not exist when X4 is nitrogen; or
Xi and X2 are carbon and R2 and R3 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; or
X2 and X3 are carbon and R3 and R4 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; A is a moiety of Formula II or Formula III:
Figure imgf000022_0001
where
Yi is selected from the group consisting of nitrogen, oxygen, and sulfur;
Y2 and Y3 is each independently selected from the group consisting of carbon, CH, oxygen, and sulfur;
Y4 is carbon or nitrogen;
R6-R9 is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -OR15, -NO2, -N(Ris)2, -NHC(=0)Ris, -NH(SO2)Ar, -(CRi6Rn)n-C(O)ORi5, (CR16Ri7)n-S(=O)R15, and -(CR16Ri7)n-S(=O)2Ri5, where Ar is an optionally substituted aryl, and where n is an integer between 0 and 10, inclusive, provided that R6 does not exist when Y1 is oxygen or sulfur, and provided that R9 does not exist when Y4 is nitrogen; or
Y2 and Y3 are carbon and R7 and R8 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; bond a is single bond or double bond, such that Y2 and Y3 have a complete octet along with R7 and R8; Z1-Z5 is each independently carbon or nitrogen, provided that at least two of Z1-Z5 are carbon;
R1O-R14 is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -OR15, -NO2, -N(R15)2, -NHC(=0)R15, -NH(SO2)Ar, and -(CR16R17)n-C(=O)OR15, where Ar is an optionally substituted aryl, and where n is an integer between 0 and 10, inclusive, provided that R1O does not exist when Z1 is nitrogen, provided that R11 does not exist when Z2 is nitrogen, provided that R12 does not exist when Z3 is nitrogen, provided that R^ does not exist when Z4 is nitrogen, and provided that R14 does not exist when Z5 is nitrogen;
R15 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R16 and R17 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl. [0085] In some embodiments, R1 is an optionally substituted alkyl. The alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments, R1 is hydrogen.
[0086] In other embodiments, R1 is a cationic counterion. Cationic counterions are well- known in the art. Some cationic counterions comprise metal ions, whereas others, such as the ammonium ion (NH4 +), dialkylammonium ion, dialkanolammonium ion, protonated piperazine, protonated betaine, protonated meglumine, protonated tromethamine, protonated L-lysine, protonated L-arginine, and other protonated amino acids, are non-metallic. In some embodiments, there is a covalent bond between the oxygen atom and the R1 in -0-R1. In other embodiments, the interaction between the two groups is electrostatic. In some embodiments, the cation is an ionic form of a metal. In some of these embodiments, the metal is selected from the group consisting of alkali metal, alkali earth metal, and transition metal. Examples of alkali metals include lithium, sodium, and potassium. Examples of alkali earth metals include magnesium and calcium. In some embodiments, the metal ion is complexed in a crown ether. [0087] In some embodiments, R2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments, the aryl is phenyl, while in other embodiments, the heteroaryl is pyridyl. In some embodiments, R2 is hydrogen.
[0088] In some embodiments, R3 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -OR1S, and -NO2, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments, the aryl is phenyl, while in other embodiments, the heteroaryl is pyridyl. In certain embodiments, the halo is selected from the group consisting of fluoro, chloro, bromo, and iodo. In some embodiments, R3 is chloro or bromo.
[0089] In some embodiments, R3 is -OR1S. In some of these embodiments, R15 is hydrogen or an optionally substituted alkyl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments, the alkyl is substituted with an aryl. In some of these embodiments, the aryl is a phenyl. In some embodiments, R3 is -OH or -OCH2CeH5. In certain embodiments, R3 is selected from the group consisting of hydrogen, bromo, phenyl, -NO2, -OH, and -OCH2CeH5.
[0090] In some embodiments R3 is selected from -Q=O)OR15. In some embodiments R15 is hydrogen.
[0091] In some embodiments R3 is selected from -(CR16R17)nNHC(=O)R15. In some embodiments R15 is an optionally substituted alkyl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
[0092] In some embodiments, R3 is selected from -CH2NH(SO2)R15. In some embodiments
R15 is selected from optionally substituted aryl or optionally substituted arylalkyl.
[0093] In some embodiments, R4 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, perhaloalkyl, - (CR16R17)n-C(=O)R15, and -OR15. In some embodiments, the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments, the aryl is phenyl, while in other embodiments, the heteroaryl is pyridyl. In certain embodiments, the halo is selected from the group consisting of fluoro, chloro, bromo, and iodo. In some embodiments, R4 is selected from the group consisting of hydrogen, acetyl, chloro, bromo, and phenyl.
[0094] In some embodiments, R5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments, the aryl is phenyl, while in other embodiments, the heteroaryl is pyridyl. In some embodiments, R5 is hydrogen.
[0095] In some embodiments of the compound of Formula I, X1 and X2 are carbon and R2 and
R3 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring. In some embodiments, the six-membered ring from by R2 and R3 is phenyl, while in other embodiments, the six-membered ring is pyridyl.
[0096] In some embodiments of the compound of Formula I, X1 and X2 are carbon and R3 and
R4 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring. In some embodiments, the six-membered ring from by R3 and R4 is phenyl, while in other embodiments, the six-membered ring is pyridyl.
[0097] In some embodiments, X1-X4 are carbon. In other embodiments, X1-X3 are carbon and
X4 is nitrogen.
[0098] In some embodiments, A is a moiety of Formula II.
Figure imgf000026_0001
[0099] In some embodiments, A is a moiety of Formula IIA
Figure imgf000026_0002
[0100] In some of these embodiments, R5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments, the aryl is phenyl, while in other embodiments, the heteroaryl is pyridyl. In some embodiments, R5 is hydrogen.
[0101] In some embodiments, R7 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR1S, -N(R1S)2, -NHC(=O)R15, -NHC(=O)OR15, and -(CR16Ri7)n-C(=O)OR15. In some of these embodiments, the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, and tert-butyl.
[0102] In some of the embodiments where R7 is -OR1S, R1S is hydrogen or an optionally substituted alkyl. In some of these embodiments, the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. Some of these embodiments include those in which the alkyl is substituted with an aryl. The aryl can be a phenyl. In some of these embodiments, R7 is -OH or -OCH2CeH5. [0103] In some of the embodiments where R7 is -(CR16Ri7)n-C(=O)OR15 or -
(CRi6Rn)n-C(O)Ri5 R1S is hydrogen or an optionally substituted alkyl. In some of these embodiments, the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. Some of these embodiments include those in which the alkyl is substituted with an aryl. The aryl can be a phenyl. In some embodiments, R16 and R17 is each independently hydrogen or an optionally substituted alkyl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, R7 is selected from the group consisting of methyl, -C(=O)OH, -C(=O)CH3, -CH2-CH2-C(=O)OH, and -C(=O)CH2CH3.
[0104] In some embodiments R7 is , -(CR16Rn)n-SR15, -(CR16R17)nC(=O)N(R15)2,. - (CRi6Rn)n-C(O)Ri5, - (CRi6Rn)n-C(O)ORi5, and -(CRi6Rn)n-S(O)2Ri5. [0105] In some of the embodiments where R7 is , -(CRi6Rn)n-SRi5, -(CRi6Rn)nC(=O)N(Ri5)2, - (CRi6Rn)n-C(O)Ri5, and -(CRi6Rn)n-S(O)2Ri5, Ri5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroalicyclyl, optionally substituted arylalkyl. In some of these embodiments, the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments the heteroalicyclyl is selected from pyrrolidine. In some embodiments, Ri6 and Rn is each independently hydrogen or an optionally substituted alkyl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments, n is O, 1, 2, or 3.
[0106] In some embodiments, Rs is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, - C(Ri6Rn)nN(Ri5),, -CH2NH-C(O)ORi5, - (CRi6Rn)n-C(O)Ri5, —
(CRi6Rn)n-C(O)N-(CRi6Rn)n-C(O)ORi5, -(CRi6Rn)n-C(O)N-(CRi6Rn)n-C(O) Ri5,- (CRi6Rn)nC(O)N(Ri5)2, -(CRi6Rn)n-S(O)2Ri5, or - (CRi6Rn)n-C(O)ORi5 and optionally substituted heteroaryl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In certain embodiments, Rg is hydrogen, methyl, or -CH2C(O)OH. [0107] In some of the embodiments where R8 is -C(R16Rn)nN(R1S)2, -CH2NH-C(=O)OR15, - (CR16Rn)n-C(O)R15, - (CR16R17)n-C(=O)OR15, — (CR16R17)n-C(=O)N-(CR16R17)n-C(=O)OR15, — (CRi6Rn)n-C(=O)N-(CRi6Rn)n-C(=O) Ri5, -(CRi6R17)nC(=O)N(Ri5)2,
-(CRi6Rn)n-S(=O)2Ri5, or - (CRi6Rπ)n-C(=O)ORi5, Ri5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl. In some of these embodiments, the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, and tert-butyl. Some of these embodiments include those in which the alkyl is substituted with an optionally substituted aryl, optionally substituted heteroaryl, dialkylamino, or hydroxy. The aryl can be a phenyl. In some embodiments the cycloalkyl is cyclopropyl. In some embodiments the heteroalicyclyl is selected from pyrrolidine, piperdine, piperazine, morpholine, aziridine, and azetedine. In some embodiments the heteroaryl is selected from pyridine, imidazol, indole, isoindole, oxadiazol and isoquinoline. In some embodiments, Ri6 and Rn is each independently hydrogen or an optionally substituted alkyl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments, n is O, 1, 2, or 3
[0108] In embodiments where R8 is -(CRi6Rn)nC(=O)N(Ri5)2, Ri5 is an optionally substituted arylalkyl where the arylalkyl can be selected from phenylmethyl and phenylethyl or heteroarylalkyl where the heteroarylalkyl can be selected from pyridinemethyl and pyridineethyl. [0109] In some embodiments, Rg is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In certain embodiments, R9 is hydrogen or methyl.
[0110] In some embodiments, Y2 and Y3 are carbon and R7 and R8 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring. In some embodiments, the six-membered ring from R2 and R3 is phenyl, while in other embodiments, the six-membered ring is pyridyl. [0111] In other embodiments when A is a moiety of Formula II, Yi is sulfur; Y2 is carbon; Y3 is carbon; Y4 is nitrogen, and bond a is a double bond. In certain embodiments, Yi is oxygen; Y2 is CH; Y3 is CH; Y4 is nitrogen, and bond a is a single bond. In other embodiments, Y1 is sulfur;
Y2 is CH; Y3 is CH; Y4 is nitrogen, and bond a is a single bond. In additional embodiments, Y1 is nitrogen; Y2 is CH; Y3 is CH; Y4 is nitrogen, and bond a is a single bond.
[0112] In other embodiments when A is a moiety of Formula II, Y1 is oxygen, Y2 is nitrogen,
Y3 is carbon and Y4 is nitrogen, and bond a is a double bond. In certain embodiments Y1 is oxygen, Y2 is nitrogen, Y3 is carbon, and Y4 is nitrogen and bond a is double bond. In yet another embodiment, Y1 is sulfur, Y2 is nitrogen, Y3 is carbon and Y4 is nitrogen, and bond a is a double bond.
[0113] In other embodiments when A is a moiety of Formula HA, Yl is nitrogen, Y2 is carbon,
Y3 is oxygen, and Y4 is nitrogen.
[0114] In some embodiments, A is a moiety of Formula III.
Figure imgf000029_0001
[0115] In some of these embodiments, Rio is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments, R1O is hydrogen.
[0116] In some of the embodiments where R11 is -(CR16Ri7)n-C(=O)ORi5, R15 is hydrogen or an optionally substituted alkyl. In some of these embodiments, the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. Some of these embodiments include those in which the alkyl is substituted with an aryl. The aryl can be a phenyl. In some embodiments, Ri6 and Rn is each independently hydrogen or an optionally substituted alkyl, where the alkyl can be selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, Rn is selected from the group consisting of methyl, -C(=O)OH, - C(=O)CH3, and -C(=O)CH2CH3. In certain embodiments, Rn is -C(=O)OH. [0117] In some embodiments, R12 is selected from the group consisting of hydrogen, optionally substituted alkyl, and halo, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments, the halo is selected from the group consisting of fluoro, chloro, bromo, and iodo. In some embodiments, R12 is hydrogen or bromo.
[0118] In some embodiments R12 is selected from the group consisting of , -
(CRi6Rn)n-C(O)Ri5, - (CRi6Rn)n-C(O)ORi5, -(CRi6Rn)n-C(O)NH-(CRi6Rn)n-C(O)ORi5, -(CRi6Rn)n-C(O)NH-(CRi6Rn)n-C(O)Ri5, (CRi6Rn)nC(O)N(Ri5)2, -(CRi6Rn)n-S(O)2Ri5, and -(CRi6Rn)n-C(O)0Ri5. R15 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, In some of these embodiments, the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. Some of these embodiments include those in which the alkyl is substituted with an aryl or hydroxy. The aryl can be a phenyl. In some embodiments the cycloalkyl is cyclopropyl. In some embodiments, the heteroalicyclyl is selected from pyrrolidine, piperdine, or indole. In some embodiments the heteroaryl is selected from pyridine. Ri6 and Rn is each independently hydrogen or an optionally substituted alkyl, where the alkyl can be selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments, n is O, 1, 2, or 3.
[0119] In some embodiments, R13 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. The alkyl can be selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments, R13 is hydrogen. [0120] In some embodiments, Z3 and Z4 are carbon and Ri2 and R13 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or six-membered optionally substituted heteroaryl. In some embodiments, the aryl ring formed by Ri2 and R13 is phenyl.
[0121] In some embodiments, Ri4 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. The alkyl can be selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In some embodiments, R14 is hydrogen. [0122] In some embodiments of the compounds of Formula I, Z1-Z4 are carbon and Z5 is nitrogen. In other embodiments, Z2-Z4 are carbon and Z1 and Z5 are nitrogen. [0123] In some embodiments, the compounds of Formula I are those selected from the group consisting of
Figure imgf000031_0001
[0124] In other embodiments, the compounds of Formula I are those selected from the group consisting of
Figure imgf000031_0002
Figure imgf000032_0001
[0125] In some embodiments, in the compounds of Formula I, A is selected from the group consisting of
Figure imgf000032_0002
[0126] In other embodiments, in the compounds of Formula I, A is selected from the group consisting of
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
-35 -
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
-40-
Figure imgf000042_0001
Figure imgf000043_0001
[0127] In some embodiments, in the compounds of Formula I, A is
Figure imgf000043_0002
[0128] In other embodiments, in the compounds of Formula I, A is selected from the group consisting of
Figure imgf000043_0003
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
[0129] In another aspect, disclosed herein is a compound selected from the group consisting of
Figure imgf000046_0002
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, where A is a moiety selected from the group consisting of
Figure imgf000047_0001
Ri is selected from the group consisting of hydrogen optionally substituted alkyl, and cationic counterion; and
R2-Rs and R10-R13 is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -ORi5, -NO2, -N(RiS)2, -(CRi6Ri7)n-NHC(=O)Ri5, -(CRi6Ri7)n-NHC(=O)ORi5, , -NH(SO2)Ri5, -(CRi6Rn)n-C(O)ORi5, (CR16Ri7)n-C(=O)R15, - C(R16R17)nN(R15)2, -CH2NH-C(O)OR15 , -(CR16R17)n-C(=O)NH-(CR16R17)n-C(=O)OR15,
-(CR16Rn)n-C(O)NH-(CR16Rn)n-C(O) R15, (CR16Rn)nC(O)N(R1S)2, -(CR16Rn)n-S(O)2R15 where n is an integer between O and 10, inclusive. [0130] In another aspect, disclosed herein is a compound of Formula IV:
Figure imgf000047_0002
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, where
X is selected from the group consisting of oxygen, NH, and sulfur;
R1S and R1Q is each independently selected from the group consisting of hydrogen, - (CR16Rn)n-S(O)R20, and -(CR16Rn)n-S(O)2R20, n is an integer between 0 and 10, inclusive;
R16 and R17 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl;
R20 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR1S, and -N(R1S)2; where R15 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and bond a is a single bond or a double bond.
[0131] In some embodiments, R18 is hydrogen while R1Q is -(CR16R17)n-S(=0)2R2o. In some of these embodiments, n is 1. In certain embodiments, R16 and R17 are both hydrogen. In some embodiments, R2o is selected from the group consisting of -OH, alkyl, aryl-substituted alkyl, optionally substituted aryl, and -N(R15)2.
[0132] In some embodiments, R^ is hydrogen while R18 is -(CR16R17)n-S(=0)2R2o. In some of these embodiments, n is 1. In certain embodiments, R16 and R17 are both hydrogen. In some embodiments, R2o is selected from the group consisting of -OH, alkyl, aryl-substituted alkyl, optionally substituted aryl, and -N(R1S)2.
[0133] In another aspect, disclosed herein is a compound selected from the group consisting of 2-(2-Hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, 2-(2-Hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid, 2-(5-Bromo-2-hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, 2-(5-Bromo-2-hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid, 2-(2-Hydroxy-phenyl)-4,5-dihydro-oxazole-5-carboxylic acid, 2-(2-Hydroxy-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid, 2-(3-Hydroxy-naphthalen-2-yl)-4-methyl-thiazole-5-carboxylic acid, 2-(4-Hydroxy-biphenyl-3-yl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, 2-(4-Hydroxy-biphenyl-3-yl)-4-methyl-thiazole-5-carboxylic acid, 2-(5-Bromo-2-hydroxy-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid, 2-(2-Hydroxy-4-nitro-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid, 2-(5-Acetyl-2-hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid, 2-(4-Bromo-2-hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid, 2-(5-Chloro-2-hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid, 2-(2-Hydroxy-4-nitro-phenyl)-4-methyl-thiazole-5-carboxylic acid, 2-(4-Bromo-2-hydroxy-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid, 2-(4-Bromo-2-hydroxy-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid methyl ester, 3-(4,5-Dihydro-lH-imidazol-2-yl)-naphthalen-2-ol,
2-(3-Hydroxy-naphthalen-2-yl)-4,5-dihydro-3H-imidazole-4-carboxylic acid, 2-(4,5-Dihydro-lH-imidazol-2-yl)-pyridin-3-ol, l-Chloro-3-(4,5-dihydro-lH-imidazol-2-yl)-isoquinolin-4-ol, 2-(5-Methyl-4,5-dihydro-lH-imidazol-2-yl)-pyridin-3-ol, 2-(2,4-Dihydroxy-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid, 5-Bromo-2-(3-hydroxy-pyridin-2-yl)-pyrimidine-4-carboxylic acid, 2-(4-Benzyloxy-2-hydroxy-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid, 2-(3-Hydroxy-pyridin-2-yl)-pyrimidine-4-carboxylic acid,
(R)-2-(3-Hydroxy-5-phenyl-pyridin-2-yl)-4,5-dihydro-thiazole-4-carboxylic acid, (R)-2-(3-Hydroxy-pyridin-2-yl)-4,5-dihydro-thiazole-4-carboxylic acid, (S)-2-(3-Hydroxy-pyridin-2-yl)-4,5-dihydro-thiazole-4-carboxylic acid, 2-(l-Hydroxy-naphthalen-2-yl)-4,5-dihydro-oxazole-5-carboxylic acid, 3'-Hydroxy-[2,2']bipyridinyl-4-carboxylic acid, 3-(lH-Benzoimidazol-2-yl)-l-chloro-isoquinolin-4-ol, (R)-2-(2-Hydroxy-4-nitro-phenyl)-4,5-dihydro-thiazole-4-carboxylic acid, (S)-2-(2-Hydroxy-4-nitro-phenyl)-4,5-dihydro-thiazole-4-carboxylic acid, 2-(l-Chloro-4-hydroxy-isoquinolin-3-yl)-lH-benzoimidazole-5-carboxylic acid, 4-Hydroxy-2-(3 -hydroxy-pyridin-2-yl)-pyrimidine-5 -carboxylic acid, 2-(6-Bromo-3-hydroxy-pyridin-2-yl)-4-hydroxy-pyrimidine-5-carboxylic acid, 2-(3-Hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-acetic acid, 2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo- 1 ,6-dihydro-pyrimidin-5-yl] -acetic acid, 6-(5-Carboxymethyl-6-oxo- 1 ,6-dihydro-pyrimidin-2-yl)-5-hydroxy-nicotinic acid, N-Benzyl-2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide, 2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl] -acetic acid butyl ester, 2-(3-Hydroxy-pyridin-2-yl)-thiazole-4-carboxylic acid benzyl amide, N-Benzyl-2-[2-(3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-acetamide,
{2-[2-(3-Hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-acetylamino} -acetic acid,
2-(3,5-Dihydroxy-pyridin-2-yl)-3H-quinazolin-4-one,
5-Hydroxy-6-(4-oxo-3,4-dihydro-quinazolin-2-yl)-nicotinonitrile,
5-Hydroxy-6-(4-oxo-3,4-dihydro-quinazolin-2-yl)-nicotinic acid,
5-Hydroxy-6-(6-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)-nicotinonitrile,
5-Hydroxy-6-(6-methoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-nicotinonitrile,
5-Hydroxy-6-(6-hydroxy-4-oxo-3,4-dihydro-inazolin-2-yl)-nicotinonitrile,
N-Benzyl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide,
6-[6-(3,5-Dichloro-phenoxy)-4-oxo-3,4-dihydro-quinazolin-2-yl]-5-hydroxy- nicotinonitrile,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(3-fluoro-benzyl)-acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(4-fluoro-benzyl)-acetamide,
{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino} -acetic acid,
(S)-{2-[2-(5-Bromo-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino}-phenyl-acetic acid methyl ester,
(R)-{2-[2-(5-Bromo-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino}-phenyl-acetic acid methyl ester,
(S)-{2-[2-(5-Bromo-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino}-phenyl-acetic acid,
(R)-{2-[2-(5-Bromo-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino}-phenyl-acetic acid,
N-(2-Chloro-benzyl)-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide, N-(3-Chloro-benzyl)-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide, N-(4-tert-Butyl-benzyl)-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide, 2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-(3 -trifluoromethyl-benzyl)- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-(4-dimethylamino-benzyl)- acetamide, 2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-( 1 -methyl- 1 -phenyl-ethyl)- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-pyridin-2-ylmethyl-acetamide, 2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-pyridin-3 -ylmethyl-acetamide, 2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-pyridin-4-ylmethyl-acetamide, N-(4-Chloro-benzyl)-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide, 2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-pyridin-2-yl-ethyl)-acetamide, 2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-pyridin-3-yl-ethyl)-acetamide, 2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(3-methoxy-benzyl)-acetamide, 2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-pyridin-4-yl-ethyl)-acetamide, N-Benzhydryl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide, 2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-(I H-indol-5-ylmethyl)- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-phenethyl-acetamide, N- {2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -acetyl} -methanesulfonamide, N-{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetyl}-benzenesulfonamide, N-{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetyl}-C-phenyl- methanesulfonamide,
N-(6-Chloro-pyridin-3-ylmethyl)-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]- acetamide,
{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino} -acetic acid methyl ester,
(R)2-[2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-((R)-2-hydroxy- 1 -phenyl- ethyl)-acetamide,
(S)2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-((S)-2-hydroxy-l-phenyl- ethyl)-acetamide,
[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetic acid, {2-[5-(Acetylamino-methyl)-3-hydroxy-pyridin-2-yl]-thiazol-4-yl} -acetic acid, {2-[5-(Benzenesulfonylamino-methyl)-3-hydroxy-pyridin-2-yl]-thiazol-4-yl} -acetic acid, {2-[3-Hydroxy-5-(phenylmethanesulfonylamino-ethyl)-pyridin-2-yl]-thiazol-4-yl} -acetic acid, 2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-methyl-N-(2-pyridin-2-yl-ethyl)- acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(4-hydroxy-phenyl)-ethyl]- acetamide,
2-(2-(5-cyano-3-hydroxypyridin-2-yl)-thiazol-4-yl)-N-(4-sulfamoylphenethyl)- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-(3 -imidazol- 1 -yl-propyl)- acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(2-oxo-pyrrolidin-l-yl)-ethyl]- acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(lH-imidazol-4-yl)-ethyl]- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-morpholin-4-yl-ethyl)- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(3-morpholin-4-yl-propyl)- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-pyrrolidin-l-yl-ethyl)- acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(lH-indol-3-yl)-ethyl]- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-piperi din- 1-yl-ethyl)- acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[3-(2-oxo-pyrrolidin-l-yl)- propyl] -acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(3,4-dihydroxy-phenyl)- ethyl] -acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(5-hydroxy-lH-indol-3-yl)- ethyl] -acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(4-methyl-piperazin-l-yl)- ethyl] -acetamide, N-Benzyl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo- 1 ,6-dihydro-pyrimidin-5 -yl] -N-phenethyl- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-(3 -phenyl- propyl)-acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-[3-(2-oxo- pyrrolidin- 1 -yl)-propyl] -acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo- 1 ,6-dihydro-pyrimidin-5 -yl] -N-pyridin-3 - ylmethyl-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-(2-pyri din- 2-yl-ethyl)-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-(2-pyri din- 3 -yl-ethyl)-acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-[2-(3- trifluoromethyl-phenyl)-ethyl]-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo- 1 ,6-dihydro-pyrimidin-5 -yl] -N-phenyl- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl] -N- cyclopropyl-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-(2-oxo-2- phenyl-ethyl)-acetamide,
N-Butyl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]- acetamide,
5-Hydroxy-6-[6-oxo-5-(2-oxo-2-pyrrolidin-l-yl-ethyl)-l,6-dihydro-pyrimidin-2-yl]- nicotinonitrile,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-((R)-2-hydroxy- 1 -phenyl-ethyl)- acetamide,
2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -acetic acid benzyl ester, [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -acetic acid 2-pyridin-2-yl-ethyl ester, 5-Hydroxy-6-{5-[2-(2-methyl-2,3-dihydro-indol-l-yl)-2-oxo-ethyl]-6-oxo-l,6-dihydro- pyrimidin-2-yl} -nicotinonitrile,
5-Hydroxy-6-[6-oxo-5-(2-oxo-2-piperidin-l-yl-ethyl)-l,6-dihydro-pyrimidin-2-yl]- nicotinonitrile,
5 -Hydroxy-6- [4-(2-oxo-2-pyrrolidin- 1 -yl-ethyl)-thiazol-2-yl] -nicotinonitrile,
5 -Hydroxy-6-[4-(2-oxo-2-piperidin-l-yl-ethyl)-thiazol-2-yl] -nicotinonitrile,
N-Benzyl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-ethyl-acetamide,
N-Benzyl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-dimethylamino- ethyl)-acetamide,
6-{4-[2-(6,7-Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-2-oxo-ethyl]-thiazol-2-yl}-5- hydroxy-nicotinonitrile,
5-Hydroxy-6-(4-phenylmethanesulfonylmethyl-thiazol-2-yl)-nicotinonitrile,
6-{4-[2-(2,6-Dimethyl-morpholin-4-yl)-2-oxo-ethyl]-thiazol-2-yl}-5-hydroxy- nicotinonitrile,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N,N-diisopropyl-acetamide,
6-(4-Benzenesulfonylmethyl-thiazol-2-yl)-5-hydroxy-nicotinonitrile,
5 -Hydroxy-6- [4-(2-phenyl-ethanesulfonylmethyl)-thiazol-2-yl] -nicotinonitrile,
{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]- acetylamino} -acetic acid,
5-Hydroxy-6- {4-[2-oxo-2-(4-phenyl-piperidin- 1 -yl)-ethyl]-thiazol-2-yl} -nicotinonitrile,
5 -Hydroxy-6- [6-oxo-5 -(2 -phenyl-ethanesulfonylmethyl)- 1 ,6-dihydro-pyrimidin-2-yl] - nicotinonitrile,
6-{4-[(Benzyl-ethyl-carbamoyl)-methyl]-thiazol-2-yl}-5-hydroxy-nicotinic acid,
6-{4-[2-(3-Diethylamino-pyrrolidin-l-yl)-2-oxo-ethyl]-thiazol-2-yl}-5-hydroxy- nicotinonitrile,
5-Hydroxy-6-{6-oxo-5-[2-oxo-2-(4-phenyl-piperidin-l-yl)-ethyl]-l,6-dihydro-pyrimidin-
2-yl} -nicotinonitrile,
6-(4-Benzenesulfonylmethyl-thiazol-2-yl)-5-hydroxy-nicotinic acid,
6-{4-[2-(5-Bromo-2-oxo-2H-pyridin-l-yl)-2-oxo-ethyl]-thiazol-2-yl}-5-hydroxy- nicotinonitrile,
5-Hydroxy-6-{4-[2-(4-methyl-piperazin-l-yl)-2-oxo-ethyl]-thiazol-2-yl} -nicotinonitrile, 6-[4-(2-[l,4']Bipiperidinyl-r-yl-2-oxo-ethyl)-thiazol-2-yl]-5-hydroxy-nicotinonitrile,
6-{4-[2-(l,3-Dihydro-isoindol-2-yl)-2-oxo-ethyl]-thiazol-2-yl}-5-hydroxy-nicotinonitrile,
6- {4-[2-(3 ,4-Dihydro- 1 H-isoquinolin-2-yl)-2-oxo-ethyl]-thiazol-2-yl} -5 -hydroxy- nicotinonitrile,
5-Hydroxy-6-[4-(2-indol-l-yl-2-oxo-ethyl)-thiazol-2-yl]-nicotinonitrile,
6-{5-[2-(l,3-Dihydro-isoindol-2-yl)-2-oxo-ethyl]-6-oxo-l,6-dihydro-pyrimidin-2-yl}-5- hydroxy-nicotinonitrile,
5-Hydroxy-6-(6-oxo-5-phenylmethanesulfonylmethyl-l,6-dihydro-pyrimidin-2-yl)- nicotinonitrile,
6- {5-[2-(3 ,4-Dihydro- lH-isoquinolin-2-yl)-2-oxo-ethyl]-6-oxo-l,6-dihydro-pyrimidin-2- yl } -5 -hydroxy-nicotinonitrile,
5-Hydroxy-6- {4-[2-oxo-2-((R)-2-trifluoromethyl-pyrrolidin- 1 -yl)-ethyl] -thiazol-2-yl} - nicotinonitrile,
6- {4-[2-(5-Bromo- 1 ,3-dihydro-isoindol-2-yl)-2-oxo-ethyl]-thiazol-2-yl} -5-hydroxy- nicotinonitrile,
5-Hydroxy-6-{4-[2-((S)-2-hydroxymethyl-pyrrolidin-l-yl)-2-oxo-ethyl]-thiazol-2-yl}- nicotinonitrile,
(S)- 1 - {2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetyl} -pyrrolidine-2- carboxylic acid,
6-{4-[2-(5-Amino-3,4-dihydro-lH-isoquinolin-2-yl)-2-oxo-ethyl]-thiazol-2-yl}-5- hydroxy-nicotinonitrile,
(S)-2-{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetyl}-l,2,3,4-tetrahydro- isoquinoline-3-carboxylic acid tert-butylamide,
6- [4-(2-Azetidin-l-yl-2-oxo-ethyl)-thiazol-2-yl] -5 -hydroxy-nicotinonitrile, 6- {4-[2-(4-Fluoro-l ,3-dihydro-isoindol-2-yl)-2-oxo-ethyl]-thiazol-2-yl} -5-hydroxy- nicotinonitrile,
6- {4-[2-(5-Fluoro-l ,3-dihydro-isoindol-2-yl)-2-oxo-ethyl]-thiazol-2-yl} -5-hydroxy- nicotinonitrile,
6-{4-[2-(l,3-Dihydro-isoindol-2-yl)-2-oxo-ethyl]-5-methyl-thiazol-2-yl}-5-hydroxy- nicotinonitrile, 6-{5-[2-(4-Fluoro-l,3-dihydro-isoindol-2-yl)-2-oxo-ethyl]-6-oxo-l,6-dihydro-pyrimidin- 2-yl}-5-hydroxy-nicotinonitrile,
[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-5-phenyl-thiazol-4-yl] -acetic acid, 5 -Hydroxy-6- [4-(2-oxo-2-pyrrolidin- 1 -yl-ethyl)-5 -phenyl-thiazol-2-yl] -nicotinonitrile, 6-{4-[2-(l,3-Dihydro-isoindol-2-yl) -2-oxo-ethyl]-5-phenyl-thiazol-2-yl}-5-hydroxy- nicotinonitrile,
5 -Hydroxy-4-methyl-6- [4-(2-oxo-2-pyrrolidin- 1 -yl-ethyl)-thiazol-2-yl] -nicotinonitrile, 6-{4-[2-(l,3-Dihydro-isoindol-2-yl)-2-oxo-ethyl]-thiazol-2-yl}-5-hydroxy-4-methyl- nicotinonitrile, l-{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetyl}-aziridine-2-carboxylic acid methyl ester,
5 -Hydroxy-6- {4- [2-oxo-2-((S)-2-trifluoromethyl-pyrrolidin-l-yl)-ethyl] -thiazol-2-yl}- nicotinonitrile,
6-{5-[2-(5-Bromo-l,3-dihydro-isoindol-2-yl)-2-oxo-ethyl]-6-oxo-l,6-dihydro-pyrimidin- 2-yl}-5-hydroxy-nicotinonitrile,
5 -Hydroxy-6- [5 -methyl-4-(2-oxo-2-pyrrolidin- 1 -yl-ethyl)-thiazol-2-yl] -nicotinonitrile, 6- [4-(2- Azetidin- 1 -yl-2-oxo-ethyl)-5 -methyl-thiazol-2-yl] -5 -hydroxy-nicotinonitrile, 6- [4-(2-Azetidin-l-yl-2-oxo-ethyl)-5 -phenyl-thiazol-2-yl] -5 -hydroxy-nicotinonitrile, 2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-5-methyl-thiazol-4-yl]-N-(2-pyridin-2-yl-ethyl)- acetamide,
5-Hydroxy-6-[4-(3-phenyl-[l,2,4]oxadiazol-5-ylmethyl)-thiazol-2-yl]-nicotinonitrile, 2-[2-(5-Cyano-3-hydroxy-4-methyl-pyridin-2-yl)-5-methyl-thiazol-4-yl]- N-(2-pyridin-2- yl-ethyl)-acetamide,
2-[2-(5-Cyano-3-hydroxy-4-methyl-pyridin-2-yl)-5-phenyl-thiazol-4-yl]- N-(2-pyridin-2- yl-ethyl)-acetamide,
2-[2-(5-Cyano-3-hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl]-N-(2-pyridin-2-yl-ethyl)- acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-5-phenyl-thiazol-4-yl]-N-(2-pyridin-2-yl-ethyl)- acetamide,
2-[2-(5-Cyano-3-hydroxy-4-methyl-pyridin-2-yl)-5-methyl-thiazol-4-yl]- N-(3-imidazol- 1 -yl-propyl)-acetamide, 2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl] -N-methyl-N-(2-pyridin-2- yl-ethyl)-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl] -N-(3 -morpholin-4-yl- propyl)-acetamide,
[2-(5-Cyano-3-hydroxy-pyridin-2-yl) -thiazol-4-yl]-carbamic acid butyl ester,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-cyclopropylmethyl-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-cyclopropyl-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl]-N-(2-diethylamino-ethyl)- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-5-methyl-thiazol-4-yl]- N-(2- diethylamino-ethyl)-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl] -N-cyclopropylmethyl- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl]-N-cyclopropyl-acetamide,
2-[2-(5-Cyano-3-hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl]-N-(2,2,2-trifluoro-ethyl)- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl]-N-ethyl-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-5-methyl-thiazol-4-yl]- N-ethyl- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-5-methyl-thiazol-4-yl]- N-(2- pyrrolidin- 1 -yl-ethyl)-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl] -acetamide,
2-(5-Phenylmethanesulfonylmethyl-[l,2,4]oxadiazol-3-yl)-pyridin-3-ol,
6-(5-Benzylsulfanylmethyl-[ 1 ,2,4]oxadiazol-3-yl)-5-hydroxy-nicotinic acid,
5-Hydroxy-6-(5-phenylmethanesulfonylmethyl-[ 1 ,2,4]oxadiazol-3-yl)-nicotinic acid,
6-(5-Ethylsulfanylmethyl-[l,2,4]oxadiazol-3-yl)-5-hydroxy-nicotinic acid,
6-(5-Ethanesulfonylmethyl-[ 1 ,2,4]oxadiazol-3-yl)-5-hydroxy-nicotinic acid,
3-(3-Hydroxy-5-methyl-pyridin-2-yl) -[1 ,2,4]oxadiazole-5-carboxylic acid dimethylamide,
5-Hydroxy-6-(5-phenylsulfanylmethyl-[ 1 ,2,4]oxadiazol-3-yl)-nicotinic acid,
6-(5-Benzenesulfonylmethyl-[ 1 ,2,4]oxadiazol-3-yl)-5-hydroxy-nicotinic acid, 2-[3-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-5-yl]-N,N-dimethyl-acetamide, 3 - [3 -(5 -Cyano-3 -hydroxy-pyridin-2-yl)- [ 1 ,2,4]oxadiazol-5 -yl] -propionic acid, 6-[5-(2-Carboxy-ethyl)-[ 1 ,2,4]oxadiazol-3-yl]-5-hydroxy-nicotinic acid, 2-[3-(5-Bromo-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-5-yl]-N,N-dimethyl-acetamide, 2- [3 -(5 -Bromo-3 -hydroxy-pyridin-2-yl)- [ 1 ,2,4]oxadiazol-5-yl]- 1 -pyrrolidin-1 -yl- ethanone,
N-Benzyl-2-[3-(5-bromo-3-hydroxy-pyridin-2-yl)-[ 1 ,2,4]oxadiazol-5-yl]- acetamide, N-Benzyl-2-[5-(5-cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]- acetamide, 2-[5-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]-N-phenethyl-acetamide, 2-[5-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]-N-(2-pyridin-2-yl-ethyl)- acetamide,
2-[5-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]-N-[2-(4-hydroxy-phenyl)- ethyl] -acetamide,
2-[5-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]-N-pyridin-2-ylmethyl- acetamide,
[2-(3-Hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetic acid
2-[5-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]-N-pyridin-3-ylmethyl- acetamide, and
2-[5-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]-N-pyridin-4-ylmethyl- acetamide or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
[0134] In another aspect, the compounds disclosed herein have increased or decreased potency at HIF prolyl hydroxylases, bind the open or closed conformations of HIF pyrolyl hydroxylases, have more optimal pharmacokinetics, improved dosing schedules, less toxicity, have higher selectivity for HIF PH2 (less off-target activity), increase or decrease expression of HIF- regulated genes to a greater or lesser extent, or combinations of the preceding as compared to other HIF prolyl hydroxylase modulators.
[0135] In yet another embodiment, the compounds disclosed herein have greater potency at HIF PHD3 as compared to HIF-PHD2. SYNTHESIS
[0136] In another aspect, disclosed herein is a method of synthesizing the compounds of
Formula I. Compounds disclosed herein can be synthesized by using generally accepted organic synthetic methods, including the methodology shown in Scheme 1, 2, or 3, below. Those of ordinary skill in the art recognize that some functional groups can be protected/deprotected using various protecting groups before a certain reaction takes place. The use of these protecting groups is well-known in the art, as for example set forth in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein in its entirety.
[0137] Various starting materials including aryl carboxylic acid derivatives may be prepared according to a variety of the known synthetic methods. Some of these compounds are also commercially available from manufacturers and suppliers of reagents, such as Aldrich, Sigma,
TCI, Wako, Kanto, Fluorchem, Acros, Abocado, Alfa, Fluka, etc.
[0138] Depending on the choice of the ring A, the compounds of Formula I can be synthesized by a general synthetic procedure set forth in one of Schemes 1, 2, or 3, below.
Scheme 1
General Synthetic Scheme for the Compounds of Formula I
Figure imgf000059_0001
[0139] Fluoroarylnitrile and acetohydroxamic acid may react in the presence of a base to form isoxazolo[4,5-b]pyridin-3-ylamine. The resulting compound may be subject to a reduction reaction to obtain 3-Hydroxy-pyridine-2-carboxamidine. A pyrimidine group may be introduced through the reaction of diethyl ethoxymethylenemalonate with carboxamidine, and the pyrimidine-grafted compounds may be modified into their various derivatives using well-known methods.
Scheme 2
General Synthesis of Formula II
Figure imgf000060_0001
Lawesson s reagent
1 LiHMDS.THF 2 I21 THF A" A1 deprotection
Figure imgf000060_0002
Figure imgf000060_0003
[0140] Oxazoline or thiazoline may be synthesized from hydroxybenznitrile through the reaction with isoserine or isocysteine (Synth. Commun., 1991, 21, 265-270) (reaction a), and imidazoline may be synthesized through the reaction of 1,2-diamine with nitrile or ester (reaction b). The oxazoline and thiazoline may be also synthesized through the intramolecular cyclization of amide produced by the coupling reaction of acid with homoalanine (reaction c).
Scheme 3
General Synthesis of Formula III
Figure imgf000061_0001
[0141] Thiazole may be synthesized by the condensation of thioamide and β-ketoester, and a starting material, thioamide, may be synthesized from amides, esters, acids, and the like using various well-known method, as well as synthesized through the reaction of nitrile with diaminesulfϊde as shown in the Scheme 3.
[0142] Other compounds disclosed herein can be synthesized using the synthetic route set forth in Scheme 4.
Scheme 4
Figure imgf000061_0002
Oxone / H2O1EtOH
Figure imgf000061_0003
Scheme 5
"OC NaOMe / MeOH
Figure imgf000062_0001
Reflux, 8hr -XC H2O, 90°C, 12hr
Figure imgf000062_0002
Figure imgf000062_0003
Scheme 6
Figure imgf000062_0004
P)
Figure imgf000062_0005
PHARMACEUTICAL COMPOSITIONS [0143] In another aspect, disclosed herein are pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of Formula I and a physiologically acceptable carrier, diluent, or excipient.
[0144] The term "pharmaceutical composition" refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to a subject. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like.
[0145] The term "carrier" defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example dimethyl sulfoxide (DMSO) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of a subject.
[0146] The term "diluent" defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.
[0147] The term "physiologically acceptable" defines a carrier or diluent that does not abrogate the biological activity and properties of the compound and/or is not harmful to the subject to which it is administered.
[0148] The pharmaceutical compositions described herein can be administered to a subject per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds of the instant application may be found in "Remington's
Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.
[0149] Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
[0150] Alternatively, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into the area of pain, often in a depot or sustained release formulation. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the targeted organ. [0151] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping or tabletting processes. [0152] Pharmaceutical compositions for use in accordance with the present disclosure thus may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.
[0153] For injection, the agents disclosed herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. [0154] For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination disclosed herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone
(PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
[0155] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
[0156] Pharmaceutical preparations, which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
[0157] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
[0158] For administration by inhalation, the compounds for use according to the present disclosure are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
[0159] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
[0160] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly, concentrated solutions.
[0161] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
[0162] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
[0163] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[0164] A pharmaceutical carrier for the hydrophobic compounds disclosed herein is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A common cosolvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant
Polysorbate 80™, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of
POLYSORBATE 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may be used.
[0165] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for stabilization may be employed.
[0166] Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acids or base forms.
[0167] Pharmaceutical compositions suitable for use in the methods disclosed herein include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
[0168] The exact formulation, route of administration and dosage for the pharmaceutical compositions disclosed herein can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1). Typically, the dose about the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight, or 1 to 500 mg/kg, or 10 to 500 mg/kg, or 50 to 100 mg/kg of the patient's body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. Note that for almost all of the specific compounds mentioned in the present disclosure, human dosages for treatment of at least some condition have been established. Thus, in most instances, the methods disclosed herein will use those same dosages, or dosages that are between about 0.1% and 500%, or between about 25% and 250%, or between 50% and 100% of the established human dosage. Where no human dosage is established, as will be the case for newly discovered pharmaceutical compounds, a suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
[0169] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg of each ingredient, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of each ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical compositions disclosed herein or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day. Alternatively the compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day. Thus, the total daily dosage by oral administration of each ingredient will typically be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will typically be in the range 0.1 to 400 mg. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
[0170] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety, which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
[0171] Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen, which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. [0172] In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
[0173] The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
[0174] The compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound disclosed herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
METHODS OF USE
[0175] Throughout the present disclosure and the adjoining claims, the recitation of the term
"compound of Formula I" includes in its scope those compounds as described herein, including any pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
[0176] In another aspect, disclosed herein are methods of controlling the expression level of
HIF in a cell, the method comprising administering to the cell an amount of at least one compound of Formula I sufficient to modulate the expression level of HIF in the cell. Similarly, disclosed herein are methods of controlling the expression level of HIF in a cell comprising contacting the cell with an amount of at least one compound of Formula I sufficient to modulate the expression level of HIF in the cell.
[0177] The term "administering" in the context of administering a compound refers to preparing a formulation, as discussed herein, containing the compound being administered, and administering the formulation by any known method to the subject or to the cell. For example, a solution containing the compound can be injected to the subject or be added to the medium containing the cells, or the subject can orally ingest a formulation containing the compound. The term "contacting" refers to bringing the subject or the cell into contact with the compound. Thus, a formulation of a prodrug can be administered to a subject, whereupon the prodrug undergoes metabolism. The metabolite is then either in the systemic circulation or within the cytoplasm. In this situation, the prodrug is "administered" to the subject, but both the subject and the cells are "contacted" with the metabolite.
[0178] In another aspect, disclosed herein are methods of controlling the expression level of HIF in a subject comprising identifying a subject in need thereof and administering to the subject an amount of at least one compound of Formula I sufficient to modulate the expression level of HIF in the subject. Similarly, disclosed herein are methods of controlling the expression level of HIF in a subject comprising identifying a subject in need thereof and contacting the subject with an amount of at least one compound of Formula I sufficient to modulate the expression level of HIF in the subject.
[0179] In another aspect, disclosed herein are methods for modulating the amount of HIF in a cell comprising administering to the cell, or contacting the cell with, an amount of at least one compound of Formula I sufficient to modulate the amount of HIF in the cell. Similarly, disclosed herein are methods for modulating the amount of HIF in a cell comprising administering to the cell, or contacting the cell with, an amount of at least one compound of Formula I sufficient to modulate the amount of HIF in the cell. The term "modulates" or "modulating" refers to the ability of a compound to alter the level or concentration of HIF. In some embodiments, the modulator increases the levels, or increases the concentration of HIF in the cell. In other embodiments, the modulator lowers the levels or concentration of HIF in the cell. Preferably, the modulator increases the levels or concentration of HIF in the cell. [0180] In another aspect, disclosed herein are methods of inhibiting hydroxylation of HIF α in a cell comprising administering to the cell an amount of at least one compound of Formula I sufficient to inhibit the hydroxylation of HIFα in the cell. Similarly, disclosed herein are methods of inhibiting hydroxylation of HIFα in a cell comprising contacting the cell with an amount of at least one compound of Formula I sufficient to inhibit the hydroxylation of HIFα in the cell.
[0181] In another aspect, disclosed herein are methods of inhibiting hydroxylation of HIFα in a subject comprising identifying a subject in need thereof and administering to the subject an amount of at least one compound of Formula I sufficient to inhibit the hydroxylation of HIFα in the subject. Similarly, disclosed herein are methods of inhibiting hydroxylation of HIFα in a cell comprising identifying a subject in need thereof and contacting the subject with an amount of at least one compound of Formula I sufficient to inhibit the hydroxylation of HIFα in the subject. [0182] In another aspect, disclosed herein are methods of modulating (increasing or decreasing) expression of HIF -regulated genes in a cell comprising administering to the cell an amount of at least one compound of Formula I sufficient to modulate expression of HIF- regulated genes in the cell. Similarly, disclosed herein are methods of modulate expression of HIF-regulated genes in a cell comprising contacting the cell with an amount of at least one compound of Formula I sufficient to modulate expression of HIF-regulated genes in the cell. [0183] In another aspect, disclosed herein are methods of modulating expression of HIF- regulated genes in a subject comprising identifying a subject in need thereof and administering to the subject an amount of at least one compound of Formula I sufficient to modulate expression of HIF-regulated genes in the subject. Similarly, disclosed herein are methods of modulating expression of HIF-regulated genes in a subject comprising identifying a subject in need thereof and contacting the subject with an amount of at least one compound of Formula I sufficient to modulate expression of HIF-regulated genes in the subject.
[0184] In another aspect, disclosed herein are methods for increasing HIF levels or HIF activity in a cell comprising administering to the cell an amount of at least one compound of Formula I sufficient to increase HIF levels or HIF activity in the cell. Similarly, disclosed herein are methods for increasing HIF levels or HIF activity in a cell comprising contacting the cell with an amount of at least one compound of Formula I sufficient to increase HIF levels or HIF activity in the cell.
[0185] In another aspect, disclosed herein are methods for increasing HIF levels or HIF activity in a subject comprising identifying a subject in need thereof and administering to the subject an amount of at least one compound of Formula I sufficient to increase HIF levels or HIF activity in the subject. Similarly, disclosed herein are methods for increasing HIF levels or HIF activity in a subject comprising identifying a subject in need thereof and contacting the subject with an amount of at least one compound of Formula I sufficient to increase HIF levels or HIF activity in the subject. [0186] In another aspect, disclosed herein are methods of treating a disorder in a subject where it is desired to modulate HIF levels or activity, the method comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of at least one compound of Formula I. Similarly, disclosed herein are methods of treating an HIF -related disorder in a subject comprising identifying a subject in need thereof and contacting the subject with a therapeutically effective amount of at least one compound of Formula I. By HIF-related disorder is meant a disorder in which the modulation of HIF levels or activity provides a therapeutic effect.
[0187] In some embodiments, the HIF-related disorder is selected from the group consisting of ischemic disorders, hypoxic disorders, anemic disorders (including, but not limited to, anemia associated with autoimmune diseases, rheumatoid arthritis, systemic lupus, chronic infections such as, without limitation, HCV, and HIV, inflammatory bowel disease, chemotherapy-induced, chronic heart disease, chronic kidney disease, chronic obstructive pulmonary disease (COPD), end stage renal disease, prematurity, hypothyroidism, malnutrition, blood disorders, including but not limited to, sickle cell anemia, and β-thalassemia, malignancies), stenocardia, neurological disorders, stroke, epilepsy, neurodegenerative disease, myocardial infarction, liver ischemia, renal ischemia, chronic kidney disease, peripheral vascular disorders, ulcers, burns, chronic wounds, pulmonary embolism, ischemic-reperfusion injury, ischemic-reperfusion injuries associated with surgeries and organ transplantations, respiratory distress syndrome, prevention of broncho-pulmonary dysplasia in pre-maturity, pulmonary hypertension, auto-immune diseases, side effects of diabetes, diabetic retinopathy, macular degeneration, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, Eales' disease, Behcet's disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, trauma and post-laser complications, diseases associated with rubeosis, metabolic disorders, for example diabetes, proliferative vitreoretinopathy, and depression. [0188] The term "treating" or "treatment" does not necessarily mean total cure. Any alleviation of any undesired signs or symptoms of the disease to any extent or the slowing down of the progress of the disease can be considered treatment. Furthermore, treatment may include acts that may worsen the patient's overall feeling of well being or appearance. Treatment may also include lengthening the life of the patient, even if the symptoms are not alleviated, the disease conditions are not ameliorated, or the patient's overall feeling of well being is not improved. [0189] In another aspect, disclosed herein are methods of treating a disorder in a subject comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of at least one compound of Formula I, wherein the disorder is selected from the group consisting of ischemic disorders, hypoxic disorders, anemic disorders (including, but not limited to, anemia associated with autoimmune diseases, rheumatoid arthritis, systemic lupus, chronic infections such as, without limitation, HCV, and HIV, inflammatory bowel disease, chemotherapy-induced, chronic heart disease, chronic kidney disease, chronic obstructive pulmonary disease (COPD), end stage renal disease, prematurity, hypothyroidism, malnutrition, blood disorders, including but not limited to, sickle cell anemia, and β-thalassemia, malignancies), stenocardia, neurological disorders, stroke, epilepsy, neurodegenerative disease, myocardial infarction, liver ischemia, renal ischemia, chronic kidney disease, peripheral vascular disorders, ulcers, burns, chronic wounds, pulmonary embolism, ischemic-reperfusion injury, ischemic-reperfusion injuries associated with surgeries and organ transplantations, respiratory distress syndrome, prevention of broncho-pulmonary dysplasia in pre-maturity, pulmonary hypertension, auto-immune diseases, side effects of diabetes, diabetic retinopathy, macular degeneration, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, Eales' disease, Behcet's disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, trauma and post-laser complications, diseases associated with rubeosis, metabolic disorders, for example diabetes, proliferative vitreoretinopathy, and depression. Similarly, disclosed herein are methods of treating a disorder in a subject comprising identifying a subject in need thereof and contacting the subject with a therapeutically effective amount of at least one compound of Formula I, wherein the disorder is selected from the group consisting of anemic disorders, neurological disorders, stroke, trauma, epilepsy, neurodegenerative disease, myocardial infarction, liver ischemia, renal ischemia, peripheral vascular disorders, ulcers, burns, chronic wounds, pulmonary embolism, and ischemic-reperfusion injury.
[0190] In another aspect, disclosed herein are methods of inhibiting the activity of a hydroxylase enzyme which modifies the alpha subunit of HIF comprising contacting the enzyme with at least one compound of Formula I.
[0191] In another aspect, disclosed herein are methods of modulating the expression level of HIF and/or EPO by inhibiting the hydroxylation of HIFα, and thus stabilizing HIF and/or modulating expression of HIF -regulated genes. The method may be useful to prevent, remedy and treat conditions associated with HIF and/or EPO including anemia, ischemia and hypoxia. [0192] Ischemia, anemia, and hypoxia are three conditions associated with HIF, and include, but are not limited to, of ischemic disorders, hypoxic disorders, anemic disorders (including, but not limited to, anemia associated with autoimmune diseases, rheumatoid arthritis, systemic lupus, chronic infections such as, without limitation, HCV, and HIV, inflammatory bowel disease, chemotherapy-induced, chronic heart disease, chronic kidney disease, chronic obstructive pulmonary disease (COPD), end stage renal disease, prematurity, hypothyroidism, malnutrition, blood disorders, including but not limited to, sickle cell anemia, and β-thalassemia, malignancies), stenocardia, neurological disorders, stroke, epilepsy, neurodegenerative disease, myocardial infarction, liver ischemia, renal ischemia, chronic kidney disease, peripheral vascular disorders, ulcers, burns, chronic wounds, pulmonary embolism, ischemic-reperfusion injury, ischemic-reperfusion injuries associated with surgeries and organ transplantations, respiratory distress syndrome, prevention of broncho-pulmonary dysplasia in pre-maturity, pulmonary hypertension, auto-immune diseases, side effects of diabetes, diabetic retinopathy, macular degeneration, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, Eales' disease, Behcet's disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, trauma and post-laser complications, diseases associated with rubeosis, metabolic disorders, for example diabetes, proliferative vitreoretinopathy, and depression. In some embodiments, the methods disclosed herein provide for stabilizing HIFα before/after the advent of the ischemia or hypoxia or in ischemia or hypoxia when the ischemia or hypoxia is associated with myocardial infarctions, strokes, or renal ischemia-reperfusion injuries.
[0193] In another aspect, disclosed herein are methods for treating a variety of ischemic- and/or hypoxic-related disorders using the compounds of Formula I. In certain embodiments, the methods disclosed herein are advantageous for the treatment when the compounds are administered before or after the advent of ischemia or hypoxia. For example, the methods disclosed herein may reduce mortality rates and improve cardiac structure and performance after the advent of the myocardial infarction.
[0194] Furthermore, disclosed herein are methods to treat liver disorders comprising administering the compounds of Formula I before or after exposure to conditions and/or agents that are associated with liver disease. For example, hypoxia is associated with liver disease, particularly chronic liver disease that is associated with compounds toxic to the liver, such as ethanol. In addition, the expression of genes known to be regulated by HIFα, for example nitric oxide synthase and glucose transporter- 1, is increased in alcoholic liver diseases. [0195] Accordingly, disclosed herein are methods for treating conditions associated with ischemia or hypoxia, where the method includes administrating to subjects a therapeutically effective amount of at least one compound of Formula I.
[0196] In some embodiments, the compounds of Formula I are administered to patients after the onset of conditions such as acute ischemia, for example myocardial infarction, pulmonary embolism, bowel infarction, ischemic strokes, and renal ischemia-reperfusion injuries. In other embodiments, the compounds of Formula I are administered to patients after the patients are diagnosed with conditions associated with chronic ischemia, for example, without limitation, cardiachepatopathy, macular degeneration, pulmonary embolism, acute respiratory dysfunction, neonatal respiratory distress syndrome, and congestive heart failure. In other embodiments, the compounds of Formula I are administered to patients after trauma or injuries. [0197] In another aspect, disclosed herein are methods for treating with the compounds disclosed herein patients at risk of developing ischemic or hypoxic conditions. High risk individuals, for example, include, but are not limited to, atherosclerotic patients. Risk factors in atherosclerosis include, for example without limitation, hyperlipidemia, smoking, hypertension, diabetes, hyperinsulinemia, and visceral obesity. Accordingly, disclosed herein are methods for preventing or mitigating ischemic tissue injuries, where the method includes administrating to subjects in need thereof a therapeutically effective amount of a compound of Formula I. In some embodiments, the compounds disclosed herein may be administered to treat conditions, such as, hypertension, diabetes, obliterative artery disease, chronic venous insufficiency, Raynaud's disease, chronic ulcer of skin, hepatopathy, congestive heart failure, and systemic sclerosis. [0198] In some embodiments, the methods disclosed herein are used to stimulate angiogenesis and/or formation of granulation tissue in injured tissues, and ulcers. For example, the compounds disclosed herein are effective in stimulating the formation of granulation tissue in the wound healing processes. Secretion of growth factors from inflammatory cells, blood platelets, and activated endothelia stimulates the translocation of fibroblast and endothelial cells and the growth in the granulation tissues. The methods disclosed herein are effective in stimulating the formation of granulation tissues. Accordingly, disclosed herein are methods for treating, for example, patients suffering from tissue injuries due to infarctions, patients suffering from injuries induced by trauma, or patients suffering from chronic injuries or ulcers caused by disorders, such as, diabetes. The methods disclosed herein include administering to subjects in need thereof a therapeutically effective amount of a compound of Formula I.
[0199] In another aspect, disclosed herein are methods for pre-treating subjects to reduce or prevent the development of tissue injuries associated with ischemia or hypoxia, by employing the compounds disclosed herein. The methods disclosed herein have advantages for the treatment when the compounds are administered before the advent of the ischemia or hypoxia. For example, the methods disclosed herein reduce mortality rates and significantly improve cardiac structure and performance when the compounds disclosed herein are administered before the induction of myocardial infarction. In addition, the methods disclosed herein provide a therapeutic effect associated with renal failure when the compounds disclosed herein are administered before and/or during the advent of ischemia-reperfusion injuries. [0200] Accordingly, disclosed herein are methods for pre-treating subjects to reduce or prevent tissue injuries associated with ischemia or hypoxia, and the methods include administering a therapeutically effective amount of a compound disclosed herein to patients suffering from ischemic disorders, for example, those having a history of myocardial infarction, or patients suffering from symptoms of serious ischemia, for example stenocardia. In some embodiments, the compounds disclosed herein may be administered to humans who are under conditions that are associated with possible ischemia, for example general anesthesia, or who work temporarily at high altitudes. In other embodiments, the compounds disclosed herein may be used in organ transplant procedures by previously treating organ donors with the compounds disclosed herein to maintain the organs that have been removed from the donors before the organs are transplanted into recipients.
[0201] In another aspect, disclosed herein are methods for regulating angiogenesis in a subject comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of at least one compound of Formula I. Similarly, disclosed herein are methods for regulating angiogenesis in a subject comprising identifying a subject in need thereof and contacting the subject with a therapeutically effective amount of at least one compound of Formula I.
[0202] In another aspect, disclosed herein are methods for vascularizing ischemic tissue in a subject comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of at least one compound of Formula I. Similarly, disclosed herein are methods for vascularizing ischemic tissue in a subject comprising identifying a subject in need thereof and contacting the subject with a therapeutically effective amount of at least one compound of Formula I.
[0203] In another aspect, disclosed herein are methods for promoting the growth of skin graft replacements comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of at least one compound of Formula I. Similarly, disclosed herein are methods for promoting the growth of skin graft replacements comprising identifying a subject in need thereof and contacting the subject with a therapeutically effective amount of at least one compound of Formula I.
[0204] In another aspect, disclosed herein are methods for promoting tissue repair in the context of guided tissue regeneration (GTR) procedures comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of at least one compound of Formula I. Similarly, disclosed herein are methods for promoting tissue repair in the context of guided tissue regeneration (GTR) procedures comprising identifying a subject in need thereof and contacting the subject with a therapeutically effective amount of at least one compound of Formula I.
[0205] In another aspect, disclosed herein are methods for treating anemia in a subject comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, a therapeutically effective amount of at least one compound of Formula I. Similarly, disclosed herein are methods for treating anemia in a subject comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, a therapeutically effective amount of at least one compound of Formula I.
[0206] In another aspect, disclosed herein are methods for regulating anemia in a subject comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of at least one compound of Formula I. Similarly, disclosed herein are methods for regulating anemia in a subject comprising identifying a subject in need thereof and contacting the subject with a therapeutically effective amount of at least one compound of Formula I.
[0207] In another aspect, disclosed herein are methods for preventing anemia in a subject comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of at least one compound of Formula I. Similarly, disclosed herein are methods for preventing anemia in a subject comprising identifying a subject in need thereof and contacting the subject with a therapeutically effective amount of at least one compound of Formula I.
[0208] Disclosed herein are methods for increasing the level of endogenous erythropoietin (EPO). These methods may be used in vivo or in vitro, for example in cell culture-controlled media. In addition, disclosed herein are methods for increasing the level of endogenous EPO to prevent, remedy or treat conditions associated with deficient EPO levels or where increased EPO would be beneficial, such as in stroke patients, conditions associated with anemia and neurological disorders, e.g., Parkinson's disease. Increased EPO may be beneficial as a neuroprotectant and neurotrophic agent useful for treating cognitive disorders and depression and other disorders associated with structural problems and/or regeneration of nerve cells. The conditions associated with decreased EPO levels include anemias, disorders such as acute or chronic renal diseases, diabetes, cancers, ulcers, acute or chronic infections, e.g., viral infections, such as HIV, bacterial infections, or parasitic infections; inflammatory disorders, autoimmune diseases, malignancies, severe trauma including thermal trauma, etc. These conditions are generally those that result in anemia in a subject. Furthermore, the methods disclosed herein are used to treat anemia associated with treatment procedures, such as radiation therapy, chemotherapy, dialysis, or surgery. Other examples of disorders associated with anemia include abnormal hemoglobin and/or hematocyte levels that are found in the disorders such as microcytic anemia, hypochromic anemia, aplastic anemia, etc.
[0209] The methods disclosed herein may be used to increase endogenous EPO levels in subjects undergoing prevention or certain treatment procedures. Examples include HIV-infected anemic subjects being treated with azidothymidine (zidovudin) or other reverse transcriptase inhibitors, patients receiving cyclic cisplatin- or non-cisplatin-containing chemotherapy, or anemic or non-anemic patients scheduled for surgical operations. The methods of increasing endogenous EPO levels may be used to prevent, pre-treat or treat EPO-related conditions that are associated with nerve injuries or degeneracy of nerve tissues, including, but not limited to, stroke, trauma, epilepsy, spinal cord injury, and neurodegenerative disorders. [0210] In addition, the methods disclosed herein may be used to reduce the need for allogenic blood transfusions in anemic or non-anemic patients scheduled for surgery, such as joint replacement, or to facilitate autologous blood collection prior to surgery by increasing endogenous EPO levels. These methods would reduce the risk associated with non-autologous blood transfusions such as, without limitation, transmission of infectious disease. [0211] The methods disclosed herein may also be used to enhance physical performance, improve exercise abilities, and facilitate or strengthen aerobic conditioning. These methods may, for example, be used for athletes to facilitate their training, and for military personnel to improve energy and stamina.
[0212] The methods disclosed herein may be used to increase endogenous erythropoietin levels in the blood serum of animals treated in media and in vivo from cells cultured in vitro. Although the kidney is a major in vivo source of erythropoietin, other organs including brain, liver and bone marrow may be made to produce erythropoietin when stimulated to do so. The methods disclosed herein may be used to increase the expression of endogenous erythropoietin in various organs including brain, kidney and liver.
[0213] The methods disclosed herein can be used to increase cell volume and hemoglobin level in animals that are treated in vivo with the compounds disclosed herein. The increase in plasma EPO, cell volume and hemoglobin levels in blood through the action of the compounds disclosed herein is sensitive to the amount of the compounds administered. It is therefore possible to establish a therapeutic regimen to produce a uniform and controlled level of the effect of the compounds disclosed herein. [0214] The increase in cell volume and the hemoglobin in blood in the animals treated with the compounds disclosed herein causes an increase in the immature hematocytes (reticulocytes) circulating in the blood. Accordingly, disclosed herein are uses of the compounds disclosed herein for increasing reticulocyte levels in blood.
EXAMPLES
Example 1 : Synthesis of 4-Hydroxy-2-(3-hydroxy-pyridin-2-yl)-pyrimidine-5-carboxylic acid a) Synthesis of Isoxazolo|"4,5-b1pyridin-3-ylamine
[0215] 646 mg (8.59 mmol) of acetohydroxamic acid and 965 mg (8.59 mmol) of t-BuOK were dissolved in 3 ml of anhydrous DMF, and stirred at room temperature. After 30 minutes of the reaction, 700mg (5.73 mmol) of a primer 2-cyano-3-fluoropyridine was dissolved in 2 ml of DMF and added by drop. After 5 hours of the reaction, the resulting mixture was washed with water, washed with saturated saline again, and then concentrated under reduced pressure. The resulting mixture was purified via column chromatography to obtain 788 mg (yield: 68%) of the target compound. 1H NMR (300MHz, CDCl3): δ 7.54 (m, IH), 7.15 (m, IH), 6. 88 (d, IH) MS: m/z 135.
b) Synthesis of 3-Hydroxy-pyridine-2-carboxamidine
[0216] 100 mg (0.73 mmol) of the previously prepared isoxazolo[4,5-b]pyridin-3-ylamine was dissolved in 5 ml of MeOH, and then 20 mg (10% v/v) of 5% Pd/C was added. The resulting mixture was stirred at room temperature for 5 hours using an H2 balloon, and the reaction solution was filtered, and the resulting filtrate was concentrated under reduced pressure to obtain 98 mg (yield: 98%) of the target compound. 1H NMR (300MHz, CDCl3): δ 10.8-10.2 (br, IH), 7.78 (br, 2H), 7.52 (m, IH), 7.09 (m, IH), 6. 75 (d, IH) MS: m/z 137.
c) Synthesis of 4-Hydroxy-2-(3-hydroxy-pyridin-2-yl)-pyrimidine-5-carboxylic acid ethyl ester
[0217] 20 mg (0.15 mmol) of the previously prepared 3-Hydroxy-pyridine-2-carboxamidine was dissolved in 5 ml of EtOH, and 31.5 mg (0.15 mmol) of diethyl ethoxymethylenemalonate and 29.8 mg (0.45 mmol) of NaOEt were then added. 70 mg (1.86 mmol) OfNaBH4 and 144 mg (1.12 mmol) Of NiCl2 were added, warmed, and then stirred for 5 hours while heating. The resulting reaction solution was filtered to remove solids, concentrated, and purified with Prep. LC to obtain 8.9 mg (yield: 23%) of the target compound. 1H NMR (300MHz, MeOH-d4): δ 8.78 (s, IH), 8.33 (m, IH), 7.67 (m, 2H), 4.38 (q, 2H), 1.38 (t, 3H) MS: m/z 261.
d) Synthesis of 4-Hydroxy-2-(3-hydroxy-pyridin-2-yl)-pyrimidine-5-carboxylic acid
[0218] 8.9 mg (0.03 mmol) of the previously prepared 4-hydroxy-2-(3-hydroxy-pyridin-2-yl)- pyrimidine-5-carboxylic acid ethyl ester was dissolved in 3 ml of THF and 1 ml of MeOH. 2.9 mg (0.06 mmol) of LiOH.H2O was dissolved in 1 ml of H2O, and then added dropwise to the THF solution. The resulting mixture was stirred for 5 hours while heating, concentrated, and purified with Prep. LC to obtain 2.3 mg (yield: 33%) of the target compound. 1H NMR (300MHz, MeOH-d4): δ 8.80 (s, IH), 8.35 (m, IH), 7.52 (m, 2H ) MS: m/z 233.
Example 2: Synthesis of 2-(6-Bromo-3-hydroxy-pyridin-2-yl)-4-hydroxy-pyrimidine-5- carboxylic acid a) Synthesis of 2-(6-Bromo-3-hvdroxy-pyridm-2-vO-4-hvdroxy-pyrimidine-5-carboxylic acid ethyl ester
[0219] 20 mg (0.08 mmol) of the previously prepared 4-Hydroxy-2-(3-hydroxy-pyridin-2-yl)- pyrimidine-5-carboxylic acid ethyl ester was dissolved in 2 ml of acetonitrile. 34 mg (0.2 mmol) of NBS was dissolved in 1 ml of acetonitrile, and then added dropwise to the acetonitrile solution . After 2 hours of the reaction, the resulting reaction solution was concentrated, and purified with Prep. LC to obtain 20 mg (yield: 74%) of the target compound. 1H NMR (300MHz, MeOH-d4): δ 8.64 (bs, IH), 7.66 (d, IH), 7.42 (d, IH), 4.36 (q, 2H), 1.37 (t, 3H) MS: m/z 340
b) Synthesis of 2-(6-Bromo-3-hvdroxy-pyridin-2-yl)-4-hvdroxy-pyrimidine-5-carboxylic acid
[0220] 20 mg (0.06 mmol) of the previously prepared 2-(6-Bromo-3-hydroxy-pyridin-2-yl)-4- hydroxy-pyrimidine-5-carboxylic acid ethyl ester was dissolved in 3 ml of THF and ImI of MeOH. 5 mg (0.12 mmol) of LiOH.H2O was dissolved in 1 ml of H2O, and then added dropwise to the THF solution. The resulting reaction mixture was stirred for 5 hours while heating, concentrated, and purified with Prep. LC to obtain 3.03 mg (yield: 16%) of the target compound. 1H NMR (300MHz, MeOH-d4): δ 8.78 (s, IH), 7.70 (d, IH), 7.42 (d, IH ) MS: m/z 311
Example 3: Synthesis of 2-(2-Hvdroxy-phenv0-4,5-dihvdro-thiazole-5-carboxylic acid
[0221] 2-hydroxybenzonitrile (0.397 g, 3.33 mmol) and sodium bicarbonate (4.34 mmol, 0.364 g) were added to 17 ml of phosphate buffer solution (pH 6), and isocysteine HCl (0.683g, 4.34 mmol) dissolved in methanol (17 ml) was added. The resulting reaction solution was stirred at 60 0C for 15 hours, cooled at room temperature, and then purified with Cl 8 reverse phase column chromatography to obtain the target compound. 1H NMR (DMSO, 300 MHz) δ 12.85(s,lH), 11.86(s,lH), 7.67(d,lH, J=7.5), 7.52(m, IH), 7.06(m,2H), 4.58(m, 2H), 4.32(m,2H), 3.40(s,3H). m/z=224 (M+H).
Example 4: Synthesis of 2-(4-Hydroxy-biphenyl-3-yl)-4-methyl-thiazole-5-carboxylic acid a) 5 -Bromo-2-hydroxybenzothioamide
[0222] 5-Bromo-2-hydroxybenzonitrile (1 g, 5.05 mmol) was dissolved in pyridine (10 ml). Triethylamine (0.72 ml, 5.55 mmol) and ammonium sulfide (40-48 % wt solution in water (0.95 ml, 5.55 mmol)) were added dropwise to the pyridine solution, and then stirred at 50 0C for 3 to 6 hours. The resulting reaction mixture was cooled to room temperature, diluted with cold water (30 ml), and formed precipitates were filtered, washed with cold water, and recrystallized with cyclohexane to obtain the target compound (500 mg, 43 %). 1H NMR (CDCl3, 300 MHz): δ 6.73 (d, IH, J=8.7), 7.31 (dd, IH, J=8.7, 2.4), 8.02 (d, IH, J=2.4)
b) Ethyl 2-(5 -bromo-2-hvdroxyphenyl)-4-methylthiazole-5 -carboxylate
[0223] Ethyl 2-chloroacetoatetate (0.4 mL, 2.85 mmol) was added dropwise with an ethanol (10 mL) solution of 5 -bromo-2-hydroxybenzothioamide (632 mg, 2.70 mmol), and then refluxed overnight. The resulting reaction solution was cooled to room temperature, filtered, and then washed with cold ethanol to obtain the target compound (820 mg, 89 %) as a light yellow solid. 1H NMR (CDCl3, 300 MHz) δ 1.30 (t, 3H, J=I 2), 2.72 (s, 3H), 4.29 (q, 2H, J=I 2), 6.88 (d, IH, J=6.3), 7.36 (dd, 1H, J=9.O, 2.4), 7.95 (d, IH, J=I.8) c) Ethyl 2-(4-hydroxybiphenyl-3 -yl)-4-methylthiazole-5 -carboxylate)
[0224] 2 M sodium carbonate (0.45 ml, 0.9 mmol), phenyl boronic acid (36 mg, 0.3 mmol), dichlorobis(triphenylphosphino)palladium(II) (21 mg, 0.03 mmol), and ethyl 2-(5-bromo-2- hydroxyphenyl)-4-methylthiazole-5-carboxylate (100 mg, 0.3 mmol) were dissolved in acetonitrile (1 ml), and reacted for 1 hour using a MW oven (100 PW, 100 PSI, 110). Solvents were removed via vacuum distillation, and the resulting mixture was then extracted with dichloromethane (20 ml), and purified with silica gel column chromatography (ethyl acetate/hexane, 1 : 10) to obtain the target compound (66 mg, 65 %). 1H NMR (CDCl3, 300 MHz) δ 1.40 (t, 3H, J=I 2), 4.37 (q, 2H, J=I 2), 7.13 (d, IH, J=8.4), 7.34-7.37 (m, IH), 7.45 (dd, 2H, J=7.8, 7.2), 7.55-7.79 (m, 3H), 7.80 (s, IH)
d) 2-(4-Hydroxy-biphenyl-3-yl)-4-methyl-thiazole-5-carboxylic acid
[0225] An excess of 1 M sodium hydroxide was added with to an ethanol (1 ml) solution of ethyl 2-(4-hydroxybiphenyl-3-yl)-4-methylthiazole-5-carboxylate (66 mg, 0.19 mmol) , and stirred for 2 hours. The resulting reaction solution was adjusted with cone. HCl to pH 4, stirred for 1 hour, filtered, washed with cold water, and then dried to obtain the target compound (820 mg, 89 %) as a yellow solid. 1H NMR (CD3OD, 300 MHz) δ 2.75 (s, 3H), 7.07 (d, IH, J=8.7), 7.30-7.32 (m, IH), 7.42 (dd, 2H, J=7.8, 7.2), 7.56-7.61 (m, 2H), 7.73 (s, IH), 8.00 (d, IH, J=2.1). 1H NMR (CDCl3, 300 MHz) δ 7.80 (s, IH), 7.55-7.79 (m, 3H), 7.45 (dd, 2H, j=7.8, 7.2), 7.34-7.37 (m, IH), 7.13 (d, IH, j=8.4), 4.37 (q, 2H, j=7.2), 1.40 (t, 3H, j=7.2). m/z=312 (M+H).
Example 5: Synthesis of 3-(4,5-Dihvdro-lH-imidazol-2-yl)naphthalen-2-ol
[0226] Methyl 3-hydroxy-2-naphthoate (100 mg, 0.49 mmol) was dissolved in ethylene diamine (1 ml), refluxed for 6 hours, evaporated, extracted with dichloromethane (20 ml), and then purified with silica gel column chromatography (dichloromethane/methanol, 19:1) to obtain the target compound (57 mg, 54 %). 1H NMR (DMSO, 300 MHz) δ 2.94-2.97 (m, 2H), 3.57 (t, 2H, J=6.0), 7.14 (s, IH), 7.19 (d, IH, J=8.1), 7.35 (t, IH, J=I 2), 7.56 (d, IH, J=8.4), 7.72 (d, 1H, J=8.1), 8.39 (s, IH) Example 6: Synthesis of 2-(3-Hydroxy-naphthalen-2-yl)-4,5-dihydro-3H-imidazole-4-carboxylic acid
[0227] Methyl 3-hydroxy-2-naphthoate (50 mg, 0.25 mmol) and 2,3-diaminopropionic acid (70 mg, 0.49 mmol) were dissolved in 0.5 M sodium methoxide (1 ml), reacted for 10 minutes using a Microwave oven (100 PW, 100 PSI, 120), washed with water and dichloromethane, and then purified with Prep HPLC to obtain the target compound (66 mg, 65 %). 1H NMR (CD3OD, 300 MHz) δ 4.12-4.31 (m, 2H), 4.72 (dd, IH, J=12.3, 7.5), 7.28 (s, IH), 7.38 (t, IH, J=I 2), 7.55 (t, IH, J=7.8), 7.68 (d, IH, J=8.1), 7.81 (d, IH, J=8.4), 8.40 (s, IH). m/z=257 (M+H).
Example 7: Synthesis of 5-Hydroxy-6-[4-(2-oxo-2-pyrrolidin-l-yl-ethyl)-thiazol-2-yll- nicotinonitrile a) Synthesis of 5-Bromo-3-methoxy-pyridine-2-carbonitrile (2)
[0228] 2g (8.8mmol) of 5-Bromo-3-nitro-pyridine-2-carbonitrile (1) was dissolved in 25ml of MeOH, and 15ml of 0.5M NaOMe (in MeOH) was added at room temperature. The reaction mixture was heated to reflux and stirred for 8 hours at this temperature. After reaction completion, the reaction mixture was concentrated under reduced pressure. The residue was purified via column chromatography (ethyl acetate: n-Hexane = 1 : 4) and the target compound (2) was obtained 1.46 g (yield: 78%).
1H NMR (300MHz, CDCl3): δ 8.318 (d, J= 1.5Hz, IH), 7.523 (d, J= 1.5Hz, IH), 3.973 (s, 3H), MS: m/z 215 [M+l]
b) Synthesis of 5 -Bromo-3 -hydroxy-pyridine -2-carbothioic acid amide (3) [0229] 1 g (4.7mmol) of 5 -Bromo-3 -methoxy-pyridine-2-carbonitrile (2) and 0.865ml (5.2mmol) of O, O'-diethyl dithiophosphate were added to ImI of water, and the reaction mixture was heated to 90°C. After 12 hours at this temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated sodium carbonate aqueous solution. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified via column chromatography (ethyl acetate: n-Hexane = 1 : 3) and the target compound (3) was obtained 437mg (yield: 40%).
1H NMR (300MHz, CDCl3): δ 12.318 (s, IH), 9.382 (brd.s, 2H), 8.156 (s, IH), 7.622 (S, IH), MS: m/z 234 [M+l] c) Synthesis of r2-(5-Bromo-3-hvdroxy-pyridin-2-yl)-thiazol-4-yll-acetic acid butyl ester
(4)
[0230] 300mg (1.29 mmol) of 5-Bromo-3-hydroxy-pyridine-2-carbothioic acid amide (3) and 173mg (1.29 mmol) of lithium iodide were dissolved in 3 ml of n-butyl alcohol, and 352μl (2.58 mmol) of 4-chloro-3-oxo-butyric acid ethylester was added at room temperature. The reaction mixture was heated to 140°C. After 4.5 hours at this temperature, the reaction mixture was distilled to remove n-butyl alcohol. The residue was diluted with ethyl acetate and washed with water. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified via column chromatography (ethyl acetate: n-Hexane = 1 : 4, UV 360nm) and the target compound (4) was obtained 283mg (yield: 59%). 1H NMR (SOOMHZ, CDCl3): δ 11.862 (s, IH), 8.199 (d, J=1.8Hz, IH), 7.554 (d, J=2.1Hz, IH), 7.277 (d, J=12Hz, IH), 4.159 (m, 2H), 3.871(d, J=0.6Hz, 2H), 1.612 (m, 2H), 1.356 (m, 2H), 0.922 (m, 3H). MS: m/z 372 [M+l]
d) Synthesis of [2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yll-acetic acid butyl ester
(5)
[0231] 107mg (0.31 mmol) of [2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl] -acetic acid butyl ester (4), 22mg (0.18mmol) of zinc cyanide and 36mg (0.31 mmol) of tetrakis (triphenylphosphine)palladium were dissolved in 2 ml of DMF. The reaction mixture was heated to 160°C for 25minutes in a microwave reactor (150W). The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified via column chromatography (ethyl acetate: n-Hexane = 1 : 3, UV 360nm) and the target compound (5) was obtained 64.4mg (yield: 65%).
1H NMR (300MHz, CDCl3): δ 11.862 (s, IH), 8.199 (d, J=I.8Hz, IH), 7.554 (d, J=2.1Hz, IH), 7.277 (d, J=12Hz, IH), 4.159 (m, 2H), 3.871(d, J=0.6Hz, 2H), 1.612 (m, 2H), 1.356 (m, 2H), 0.922 (m, 3H). MS: m/z 319 [M+l]
e) Synthesis of [2-(5-Cvano-3-hvdroxy-pyridin-2-yl)-thiazol-4-vH -acetic acid (6) [0232] 50mg (0.16 mmol) of [2-(5-Bromo-3-hydroxy-pyridin-2-yl)-thiazol-4-yl] -acetic acid butyl ester (5) was dissolved in 2 ml of THF and 3ml of ethanol and 249μl (0.48 mmol) of 2N sodium hydroxide solution was added to the reaction solution at room temperature. After 2 hours at this temperature, the reaction mixture was diluted with water and adjusted to pH 4 with IN HCl solution. The reaction mixture was concentrated under reduced pressure to remove organic solvent. The generated precipitates were collected by filtration and dried under reduced pressure. The target compound (6) was obtained 37.3mg (yield: 89%).
1H NMR (300MHz, CDCl3): δ 8.642 (d, J=I.8Hz, IH), 7.592 (d, J=I.8Hz, IH), 7.422 (s, IH), 3.864 (s, 2H). MS: m/z 263 [M+ 1]
f) Synthesis of 5-Hvdroxy-6-[4-(2-oxo-2-pyrrolidin-l-yl-ethyl)-thiazol-2-yll-nicotino nitrile (7)
[0233] 25mg (0.096 mmol) of [2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl] -acetic acid (6), 8.83μL (0.106 mmol) of pyrrolidine and 33.8mg (0.106 mmol) of TBTU were dissolved in 2ml of DMF and 40μL of triethyl amine was added to reaction mixture at room temperature. After 12 hours at this temperature, the reaction mixture was diluted with ethyl acetate and washed with water three times. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified via Prep-HPLC (Acetonitrile/0.1% formic acid solution) and the target compound (7) was obtained 21.5mg (yield: 71.5%).
1H NMR (300MHz, DMSO-d6): δ 12.189 (s, IH), 8.580 (d, J=I.8Hz, IH), 8.048 (d, J=I.5Hz, IH), 77.777 (s, IH), 3.932 (s, 2H), 3.523 (t, 2H), 3.296 (t, 2H), 1.870 (m, 2H), 1.779 (m, 2H). MS: m/z 315 [M+l]
Example 8: Synthesis of 2-[5-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,41oxadiazol-3-yll-N-[2- (4-hvdroxy-phenyl)-ethvH-acetamide
a) Synthesis of 5-Bromo-3-methoxy-pyridine-2-carbonitrile (2)
[0234] 2g (8.8mmol) of 5-Bromo-3-nitro-pyridine-2-carbonitrile (1) was dissolved in 25ml of MeOH, and 15ml of 0.5M NaOMe (in MeOH) was added at room temperature. The reaction mixture was heated to reflux and stirred for 8 hours at this temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified via column chromatography (ethyl acetate: n-Hexane = 1 : 4) and the target compound (2) was obtained 1.46 g (yield: 78%).
1H NMR (300MHz, CDCl3): δ 8.318 (d, J= 1.5Hz, IH), 7.523 (d, J= 1.5Hz, IH), 3.973 (s, 3H), MS: m/z 215 [M+l]
b) Synthesis of 5-Bromo-3-methoxy-pyridine-2-carboxylic acid (3)
[0235] 1.4g (6.57mmol) of 5-Bromo-3-methoxy-pyridine-2-carbonitrile (2) was dissolved in 20ml of THF and to the reaction mixture was added 10.95ml (32.85mmol) of 3N NaOH aqueous solution. The mixture was heated to reflux. After 5 hours at this temperature, the reaction mixture was cooled and adjusted to pH3 with 6N HCl. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The target compound (3) was obtained 1.25g (yield: 82%). MS: m/z 233 [M+l]
c) Synthesis of 5-Bromo-3-methoxy-pyridine-2-carbonyl chloride (4)
[0236] 1.2g (5.17 mmol) of 5-Bromo-3-methoxy-pyridine-2-carboxylic acid (3) was dissolved in 20ml of MC and to the reaction mixture was added 1.35ml (15.51mmol) of oxalyl chloride. Two drops of DMF was added and stirred for lhr at room temperature. The reaction mixture was concentrated under reduced pressure. The target compound (4) was obtained 1.3Og and the target compound (4) use to next step without purification (yield: quantitative yield %).
d) Synthesis of (N-Hydroxycarbamimidoyl)- acetic acid tert-butyl ester (6) [0237] 2g (14.17 mmol) of cyano-acetic acid tert-butyl ester (5), 1.28g (18.42mmol) of hydroxylamine mono-hydrochloric acid and 2.96ml (21.25 mmol) of triethylamine were dissolved in 30 ml of t-butanol. The reaction mixture was heated to reflux for 5 hours, and after cooling was adjusted to pH7 with IN HCl. The organic solvent was concentrated under reduced pressure and the residue was diluted with ethyl acetate and washed with water. The organic layer was dried with magnesium sulfate and was concentrated under reduced pressure. The target compound (6) was obtained 2.17g by re-crystallization (yield: 88%). e) Synthesis of 3-r(5-Bromo-3-methoxy-pyridine-2-carbonyl)-aminol-3-r(Z)-hydroxy - iminol -propionic acid tert-butyl ester (7)
[0238] Ig (5.74 mmol) of (N-Hydroxycarbamimidoy^-acetic acid tert-butyl ester (6) was dissolved in 20ml of MC and 2.4ml (17.22 mmol) of triethylamine was added. The solution of 1.3g (D5.17mmol) of crude 5-Bromo-3-methoxy-pyridine-2-carbonyl chloride (4) and 10ml of MC was slowly added to the reaction solution at room temperature. After 5 hours at this temperature, the reaction mixture was diluted with MC and washed with H2O. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified via column chromatography (ethyl acetate: n-Hexane = 1 : 3) and the target compound (7) was obtained 1.75 g (yield: 78%). MS: m/z 389 [M+l]
f) Synthesis of r5-(5-Bromo-3-methoxy-pyridin-2-yl)-ri,2,41oxadiazol-3-yll-acetic acid tert-butyl ester (8)
[0239] 1.75g (4.51 mmol) of 3-[(5-Bromo-3-methoxy-pyridine-2-carbonyl)-amino]-3-[(Z)- hydroxyimino] -propionic acid tert-butyl ester (7) was added in 50ml of toluene and the reaction mixture was heated to reflux for 12 hours. The reaction mixture was concentrated under reduced pressure and the target compound (8) was obtained 1.54g by re-crystallization (yield: 92%). 1H NMR (300MHz, CDCl3): δ 8.42 (s, IH), 7.62 (s, IH), 4.02 (s, 3H), 3.84 (s, 2H), 1.43 (s, 9H). MS: m/z 371 [M+l]
g) Synthesis of [S-fS-Cvano-S-methoxy-pyridin^-vD-ri^Λloxadiazol-S-yll-acetic acid tert-butyl ester (9)
[0240] 500mg (1.35 mmol) of [5-(5-Bromo-3-methoxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]- acetic acid tert-butyl ester (8), 95.1mg (0.81 mmol) of zinc cyanide and 156mg (0.135 mmol) of tetrakis(triphenylphosphine)palladium were dissolved in 5 ml of DMF. The reaction mixture was heated to 160°C for 25minutes in microwave reactor (150W). The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried with magnesium sulfate and was concentrated under reduced pressure. The residue was purified via column chromatography (Ethyl acetate: n-Hexane = 1 : 3, UV 360nm) and the target compound (9) was obtained 257mg (yield: 60%). MS: m/z 318 [M+l]
h) Synthesis of [S-fS-Cyano-S-hydroxy-pyridin-l-yπ-fl^Λloxadiazol-S-yll-acetic acid (10)
[0241] 250mg (1.01 mmol) of 5-(5-Cyano-3-methoxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]- acetic acid tert-butyl ester (9) and 1.17g (10.1 mmol) of pyridine hydrochloric acid salt were added in a sealed tube and heated to 140°C. After 2.5 hours at this temperature, the reaction mixture was diluted with ethyl acetate and washed with H2O. The product was extracted with saturated sodium bicarbonate solution from the organic layer and the aqueous layer was acidified with IN HCl. The product was re-extracted with ethyl acetate from the aqueous layer and the organic layer was dried with magnesium sulfate and concentrated under reduced pressure. The target compound (10) was obtained 182mg (yield: 73%).
1H NMR (300MHz, DMSO-d6): δ 8.66 (d, J=I.5Hz, IH), 7.95 (d, J=I.5Hz, IH), 3.95 (s, 2H), MS: m/z 248 [M+l]
i) Synthesis of 2-[5-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,41oxadiazol-3-yll-N-[2-(4- hydroxy-phenyl)-ethyl]-acetamide (11)
[0242] 50mg (0.202 mmol) of [5-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]- acetic acid (10), 30.6mg (0.223 mmol) of 4-hydroxy-phenethylamine and 72mg (0.223 mmol) of TBTU were dissolved in 5ml of DMF and 56μl (0.405 mmol) of triethylamine was added to reaction mixture at room temperature. After 12 hours at this temperature, the reaction mixture was diluted with ethyl acetate and was washed with water three times. The organic layer was dried with magnesium sulfate and was concentrated under reduced pressure. The residue was purified via Prep-HPLC (Acetonitrile/0.1% formic acid solution) and the target compound (11) was obtained lOmg (yield: 13.5%).
1H NMR (300MHz, DMSO-d6, TFA): δ 8.66 (s, IH), 8.32 (t, J = 6.0 Hz, IH), 7.97 (s, IH), 6.99 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.4 Hz, 2H), 3.74 (s, 2H), 3.26-3.19 (m, 2H), 2.59 (t, J = 6.9 Hz, 2H), MS: m/z 367 [M+l].
Example 9: Analytical Data
[0243] Analytical data of the final target compounds that were synthesized using the above- mentioned methods are listed, as follows. 4-Hydroxy-2-(3 -hydroxy-pyridin-2-yl)-pyrimidine-5 -carboxylic acid
[0244] 1H NMR (300 MHz, CD3OD) δ 8.80 (s, IH), 8.35 (m, IH), 7.52 (m, 2H).
2-(6-Bromo-3 -hydroxy-pyridin-2-yl)-4-hydroxy-pyrimidine-5 -carboxylic acid [0245] 1H NMR (300 MHz, CD3OD) δ 8.78 (s, IH), 7.70 (d, IH), 7.42 (d, IH).
5-Bromo-2-(3-hydroxy-pyridin-2-yl)-pyrimidine-4-carboxylic acid
[0246] 1H NMR (300 MHz, CD3OD) δ 9.12 (br, 2H), 8.28 (m, IH), 7.49 (br, 2H). m/z=297
(M+H).
2-(3-Hydroxy-pyridin-2-yl)-pyrimidine-4-carboxylic acid
[0247] 1H NMR (300 MHz, CD3OD) δ 9.02 (br, 2H), 8.28 (s, IH), 7.58 (s, IH), 7.47 (br, 2H). m/z=218 (M+H).
2-(2-Hydroxy-4-nitro-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid
[0248] 1H NMR (300 MHz, CD3OD) δ 7.76 (s, IH), 7.75 (d, IH, J=7.8 Hz), 7.67 (d, IH, J=8.7 Hz), 4.99 (dd, IH, j=16, 3.8 Hz), 4.71 (dd, IH, j=9.4, 3.8 Hz), 4.61 (dd, IH, j=16, 9.3 Hz). m/z=269 (M+H).
2-(2-Hydroxy-4-bromo-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid
[0249] 1H NMR (300 MHz, CD3OD) δ 7.31 (d, IH, j=8.7 Hz), 7.14 (d, IH, J=I.8 Hz),, 7.06 (dd, IH, J=8.4, 1.8 Hz), 4.90 (dd, IH, j=16, 3.6 Hz), 4.64 (dd, IH, j=9.3, 3.9 Hz), 4.53 (dd, IH, j=16, 9.3 Hz).
2-(3-Hydroxy-naphthalen-2-yl)-4,5-dihydro-3H-imidazole-4-carboxylic acid
[0250] 1H NMR (CD3OD, 300 MHz) δ 4.12-4.31 (m, 2H), 4.72 (dd, IH, J=12.3, 7.5), 7.28 (s,
IH), 7.38 (t, IH, J=I 2), 7.55 (t, IH, J=7.8), 7.68 (d, IH, J=8.1), 7.81 (d, IH, J=8.4), 8.40 (s, IH)
(R)-2-(3-Hydroxy-5-phenyl-pyridin-2-yl)-4,5-dihydro-thiazole-4-carboxylic acid [0251] 1H NMR (300 MHz, DMSO-d6) δ 12.2(s, IH), 8.57(s, IH), 7.82-7.77(m, 2H), 7.51-7.48 (m, 3H), 5.81 (t, IH, J=9.9 Hz), 3.66-3.57 (m, 2H). m/z=301 (M+H).
(R)-2-(3-Hydroxy-pyridin-2-yl)-4,5-dihydro-thiazole-4-carboxylic acid
[0252] 1H NMR (300 MHz, DMSO-d6) δ 8.89 (d, IH, J=7.5 Hz), 8.61-8.58 (m, IH), 8.18 (d,
1H, J=8.1 Hz), 7.44 (q, 1H, J=7.1 Hz), 4.73-4.62 (m, IH), 3.30-3.09 (m, IH). m/z=225 (M+H).
(S)-2-(3-Hydroxy-pyridin-2-yl)-4,5-dihydro-thiazole-4-carboxylic acid
[0253] 1H NMR (300 MHz, DMSO-d6) δ 8.97 (d, IH, J=7.5 Hz), 8.60-8.58 (m, IH), 8.17 (d,
1H, J=8.1 Hz), 7.48-7.44 (m, IH), 4.72-4.65 (m, IH), 3.39-3.24 (m, IH). m/z=225 (M+H).
3'-Hydroxy-[2,2']bipyridinyl-4-carboxylic acid
[0254] 1H NMR (300 MHz, DMSO) δ 8.90-8.85 (m, IH), 8.64 (s, IH), 8.35 (br s, IH), 8.15 (br s, IH), 7.98 (br s, IH), 7.90 (br s, IH). m/z=217 (M+H).
3-(lH-Benzoimidazol-2-yl)-l-chloro-isoquinolin-4-ol
[0255] 1H NMR (300 MHz, CD3OD) δ 8.47 (d, IH), 8.28 (d, IH), 7.82-7.72 (m, 3H), 7.34 (s,
IH), 7.24 (m, 2H). m/z=297 (M+H).
(R)-2-(2-Hydroxy-4-nitro-phenyl)-4,5-dihydro-thiazole-4-carboxylic acid
[0256] 1H NMR (300 MHz, CDCl3) δ 7.84(s,lH), 7.70,(m,lH), 7.58(d,lH)
5.44(t,lH),3.77(m,2H). m/z=269 (M+H).
(S)-2-(2-Hydroxy-4-nitro-phenyl)-4,5-dihydro-thiazole-4-carboxylic acid
[0257] 1H NMR (300 MHz, CDCl3) δ 7.84(s,lH), 7.70,(m,lH), 7.58(m,lH)
5.44(m,lH),3.77(m,2H). m/z=269 (M+H).
2-(l-Chloro-4-hydroxy-isoquinolin-3-yl)-lH-benzoimidazole-5-carboxylic acid
[0258] 1H NMR (300 MHz, CD3OD + DMSO) δ 8.55 (d, IH), 8.34 (m, 2H ), 8.00 (d, IH),
7.89-7.78 (m, 2H), 7.68 (m, IH). m/z=341 (M+H). 2-(2-Hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester
[0259] 1H NMR (CDCl3, 300 MHz) δ 7.98 (d, IH, J=8.1) 7.29-7.35 (m, IH), 6.97 (d, IH,
J=7.8), 6.87-6.92 (m, IH), 4.30 (q, 2H, J=I 2), 2.76 (s, 3H), 1.31 (t, 3H). m/z=264 (M+H).
2-(2-Hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid
[0260] 1H NMR (CDCl3, 300 MHz) δ 7.98 (d, IH, j=8.1) 7.29-7.35 (m, IH), 6.97 (d, IH, j=7.8), 6.87-6.92 (m, IH), 2.76 (s, 3H). m/z=236 (M+H).
2-(5-Bromo-2-hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester
[0261] 1H NMR (CDCl3, 300 MHz) δ 7.95 (d, IH, J=I.8), 7.36 (dd, IH, J=9.0, 2.4),
6.88(d,lH,J=6.3), 4.29(q, 2H, 1=12), 2.72 (s, 3H), 1.30 (t, 3H, 1=12). m/z=343 (M+H).
2-(5-Bromo-2-hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid
[0262] 1H NMR (CDCl3, 300 MHz) δ 7.95 (d, IH, J=I.8), 7.36 (dd, IH, J=9.0, 2.4),
6.88(d,lH,J=6.3), 2.72 (s, 3H). m/z=315 (M+H).
2-(2-Hydroxy-phenyl)-4,5-dihydro-oxazole-5-carboxylic acid
[0263] 1H NMR (DMSO, 300 MHz) δ 12.85(s,lH), 11.86(s,lH), 7.67(d,lH, J=7.5), 7.52(m,
IH), 7.06(m,2H), 4.10(m, 2H), 3.85(m,3H), 3.28(s,3H). m/z=208 (M+H).
2-(3-Hydroxy-naphthalen-2-yl)-4-methyl-thiazole-5-carboxylic acid
[0264] 1H NMR (DMSO, 300 MHz) δ 8.79 (s, IH), 7.97 (d, IH, J=8.1), 7.73 (d, IH, J=8.4),
7.46 (t, IH, J=8.4), 7.29-7.36 (m, 2H), 2.71 (s, 3H). m/z=286 (M+H).
2-(4-Hydroxy-biphenyl-3-yl)-4-methyl-thiazole-5-carboxylic acid ethyl ester
[0265] 1H NMR (CDCl3, 300 MHz) δ 7.80 (s, IH), 7.55-7.79 (m, 3H), 7.45 (dd, 2H, J=7.8,
7.2), 7.34-7.37 (m, IH), 7.13 (d, IH, J=8.4), 4.37 (q, 2H, 1=12), 1.40 (t, 3H, 1=12). m/z=340
(M+H).
2-(5-Bromo-2-hydroxy-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid [0266] 1H NMR (DMSO, 300 MHz) δ 12.67(s,lH), 11.85(s,lH), 7.81(s,lH), 7.42(m, IH), 6.82(m,2H), 4.60(m, 2H), 4.40(m,2H), 3.4(m,lH). m/z=303 (M+H).
2-(5-Acetyl-2-hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid
[0267] 1H NMR (DMSO, 300 MHz) δ 8.76 (s, IH), 7.94 (d, IH, J=8.4), 7.19 (d, 2H, J=8.4),
2.67 (s, 3H), 2.54 (s, 3H). m/z=278 (M+H).
2-(4-Bromo-2-hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid
[0268] 1H NMR (DMSO, 300 MHz) δ 8.09 (d, IH, J=8.4), 7.21 (s, IH), 7.14 (d, 2H, J=8.1),
2.65 (s, 3H). m/z=315 (M+H).
2-(5-Chloro-2-hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid
[0269] 1H NMR (CDCl3, 300 MHz) δ 7.92(d, IH, J=2.4), 7.38 (dd, IH, J=8.7, 2.4),
6.86(d,lH,J=6.4), 2.70 (s, 3H). m/z=271 (M+H).
2-(2-Hydroxy-4-nitro-phenyl)-4-methyl-thiazole-5-carboxylic acid
[0270] 1H NMR (DMSO, 300 MHz) δ 8.12 (d, IH, J=2.4), 7.77 (dd, IH, J=8.4, 2.7), 7.05 (d,
IH, J=9.0), 2.65 (s, 3H). m/z=281 (M+H).
2-(4-Bromo-2-hydroxy-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid
[0271] 1H NMR (300 MHz, CD3OD) δ 7.31 (d, IH, J=8.7 Hz), 7.14 (d, IH, J=I.8 Hz),, 7.06 (dd, IH, J=8.4, 1.8 Hz), 4.90 (dd, IH, J=16, 3.6 Hz), 4.64 (dd, IH, J=9.3, 3.9 Hz), 4.53 (dd, IH, J=16, 9.3 Hz). m/z=303 (M+H).
2-(4-Bromo-2-hydroxy-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid methyl ester
[0272] 1H NMR (DMSO, 300 MHz) δ 11.85(s,lH), 7.52(m,2H), 7.15(d,lH,J=7.5),
4.74(m,lH), 4.52(m,lH), 3.71(s,3H), 3.38(m,lH). m/z=317 (M+H).
3-(4,5-Dihydro-lH-imidazol-2-yl)-naphthalen-2-ol [0273] 1H NMR (DMSO, 300 MHz) δ 8.39 (s, IH), 7.72 (d, IH, J=8.1), 7.56 (d, IH, J=8.4), 7.35 (t, IH, J=7.2), 7.19 (d, IH, J=8.1), 7.14 (s, IH), 3.57 (t, 2H, J=6.0), 2.94-2.97 (m, 2H). m/z=213 (M+H).
2-(4,5-Dihydro-lH-imidazol-2-yl)-pyridin-3-ol
[0274] 1H NMR (300 MHz, CD3OD) δ 8.48 (br, IH), 8.14 (m, IH), 7.45 (m, IH), 3.75-3.44
(m, 4H). m/z=164 (M+H).
l-Chloro-3-(4,5-dihydro-lH-imidazol-2-yl)-isoquinolin-4-ol
[0275] 1H NMR (300 MHz, DMSO) δ 11.28 (broad, IH), 8.30 (m, IH), 7.94 (m, IH), 7.62 (m,
2H), 3.48 (m, 2H), 2.92 (m, 2H). m/z=249 (M+H).
2-(5-Methyl-4,5-dihydro-lH-imidazol-2-yl)-pyridin-3-ol
[0276] 1H NMR (300 MHz, CD3OD) δ 8.15 (m, IH), 7.45 (m, IH), 7.38 (m, IH), 3.63-3.60
(m, 3H), 1.34 (d, 3H). m/z=178 (M+H).
2-(2,4-Dihydroxy-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid
[0277] 1H NMR (300 MHz, DMSO) δ 12.36 (s, IH), 10.19 (s, IH), 7.19 (d, J = 8.4 Hz, IH),
6.35 (d, J = 8.4 Hz, IH), 6.29 (s, IH), 4.74-4.60 (m, 2H), 4.49-4.38 (m, IH). m/z=240 (M+H).
2-(4-Benzyloxy-2-hydroxy-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid
[0278] 1H NMR (300 MHz, DMSO-d6) d 12.40 (br, IH), 7.44-7.28 (m, 6H), 6,59-6.57 (m, 2H),
5.13 (s, 2H), 4.77-4.67 (m, 2H), 4.51-4.41 (m, IH). m/z=330 (M+H).
2-(l-Hydroxy-naphthalen-2-yl)-4,5-dihydro-oxazole-5-carboxylic acid
[0279] 1H NMR (CD3OD, 300 MHz) δ 8.32 (d, IH, J= 8.7), 7.75-7.80 (m, 2H), 7.46-7.54 (m,
2H), 7.28 (d, IH, J=8.4), 5.05 (t, IH, J=8.7), 4.40 (t, IH, J=I Ll), 4.17-4.11 (m, IH). m/z=258
(M+H).
2-(3-Hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-acetic acid [0280] 1H NMR (300 MHz, DMS(HCF3COOH) δ 8.22(s, IH), 8.00(s, IH), 7.46(m, 2H), 3.40(s, 2H)
2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo- 1 ,6-dihydro-pyrimidin-5-yl] -acetic acid
[0281] 1H NMR (300MHz, CD3OD):δ 8.53 (s, IH), 8.04 (s, IH), 7.85 (s, IH), 3.54 (s, 2H)
6-(5-Carboxymethyl-6-oxo- 1 ,6-dihydro-pyrimidin-2-yl)-5-hydroxy-nicotinic acid
[0282] 1H NMR (300MHz, CD3OD):δ 8.77 (s, IH), 8.13 (s, IH), 7.90 (s, IH), 3.54 (s, 2H)
N-Benzyl-2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide
[0283] 1H NMR (300 MHz, CDCl3) 8.17 (d, J=4.5Hz, IH), 7.37 (m, IH), 7.363-7.22 (m, 7H),
6.02 (br.s, IH), 4.87 (d, J = 5.7 Hz, 2H), 3.83 (s, 2H).
2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl] -acetic acid butyl ester
[0284] 1H NMR (300 MHz, CDCl3) 12.03 (br.s, IH), 8.38 (d, J=I.8Hz, IH), 7.61 (d, J=I.8Hz,
IH), 7.435 (s, IH), 4.17 (m, 2H), 3.90 (s, IH), 1.64 (m, 2H). 1.36 (m, 2H), 0.93 (t, 3H).
2-(3-Hydroxy-pyridin-2-yl)-thiazole-4-carboxylic acid benzyl amide
[0285] 1H NMR (300 MHz, CDCl3) δ 10.69 (s, IH), 8.270 (s, IH), 8.217 (dd, Jl = 4.5, J2=1.5,
IH), 7.381-7.262 (m, 5H), 4.705 (d, J = 6.3, 2H)
N-Benzyl-2-[2-(3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-acetamide
[0286] 1H NMR (300 MHz, DMSO-d6) δ 8.46 (s, IH), 8.23 (s, IH), 7.91 (s, IH), 7.49-7.43 (m,
2H), 7.23-7.20 (m, 5H), 4.27 (d, J = 5.7 Hz, 2H)
{2-[2-(3-Hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-acetylamino} -acetic acid [0287] 1H NMR (300 MHz, DMSO-d6) δ 8.29-8.25 (m, 2H), 7.92 (br s, IH), 7.57-7.46 (m, 2H), 3.73 (d, J = 6.0 Hz, 2H)
2-(3,5-Dihydroxy-pyridin-2-yl)-3H-quinazolin-4-one [0288] 1H NMR (300 MHz, DMSO-d6) δ 8.12(d, J = 7.8Hz, IH), 7.86 (d, J = 2.1 Hz, IH), 7.83-7.78(m, 2H), 7.53-7.47 (m, lH),6.75(d, J = 2.4 Hz, IH)
5-Hydroxy-6-(4-oxo-3,4-dihydro-quinazolin-2-yl)-nicotinonitrile
[0289] 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, IH), 8.18-8.11 (m, IH), 7.97-7.85(m, 3H),
7.61-7.55 (m, IH)
5-Hydroxy-6-(4-oxo-3,4-dihydro-quinazolin-2-yl)-nicotinic acid
[0290] 1H NMR (300 MHz, DMSO-d6) δ 12.12 (br.s, IH), 8.23 (s, IH), 8.07-8.00 (m, IH),
7.02-6.98 (m, 3H), 7.50-7.46 (m, IH)
5-Hydroxy-6-(6-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)-nicotinonitrile
[0291] 1H NMR (300MHz, CDCl3):δ 8.43 (s, IH), 8.17 (s, IH), 7.48 (m, 3H), 2.54 (s, 3H)
5-Hydroxy-6-(6-methoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-nicotinonitrile
[0292] 1H NMR (300 MHz, DMSO-d6) δ 8.61 (s, IH), 8.06 (s, IH), 7.89 (d, J = 9.0 Hz, IH),
7.56-7.46 (m, 2H), 3.90 (s, 3H)
5-Hydroxy-6-(6-hydroxy-4-oxo-3,4-dihydro-inazolin-2-yl)-nicotinonitrile
[0293] 1H NMR (300 MHz, DMSO-d6) δ 10.48 (s, IH), 8.61(s, IH), 8.07 (s, IH), 7.81 (d, J =
8.7 Hz, IH), 7.48(d, J = 2.4 Hz, IH), 7.36-7.32 (m, IH)
N-Benzyl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide
[0294] 1H NMR (300 MHz, DMSO-d6) d 12.18 (br s, IH), 8.68 (m, IH), 8.59 (s, IH), 8.07 (s,
IH), 7.79 (s, IH), 7.32-7.21 (m, 5H), 4.29 (d, J = 5.7 Hz, 2H), 3.80 (s, 2H)
6- [6-(3 ,5 -Dichloro-phenoxy)-4-oxo-3 ,4-dihydro-quinazolin-2-yl] -5 -hydroxy-nicotinonitrile [0295] 1H NMR (300MHz, CDCl3):δ 8.45 (s, IH), 7.87 (d, IH), 7.83 (d, IH), 7.70 (s, IH), 7.56 (m, IH), 7.21 (m, IH), 6.98 (m, 2H)
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-(3 -fluoro-benzyl)-acetamide [0296] 1H NMR (300 MHz, DMSO-d6) d 12.13 (s, IH), 8.71 (t, J = 6.0 Hz, IH), 8.59 (d, J = 1.5 Hz, IH), 8.06 (d, J = 1.5 Hz, IH), 7.80 (s, IH), 7.36-7.28 (m, IH), 7.09-7.02 (m, 3H), 4.31 (d, J = 5.7 Hz, 2H), 3.81 (s, 2H)
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-(4-fluoro-benzyl)-acetamide
[0297] 1H NMR (300 MHz, DMSO-d6) d 8.67 (s, IH), 8.47 (s, IH), 7.92 (s, IH), 7.71 (s, IH),
7.31-7.26 (m, 2H), 7.13-7.07 (m, 2H), 4.27 (d, J = 5.4 Hz, 2H), 3.77 (s, 2H)
{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino} -acetic acid
[0298] 1H NMR (300 MHz, DMSO-d6) d 12.18 (br s, IH), 8.57 (d, J = 1.5 Hz, IH), 8.47 (d, J
= 5.4 Hz, IH), 8.03 (d, J = 1.5 Hz, IH), 7.78 (s, IH), 3.79-3.76 (m, 4H)
(S)- {2-[2-(5-Bromo-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino} -phenyl-acetic acid methyl ester
[0299] 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J=I .8, 1H),7.63 (d, J=I .8, IH), 7.48-7.45 (m, IH), 7.32-7.35 (m, 5H), 6.75 (d, J=6.6, IH), 5.60 (d, J= 6.9, IH), 3.87 (s, 2H), 3.74 (s, 3H)
(R)- {2-[2-(5-Bromo-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino} -phenyl-acetic acid methyl ester
[0300] 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J=I .5, IH), 7.57-7.70 (m, IH), 7.48-7.50 (m, IH), 7.34-7.45 (s, 5H), 6.79 (d, J= 7.5, IH), 5.59 (d, J= 6.9, IH), 3.87 (s, 2H), 3.74 (s, 3H)
(S)- {2-[2-(5-Bromo-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino} -phenyl-acetic acid [0301] 1H NMR (300 MHz, DMSO) δ 8.99 (d, J= 7.2, IH), 8.58 (s, IH), 8.07 (s, IH), 7.77 (s, IH), 7.39-7.33 (m, 6H), 5.34 (d, J= 7.2, IH), 3.87 (s, 2H)
(R)-{2-[2-(5-Bromo-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino}-phenyl-acetic acid [0302] 1H NMR (300 MHz, DMSO) δ 8.99 (d, J= 7.2, IH), 8.58 (s, IH), 8.06 (s, IH), 7.77 (s, IH), 7.39-7.31 (m, 6H), 5.34 (d, J= 7.5, IH), 3.87 (s, 3H)
N-(2-Chloro-benzyl)-2-[2-(5 -cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide [0303] 1H NMR (300 MHz, CD3OD) δ 8.43 (s, IH), 7.80 (s, IH), 7.63 (s, IH), 7.63-7.36 (m ,2H), 7.26-7.23 (m, 2H), 4.50 (s, 2H), 3.87 (s, 2H)
N-(3-Chloro-benzyl)-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide
[0304] 1H NMR (300 MHz, cdcl3) δ 8.39 (d, J=I.8, IH), 7.62 (d, J= 1.5, IH), 7.47 (s, IH),
7.26-7.23 (m, 3H), 7.16-7.13 (m, IH), 4.46 (s, 2H), 3.86 (s, 2H)
N-(4-tert-Butyl-benzyl)-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide
[0305] 1H NMR (300 MHz, DMSO) 8.56 (br.s, IH), 8.57 (s, IH), 8.06 (s, IH), 7.78 (s, IH),
7.30 (d, J=8.1Hz, 2H), 7.15 (d, J=8.1Hz, 2H), 4.24 (d, J=5.37Hz, 2H), 3.77(s, 2H), 1.23(m, 9H).
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-(3 -trifluoromethyl-benzyl)-acetamide [0306] 1H NMR (300 MHz, DMSO) 12.04 (br.s, IH), 8.78 (br.s, IH), 8.57 (s, IH), 8.02 (s, IH), 7.79 (s, IH), 7.54 (m, 4H), 4.38 (d, J=6.0Hz, 2H), 3.81 (s, 2H),
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(4-dimethylamino-benzyl)-acetamide [0307] 1H NMR (300 MHz, DMSO) 12.17 (br.s, IH), 8.57 (s, IH), 8.48 (br.s, IH), 8.05 (s, IH), 7.76 (s, IH), 7.06 (d, J=8.4HZ, 2H), 6.63 (d, J=8.4Hz, 2H), 4.15 (d, J=5.4Hz, 2H), 3.75 (s, 2H), 2.81(s, 6H).
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-( 1 -methyl- 1 -phenyl-ethyl)-acetamide [0308] 1H NMR (300 MHz, DMSO) 12.09 (br.s, IH), 8.55 (s, IH), 8.42 (br.s, IH), 8.03
(s, IH), 7.71 (s, IH), 7.30-7.26 (m, 5H), 4.02 (d, J=6.0Hz, 2H), 2.34 (s, 3H), 2.30 (s, 3H).
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-pyridin-2-ylmethyl-acetamide [0309] 1H NMR (300 MHz, CDCl3) d 12.00 (br s, IH), 8.60 (d, J = 4.5 Hz, IH), 8.37(s, IH), 8.07 (t, J = 7.8 Hz, IH), 7.99 (s, IH), 7.67-7.64 (m, IH), 7.59-7.54 (m, 2H), 7.49 (s, IH), 4.75 (d, J = 3.6 Hz, 2H), 3.93 (s, 2H)
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-pyridin-3 -ylmethyl-acetamide [0310] 1H NMR (300 MHz, DMSO-d6) d 12.12 (s, IH), 8.74 (s, IH), 8.58 (s, IH), 8.50-8.47 (m, 2H), 8.06 (s, IH), 7.79 (s, IH), 7.64 (d, J = 7.5 Hz, IH), 7.33-7.32 (m, IH), 4.32 (d, J = 6.0 Hz, 2H), 3.80 (s, 2H)
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-pyridin-4-ylmethyl-acetamide [0311] 1H NMR (300 MHz, DMSO-d6) d 12.12 (br s, IH), 9.01 (t, J = 5.4 Hz, IH), 8.79 (d, J = 6.3Hz, 2H), 8.61 (d, J = 1.2 Hz, IH), 8.07 (d, J = 1.2 Hz, IH), 7.85-7.83 (m, 3H), 4.56 (d, J = 6.0 Hz, 2H), 3.98 (s, 2H)
N-(4-Chloro-benzyl)-2-[2-(5 -cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide
[0312] 1H NMR (300 MHz, DMSO) δ 8.70 (s, IH), 8.58 (s, IH), 8.06 (s, IH), 7.78 (s, IH),
7.36-7.25 (2d, 4H), 4.28 (d, J= 5.7, 2H), 3.79 (s, 2H)
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-pyridin-2-yl-ethyl)-acetamide [0313] 1H NMR (300 MHz, DMSO) δ 8.59 (s, IH), 8.38-8.34 (m, IH), 8.24 (s, IH), 8.05 (s, 2H), 7.71 (s, 2H), 7.58 (m, IH), 7.26-7.21 (m, IH), 3.69-3.66 (m, 2H), 2.41 (s, 2H), 2.76-2.71 (m, 2H)
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-pyridin-3-yl-ethyl)-acetamide
[0314] 1H NMR (300 MHz, DMSO) δ 8.55 (s, 2H), 8.42 (s, IH), 8.22 (s, IH), 8.04 (s, IH),
7.72 (s, IH), 7.65-7.60 (m, IH), 7.21-7.14 (m, IH)
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-(3 -methoxy-benzyl)-acetamide [0315] 1H NMR (300 MHz, DMSO-d6) d 12.15 (s, IH), 8.64 (t, J = 5.7 Hz, IH), 8.57 (d, J = 1.5 Hz, IH), 8.04 (d, J = 1.5 Hz, IH), 7.78 (s, IH), 7.22-7.16 (m, IH), 6.83-6.75 (m, 3H), 4.26 (d, J = 6.0 Hz, 2H), 3.80 (s, 2H), 3.67 (s, 3H)
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-pyridin-4-yl-ethyl)-acetamide
[0316] 1H NMR (300 MHz, CD3OD) δ 8.43 (d, J= 1.5, IH), 8.32 (br s. 2H), 7.80 (d, J= 1.2,
IH), 7.56 (s, IH), 7.25 (d, J= 6.0, 2H), 3.73 (s, 2H), 3.53 (t, J= 6.9, 2H), 2.87 (t, J= 6.9, 3H) N-Benzhydryl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide
[0317] 1H NMR (300 MHz, DMSO-d6) d 12.15 (s, IH), 9.15 (d, J = 8.7 Hz, IH), 8.58 (d, J =
1.5 Hz, IH), 8.08 (d, J = 1.5 Hz, IH), 7.77 (s, IH), 7.34-7.20 (m, 10H), 6.11 (d, J = 8.7 Hz, IH),
3.87 (s, 2H)
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(lH-indol-5-ylmethyl)-acetamide [0318] 1H NMR (SOO MHz, DMSO-d6) d 12.18 (s, IH), 10.98 (s, IH), 8.62-8.58 (m, 2H), 8.06 (s, IH), 7.78 (s, IH), 7.39 (s, IH), 7.31-7.27 (m, 2H), 6.98 (d, J = 8.4 Hz, IH), 6.32 (s, IH), 4.35 (d, J = 5.4 Hz IH), 3.78 (s, 2H)
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-phenethyl-acetamide [0319] 1H NMR (300 MHz, DMSO-d6) d 12.14 (s, IH), 8.58 (d, J = 1.5 Hz, IH), 8.22 (t, J = 5.1 Hz, IH), 8.05 (d, J = 1.5 Hz, IH), 7.71 (s, IH), 7.26-7.11 (m, 5H), 3.69 (s, IH), 3.33-3.26 (m, 2H), 2.71 (t, J = 7.5 Hz, 2H),
N- {2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -acetyl} -methanesulfonamide
[0320] 1H NMR (300 MHz, DMSO-d6) d 12.04 (s, IH), 8.60 (d, J = 1.5 Hz, IH), 8.08 (d, J =
1.5 Hz, IH), 7.85 (s, IH), 3.94 (s, 2H), 3.23 (s, 3H)
N-{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetyl}-benzenesulfonamide
[0321] 1H NMR (300 MHz, DMSO-d6) d 12.00 (s, IH), 8.58 (s, IH), 8.06 (s, IH), 7.88 (d, J =
8.1 Hz, 2H), 7.75 (s, IH), 7.64-7.53 (m, 3H), 3.87 (s, 2H)
N-{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetyl}-C-phenyl-methanesulfonamide [0322] 1H NMR (300 MHz, DMSO-d6) d 11.96 (s, IH), 8.62 (d, J = 1.8 Hz, IH), 8.09 (d, J = 1.8 Hz, IH), 7.85 (s, IH), 7.31-7.20 (m, 5H), 4.67 (s, 2H), 3.89 (s, 2H)
N-(6-Chloro-pyridin-3-ylmethyl)-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide [0323] 1H NMR (300 MHz, DMSO-d6) d 12.09 (s, IH), 8.73 (t, J = 5.4 Hz, IH), 8.56 (d, J = 1.5 Hz, IH), 8.29 (d, J = 2.1 Hz, IH), 8.02 (d, J = 1.5 Hz, IH), 7.77 (s, IH), 7.72 (dd, J = 8.1 and 2.1 Hz, IH), 7.44 (d, J = 8.1 Hz, IH), 4.31 (d, J = 5.4 Hz, 2H), 3.79 (s, 2H) {2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino} -acetic acid methyl ester [0324] 1H NMR (300 MHz, DMSO-d6) d 12.09 (s, IH), 8.60 (t, J = 5.7 Hz, IH), 8.54 (d, J = 1.8 Hz, IH), 8.01 (s, IH), 7.76 (s, IH), 3.87 (d, J = 5.7 Hz, 2H), 3.80 (s, 2H), 3.61 (s, 3H)
(R)2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-((R)-2-hydroxy-l-phenyl-ethyl)- acetamide
[0325] 1H NMR (300 MHz, DMSO-d6) d 12.09 (s, IH), 8.63 (t, J = 7.8 Hz, IH), 8.57 (d, J =
1.2 Hz, IH), 8.06 (d, J = 1.2 Hz, IH), 7.75 (s, IH), 7.31-7.19 (m, 5H), 4.94-4.83 (m, 2H), 3.81 (s,
2H), 3.57 (d, J = 5.7 Hz, 2H)
(S)2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-((S)-2-hydroxy-l-phenyl-ethyl)- acetamide
[0326] 1H NMR (300 MHz, DMSO-d6) d 12.12 (s, IH), 8.63 (t, J = 8.4 Hz, IH), 8.57 (d, J =
1.5 Hz, IH), 8.06 (d, J = 1.5 Hz, IH), 7.75 (s, IH), 7.31-7.18 (m, 5H), 4.94-4.83 (m, 2H), 3.81 (s,
2H), 3.57 (d, J = 5.4 Hz, 2H)
[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl] -acetic acid
[0327] 1H NMR (300 MHz, DMSO-d6) d 12.09 (s, IH), 8.59 (s, IH), 8.07 (s, IH), 7.84 (s,
IH), 3.91 (s, 2H)
{2-[5-(Acetylamino-methyl)-3-hydroxy-pyridin-2-yl]-thiazol-4-yl} -acetic acid
[0328] 1H NMR (300 MHz, CD3OD) d 8.14 (s, IH), 7.64 (s, IH), 7.53 (s, IH), 4.43 (s, 2H),
3.94 (s, 2H), 2.02 (s, 3H)
{2-[5-(Benzenesulfonylamino-methyl)-3-hydroxy-pyridin-2-yl]-thiazol-4-yl} -acetic acid [0329] 1H NMR (300 MHz, CD3OD) d 7.96 (s, IH), 7.82 (d, J = 6.9 Hz, 2H), 7.59-7.45
(m, 4H), 7.24 (s, IH), 4.14 (s, 2H), 3.84 (s, 2H)
{2- [3 -Hydroxy-5 -(phenylmethanesulfonylamino-ethyl)-pyridin-2-yl] -thiazol-4-yl} -acetic acid [0330] 1H NMR (300 MHz, CD3OD) d 8.02 (s, IH), 7.46-7.34 (m, 7H), 4.35 (s, 2H),
4.12 (s, 2H), 3.85 (s, 2H)
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-methyl-N-(2-pyridin-2-yl-ethyl)- acetamide
[0331] 1H NMR (300 MHz, DMSO-d6) d 12.12 (s, IH), 8.59-8.57 (m, IH), 8.51-8.44 (m,
IH), 8.06-8.05 (m, IH), 7.74-7.60 (m, 2H), 7.32-7.14 (m, 2H), 3.97 (s, IH), 3.84 (s, IH), 3.78 (t,
J = 6.9 Hz, IH), 3.64 (t, J = 6.9 Hz, IH), 3.03-2.99 (m, 2.5 H), 2.91 (t, J = 6.9 Hz, IH), 2.84 (s,
1.5H),
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(4-hydroxy-phenyl)-ethyl]-acetamide [0332] 1H NMR (300 MHz, DMSO-d6) d 12.15 (s, IH), 9.11 (s, IH), 8.58 (d, J = 1.5 Hz,
IH), 8.19 (t, J = 5.4 Hz, IH), 8.05 (d, J = 1.5 Hz, IH), 7.71 (s, IH), 6.94 (d, J = 8.4 Hz, 2H), 6.62 (t, J = 8.4 Hz, 2H), 3.69 (s, 2H), 3.26-3.19 (m, 2H), 2.59 (t, J = 7.5 Hz, 2H)
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(4-hydroxy-phenyl)-ethyl]-acetamide [0333] 1H NMR (300 MHz, DMSO-d6) d 12.16 (s, IH), 8.56 (s, IH), 8.27 (s, IH), 8.02
(s, IH), 7.71-7.68 (m, 3H), 7.36 (t, J = 8.4 Hz, 2H), 7.26 (s, 2H), 3.69 (s, 2H), 3.36-3.29 (m, 2H),
2.79 (t, J = 6.6 Hz, 2H)
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(3-imidazol-l-yl-propyl)-acetamide [0334] 1H NMR (300 MHz, CD3OD) δ 8.43 (s, IH), 7.79 (s. IH), 7.63 (s, IH), 7.26 (br s,
3H), 4.09 (s, 2H), 3.79 (s, 2H), 2.03 (s, 2H)
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(2-oxo-pyrrolidin-l-yl)-ethyl]- acetamide
[0335] 1H NMR (300 MHz, CD3OD) δ 8.43 (s, IH), 7.79 (d, J= 1.5, IH), 7.64 (s, IH),
3.80 (s, 2H), 3.44 (t, J= 7.2, 2H), 3.24-3.19 (m, 2H), 2.36 (t, J= 8.1, 2H), 2.03 (quin., J= 7.5, 2H), 1.75 (quin., J= 6.9, 2H)
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(lH-imidazol-4-yl)-ethyl]-acetamide [0336] 1H NMR (300 MHz, DMSO-d6) d 8.43 (s, IH), 8.24 (s, IH), 8.17 (s, IH), 7.88 (s, IH), 7.65 (s, IH), 7.58 (s, IH), 6.76 (s, IH), 3.69 (s, 2H), 3.32-3.25 (m, 2H), 2.63 (t, J = 6.6 Hz, 2H)
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-morpholin-4-yl-ethyl)-acetamide [0337] 1H NMR (300 MHz, DMSO-d6+TFA) d 9.95 (br s, IH), 8.59 (d, J = 1.8 Hz, IH), 8.46 (t, J = 5.4 Hz, IH), 8.06 (d, J = 1.8 Hz, IH), 7.81 (s, IH), 4.00-3.93 (m, 2H), 3.78 (s, 2H), 3.72- 3.60 (m, 2H), 3.49-3.43 (m, 4H), 3.21-3.02 (m, 4H)
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(3-morpholin-4-yl-propyl)-acetamide [0338] 1H NMR (300 MHz, DMSO-d6+TFA) d 8.54 (d, J = 1.5 Hz, IH), 8.33 (s, IH), 7.98( d, J = 1.5 Hz, IH), 7.75(s, IH), 3.93 (d, J = 10.5 Hz, 2H), 3.73 (s, 2H), 3.61 (t, J = 11.4 Hz, 2H), 3.38 (d, J = 12.9 Hz, 2H), 3.16-2.92(m, 6H), 1.84-1.75(m, 2H)
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-pyrrolidin-l-yl-ethyl)-acetamide [0339] 1H NMR (300 MHz, DMSO-d6) d 8.58 (d, J = 1.5 Hz, IH), 8.32 (s, IH), 8.05 (d,
J = 1.5 Hz, IH), 7.79 (s, IH), 3.76 (s, 2H), 3.34 (q, J = 6.0 Hz, 2H), 3.05-2.95 (m, 6H), 1.82-1.79 (m, 4H),
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(lH-indol-3-yl)-ethyl]-acetamide [0340] 1H NMR (300 MHz, DMSO-d6) d 12.17 (br s, IH), 10.77 (s, IH), 8.59 (s, IH),
8.28 (s, IH), 8.06 (s, IH), 7.74 (s, IH), 7.50 (d, J = 7.8 Hz, IH), 7.30 (d, J = 7.8 Hz, IH), 7.12- 6.94 (m,3H), 3.72 (s, 2H), 3.40-3.31 (m, 2H), 2.83 (t, J = 7.2 Hz, 2H)
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-piperidin-l-yl-ethyl)-acetamide [0341] 1H NMR (300 MHz, DMSO-d6) d 8.61 (s, IH), 6.36 (s, IH), 8.07 (s, IH), 7.81 (s,
IH), 3.76 (s, 2H), 3.44-3.25 (m, 6H), 3.05-2.98 (m, 2H), 1.70-1.58 (m, 4H), 1.55-1.40 (m, 2H
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[3-(2-oxo-pyrrolidin-l-yl)-propyl]- acetamide
[0342] 1H NMR (300 MHz, DMSO-d6) d 12.14 (br s, IH), 8.56 (d, J = 1.2 Hz, IH), 8.15
(t, J = 5.4 Hz, IH), 8.03 (d, J = 1.2 Hz, IH), 7.76 (s, IH), 3.71 (s, 2H), 3.30-3.25 (m, 2H), 3.15 (t, J = 7.2 Hz, 2H), 3.04 (q, J = 7.2 Hz, 2H), 2.18 (t, J = 7.5 Hz, 2H), 1.93-1.85 (m, 2H), 1.63-1.56 (m, 2H)
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(3,4-dihydroxy-phenyl)-ethyl]- acetamide
[0343] 1H NMR (300 MHz, DMSO-d6) d 10.45 (s, IH), 8.56 (s, IH), 8.28 (t, J = 5.7 Hz,
IH), 8.03 (s, IH), 7.72 (s, H), 7.09 (d, J = 9.0 Hz, IH), 7.01 (s, IH), 6.81 (s, IH), 6.56 (dd, J =
9.0 and 1.8 Hz, IH), 4.10-4.04 (m, 2H), 3.72 (s, 2H), 2.74 (t, J = 6.9 Hz, 2H)
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(5-hydroxy-lH-indol-3-yl)-ethyl]- acetamide
[0344] 1H NMR (300 MHz, DMSO-d6) d 8.71 (s, IH), 8.61 (s, IH), 8.57 (s, IH), 8.26 (t,
J = 5.1 Hz, IH), 8.03 (s, IH), 7.70 (s, IH), 6.59-6.55 (m, 2H), 6.41-6.38 (m, IH), 3.69 (s, 2H),
3.24-3.16 (m, 2H), 2.52 (t, J = 8.1 Hz, 2H)
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(4-methyl-piperazin-l-yl)-ethyl]- acetamide
[0345] 1H NMR (300 MHz, DMSO-d6) d 8.59 (d, J = 1.5 Hz, IH), 8.12-8.06 (m, 3H),
7.78 (s, IH), 3.72 (s, 2H), 3.23-3.16 (m, 2H), 2.80-2.68 (m, 4H), 2.58-2.39 (m, 9H)
N-Benzyl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-acetamide [0346] 1H NMR (300 MHz, DMSO-d6) δ 8.45 (br.s, IH), 8.40 (m, IH), 7.89 (m, IH),
7.78 (m, IH), 7.42-7.15(m, 5H), 4.26 (m, 2H), 3.20(m, 2H)
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo- 1 ,6-dihydro-pyrimidin-5 -yl] -N-phenethyl- acetamide
[0347] 1H NMR (300 MHz, DMSO-d6) δ 8.58 (br.s, IH), 8.04 (m, IH), 7.85 (m, IH),
7.58 (m, IH), 7.38-7.09 (m, 5H), 3.25 (m, 2H), 3.18 (m, 2H), 2.64 (m, 2H)
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-(3 -phenyl-propyl)- acetamide [0348] 1H NMR (300 MHz, DMSO-d6) δ 8.46 (br.s, IH), 7.93 (m, 2H), 7.58 (m, IH),
7.29-7.09 (m, 5H), 3.04 (m, 2H), 2.53 (m, 4H), 1.68 (m, 2H).
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-[3-(2-oxo- pyrrolidin- 1 -yl)-propyl] -acetamide
[0349] 1H NMR (300 MHz, DMSO-d6) δ 8.56 (s, IH), 8.01 (s, IH), 7.93 (s, IH), 7.90
(br.s, IH), 3.26 (m, 4H), 3.15 (m, 2H), 3.00 (m, 2H), 2.18 (t, 2H), 1.88 (m, 2H), 1.56 (m, 2H).
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-pyridin-3- ylmethyl-acetamide
[0350] 1H NMR (300 MHz, DMSO-d6) δ 8.44 (m, 4H), 7.96 (m, 2H), 7.65 (d, J=7.8Hz,
IH), 7.32 (m, IH), 4.29 (d, J=5.1Hz, 2H), 3.34 (m, 2H).
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-(2-pyridin-2-yl- ethyl)-acetamide
[0351] 1H NMR (300 MHz, DMSO-d6) δ 8.44 (m, 4H), 7.96 (m, 2H), 7.65 (d, J=7.8Hz,
IH), 7.32 (m, IH), 4.29 (d, J=5.1Hz, 2H), 3.34 (m, 2H).
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-(2-pyridin-3-yl- ethyl)-acetamide
[0352] 1H NMR (300 MHz, DMSO-d6) δ 8.56 (s, IH), 8.39 (m, 2H), 8.02 (m, 2H), 7.88
(s, IH), 7.62 (d, J=7.8Hz, IH), 7.28 (m, 2H), 3.25 (m, 4H), 2.71 (m, 2H).
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-[2-(3- trifluoromethyl-phenyl)-ethyl]-acetamide
[0353] 1H NMR (300 MHz, DMSO-d6) δ 8.42 (br.s, IH), 8.06 (s, IH), 7.89 (m, 2H),
7.52 (m, 4H), 3.23 (m, 4H), 2.80 (m, 2H).
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-phenyl-acetamide [0354] 1H NMR (300 MHz, DMSO-d6) δ 8.86 (s, IH), 8.12 (s, IH), 7.62-7.18 (m, 7H),
6.98 (m, IH), 3.00 (m, 2H). 2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-cyclopropyl- acetamide
[0355] 1H NMR (300 MHz, DMSO-d6) δ 8.46 (br.s, IH), 8.12 (s, IH), 8.00 (m, 2H),
3.21 (m, 2H), 2.54 (m, IH), 0.57 (m, 2H), 0.38 (m, 2H).
2- [2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-(2-oxo-2 -phenyl- ethyl)-acetamide
[0356] 1H NMR (300 MHz, DMSO-d6) δ 8.26 (br.s, IH), 7.96 (m, 2H), 7.86 (m, IH),
7.64-7.51 (m, 5H), 4.60 (s, 2H), 3.39 (m, 2H).
N-Butyl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-acetamide [0357] 1H NMR (300 MHz, DMSO-d6) d 8.57 (s, IH), 8.02 (s, IH), 7.91 (s, IH), 3.25 (s,
2H), 3.05-2.97(m, 2H), 1.36-1.22(m, 4H), 0.84 (t, J = 6.9 Hz, 3H)
5-Hydroxy-6-[6-oxo-5-(2-oxo-2-pyrrolidin-l-yl-ethyl)-l,6-dihydro-pyrimidin-2-yl]- nicotinonitrile
[0358] 1H NMR (300 MHz, DMSO-d6+TFA) δ 8.62 (s, IH), 8.08 (s, IH), 7.91 (s, IH),
3.52 (t, J = 6.6 Hz, 2H), 3.42 (s, 2H), 3.27 (t, J = 6.9 Hz, 2H), 1.92-1.84 (m, 2H), 1.82-1.72 (m,
2H)
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-((R)-2-hydroxy- 1 -phenyl-ethyl)- acetamide
[0359] 1H NMR (300 MHz, DMSO) 12.10 (br.s, IH), 8.60 (s, IH), 8.42 (br.s, IH), 8.06 (s, IH),
7.80 (s, IH), 129-1Λ1 (m, 5H), 4.11 (d, J=5.8Hz, 2H), 3.98 (m, IH), 2.98 (m, 2H).
[0360] 2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -acetic acid benzyl ester
1H NMR (300 MHz, CDC13) d 8.38 (d, J = 1.8 Hz, IH), 7.61 (d, J = 1.8 Hz, IH), 7.43 (s, IH), 7.38-7.35 (m, 5H), 5.20 (s, 2H), 3.96 (s, 2H)
[2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -acetic acid 2-pyridin-2-yl-ethyl ester [0361] 1H NMR (300 MHz, CDC13) d 12.00 (br s, IH), 8.60 (d, J = 4.5 Hz, IH), 8.37(s, IH), 8.07 (t, J = 7.8 Hz, IH), 7.99 (s, IH), 7.67-7.64 (m, IH), 7.59-7.54 (m, 2H), 7.49 (s, IH), 5.20 (s, 2H), 3.33-3.26 (m, 2H), 2.71 (t, J = 7.5 Hz, 2H)
5-Hydroxy-6-{5-[2-(2-methyl-2,3-dihydro-indol-l-yl)-2-oxo-ethyl]-6-oxo-l,6-dihydro- pyrimidin-2-yl} -nicotinonitrile
[0362] 1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, IH), 8.16 (br.s, IH), 8.00 (m, IH), 7.84 (s, IH), 7.28-7.04 (m, 4H), 4.78 (m, 2H), 3.58 (m, 4H), 2.69 (m, IH), 1.28 (s, 3H).
5-Hydroxy-6-[6-oxo-5-(2-oxo-2-piperidin-l-yl-ethyl)-l,6-dihydro-pyrimidin-2-yl]- nicotinonitrile
[0363] 1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, IH), 7.95 (s, IH), 7.84 (s, IH), 3.62 (m, 2H),
3.58 (m, 4H), 1.62 (m, 6H).
5 -Hydroxy-6- [4-(2-oxo-2-pyrrolidin- 1 -yl-ethyl)-thiazol-2-yl] -nicotinonitrile [0364] 1H NMR (300MHz, DMSO-d6): d 12.189 (s, IH), 8.580 (d, J=I.8Hz, IH), 8.048 (d, J=I.5Hz, IH), 77.777 (s, IH), 3.932 (s, 2H), 3.523 (t, 2H), 3.296 (t, 2H), 1.870 (m, 2H), 1.779 (m, 2H).
5 -Hydroxy-6- [4-(2-oxo-2-piperidin-l-yl-ethyl)-thiazol-2-yl] -nicotinonitrile
[0365] 1H NMR (300MHz, DMSO-d6): d 8.57 (d, J=I.5HZ, IH), 8.05 (d, J=I.5Hz, IH), 7.77
(s, IH), 3.99 (s, 2H), 3.46 (m, 4H), 1.58-1.38 (m, 6H)
N-Benzyl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-ethyl-acetamide [0366] 1H NMR (300MHz, DMSO-d6): d 12.24 (br.s, IH), 8.58 (d, J=I.5HZ, IH), 8.06 (d, J=1.5Hz, IH), 7.79 (d, J=22.2Hz, IH), 7.34-7.18 (m, 5H), 4.61 (d, J=45.0Hz, 2H), 4.05 (d, J=33.0Hz, 2H), 3.30 (s, 2H), 1.15-1.00 (m, 3H)
N-Benzyl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-dimethylamino-ethyl)- acetamide [0367] 1H NMR (300MHz, DMSO-d6): d 8.58 (s, IH), 8.09 (d, J=22.5HZ, IH), 7.80 (d, J=15Hz, IH), 7.34-7.20 (m, 5H), 4.62 (d, J=47.7Hz, 2H), 4.05 (d, J=35.1Hz, 2H), 3.45 (q, 2H), 2.78 (d, J=48.0Hz, 2H), 2.325 (s, 3H), 2.220(s, 3H)
6-{4-[2-(6,7-Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-2-oxo-ethyl]-thiazol-2-yl}-5- hydroxy-nicotinonitrile
[0368] 1H NMR (300MHz, DMSO-d6): d 8.57 (s, IH), 8.03 (s, IH), 7.78 (d, J=5.4HZ, IH),
6.74 (d, J=15.3Hz, IH), 6.68 (d, J=5.4Hz, 2H), 4.60 (d, J=30.6Hz, 2H), 4.11 (s, 2H), 3.74 (m,
2H), 3.69 (m, 6H), 2.71 (m, 2H)
5-Hydroxy-6-(4-phenylmethanesulfonylmethyl-thiazol-2-yl)-nicotinonitrile
[0369] 1H NMR (300 MHz, CDC13) δ 11.58 (s, IH), 8.40 (s, IH), 7.66 (s, IH), 7.40-7.17 (m,
5H), 4.47 (s, 2H), 2.18 (s, 2H)
6-{4-[2-(2,6-Dimethyl-morpholin-4-yl)-2-oxo-ethyl]-thiazol-2-yl}-5-hydroxy-nicotinonitrile [0370] 1H NMR (300MHz, DMSO-d6): d 12.09 (br.s, IH), 8.56 (s, IH), 8.05 (s, IH), 7.78 (s, IH), 4.26-3.94 (m, 4H), 3.43 (m, 2H), 2.72 (t, IH), 2.25 (t, IH).
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N,N-diisopropyl-acetamide
[0371] 1H NMR (300MHz, DMSO-d6): d 12.06 (br.s, IH), 8.57 (d, J=I.5Hz, IH), 8.04 (d,
J=I.5Hz, IH), 7.75 (s, IH), 4.08 (m, IH), 3.93 (s, 2H), 3.46 (m, IH), 1.28 (m, 6H), 1.05 (m, 6H).
6-(4-Benzenesulfonylmethyl-thiazol-2-yl)-5-hydroxy-nicotinonitrile
[0372] 1H NMR (300MHz, CDC13):δ 11.09 (s, IH), 8.3 (s, IH), 7.77-7.48 (7H), 4.61 (s, 2H)
5 -Hydroxy-6- [4-(2-phenyl-ethanesulfonylmethyl)-thiazol-2-yl] -nicotinonitrile
[0373] 1H NMR (300 MHz, CDC13) d 11.55 (s, IH), 8.40 (d, J = 1.8 Hz, IH), 7.65 (d, J = 1.8
Hz, IH), 7.62 (s, IH), 7.36-7.21 (m, 5H), 4.36 (s, 2H), 3.29-3.18 (m, 4H)
{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo- 1 ,6-dihydro-pyrimidin-5-yl]-acetylamino} -acetic acid [0374] 1H NMR (300 MHz, DMSO-d6) δ 9.43 (s, IH), 8.52 (s, IH), 8.07 (s, IH), 7.84 (d, J= 1.5HZ, IH), 3.91 (s, 2H), 3.51 (t, 2H),
5-Hydroxy-6-{4-[2-oxo-2-(4-phenyl-piperidin-l-yl)-ethyl]-thiazol-2-yl}-nicotinonitrile [0375] 1H NMR (300MHz, CDC13):δ 12.08 (br s, IH), 8.39 (s, IH), 7.61 (s, IH), 7.45 (s, IH), 7.25-7.17 (m, 5H), 4.85-4.80 (m, IH), 4.13-4.09 (m, IH), 3.30-3.21 (m, IH), 2.83-2.68 (m, 2H), 1.96-1.91 (m, 2H), 1.75-1.56 (m, 2H)
5-Hydroxy-6-[6-oxo-5-(2-phenyl-ethanesulfonylmethyl)-l,6-dihydro-pyrimidin-2-yl]- nicotinonitrile
[0376] 1H NMR (300 MHz, DMSO-d6+TFA) δ 8.65 (d, J = 1.8 Hz, IH), 8.13 (s, IH), 8.11 (d,
J = 1.8 Hz, IH), 7.30-7.18 (m, 5H), 4.40 (s, 2H), 3.42-3.36 (m, 2H), 3.07-3.02 (m, 2H)
6-{4-[(Benzyl-ethyl-carbamoyl)-methyl]-thiazol-2-yl}-5-hydroxy-nicotinic acid
[0377] 1H NMR (300MHz, DMSO-d6): d 8.67 (s, IH), 7.89 (s, IH), 7.52 (d, J=30.9Hz, IH),
7.33-7.17 (m, 5H), 4.71 (d, J=32.1Hz, 2H), 4.07 (d, J=27.6Hz, 2H), 3.48 (m, 2H), 1.16 (m, 3H).
6-{4-[2-(3-Diethylamino-pyrrolidin-l-yl)-2-oxo-ethyl]-thiazol-2-yl}-5-hydroxy-nicotinonitrile [0378] 1H NMR (300MHz, DMSO-d6): d 8.58 (d, J=I.2Hz, IH), 8.12 (s, IH), 8.05 (d, J=2.1Hz, IH), 7.79 (d, J=1.8Hz, IH), 3.96 (d, J=8.7Hz, 2H), 3.82-3.04 (m, 5H), 2.70 (m, 4H), 2.26-1.64 (m, 2H), 0.99 (m, 6H).
5-Hydroxy-6- {6-oxo-5-[2-oxo-2-(4-phenyl-piperidin-l -yl)-ethyl]- 1 ,6-dihydro-pyrimidin-2-yl} - nicotinonitrile
[0379] 1H NMR (300 MHz, CDC13) δ 8.58 (s, IH), 7.95 (s, IH), 7.77 (s, IH), 7.20-7.15 (m,
5H), 4.73-4.69 (m, IH), 4.17-4.12 (m, IH), 3.70-3.53 (m, 4H), 3.25-2.17 (m, IH), 1.99-1.86
(m, 2H), 1.74-1.55 (m, 2H)
6-(4-Benzenesulfonylmethyl-thiazol-2-yl)-5-hydroxy-nicotinic acid
[0380] 1H NMR (300 MHz, CDC13) δ 8.68 (s, IH), 7.86 (s, IH), 7.69 (d, J = 8.1 Hz, 2H),
7.61-7.57 (m, IH), 7.48-7.43 (m, 3H), 4.59 (s, 2H) 6-{4-[2-(5-Bromo-2-oxo-2H-pyridin-l-yl)-2-oxo-ethyl]-thiazol-2-yl}-5-hydroxy-nicotinonitrile [0381] 1H NMR (300MHz, CDC13): d 8.47 (d, J=2.4Hz,lH), 8.40 (d, J=1.8Hz, IH), 7.91 (d, J=8.4Hz, IH), 7.63 (s, IH), 7.56 (s, IH), 7.05 (d, J=8.4Hz, IH), 4.21 (s, 2H).
5 -Hydroxy-6- {4- [2-(4-methyl-piperazin- 1 -yl)-2-oxo-ethyl] -thiazol-2-yl} -nicotinonitrile
[0382] 1H NMR (300MHz, DMSO-d6): d 8.59 (d, J=1.5Hz,lH), 8.06 (d, J=I.5Hz, IH), 7.78
(s, IH), 4.03 (s, 2H), 3.57 (m, 2H), 3.48 (m, 2H), 2.37 (m, 4H), 2.23 (s, 3H).
6-[4-(2-[l,4']Bipiperidinyl-r-yl-2-oxo-ethyl)-thiazol-2-yl]-5-hydroxy-nicotinonitrile
[0383] 1H NMR (300 MHz, CDC13) δ 8.41-8.39 (m, IH), 7.60 (d, J = 1.5 Hz, IH), 7.42 (s,
IH), 4.85-4.81 (m, IH), 4.13-4.09 (m, IH), 3.97 (s, 2H), 3.37-3.16 (m, 2H), 3.10-2.88 (m, 4H),
2.68-2.61 (m, IH), 2.22-2.18 (m, IH), 2.09-2.03 (m, IH), 1.92-1.88 (m, 4H), 1.69-1.50 (m,
4H)
6-{4-[2-(l,3-Dihydro-isoindol-2-yl) -2-oxo-ethyl]-thiazol-2-yl}-5-hydroxy-nicotinonitrile [0384] 1H NMR (300 MHz, CDC13) δ 12.09 (s, IH), 8.38 (s, IH), 7.60 (s, IH), 7.55 (s, IH), 7.33-7.30 (m, 4H), 4.96 (s, 2H), 4.87 (s, 2H), 4.03 (s, 2H)
6-{4-[2-(3,4-Dihydro-lH-isoquinolin-2-yl)-2-oxo-ethyl]-thiazol-2-yl}-5-hydroxy-nicotinonitrile [0385] 1H NMR (300 MHz, CDC13) δ 11.68 (br s, IH), 8.37-8.36 (m, IH), 7.59-7.58 (m, IH), 7.44 (d, J = 12.3 Hz, IH), 7.22-7.16 (m, 4H), 4.78 (s, IH), 4.74 (s, IH), 4.06 (d, J = 3.9 Hz, 2H), 3.88 (t, J = 5.7 Hz, IH), 3.82 (t, J = 5.7 Hz, IH), 2.90 (t, J = 5.7 Hz, 2H)
5 -Hydroxy-6- [4-(2-indol-l-yl-2-oxo-ethyl)-thiazol-2-yl] -nicotinonitrile
[0386] 1H NMR (300 MHz, CDC13) d 11.82 (br s, IH), 8.46 (d, J = 6.6 Hz, IH), 8.39 (s, IH),
7.61-7.55 (m, 4H), 7.40-7.27 (m, 2H), 6.73 (d, J = 3.6 Hz, IH), 4.53 (s, 2H)
6-{5-[2-(l,3-Dihydro-isoindol-2-yl)-2-oxo-ethyl]-6-oxo-l,6-dihydro-pyrimidin-2-yl}-5-hydroxy- nicotinonitrile [0387] 1H NMR (300 MHz, DMSO-d6+TFA) δ 8.63 (s, IH), 8.08 (s, IH), 7.97 (s, IH), 7.37- 7.27 (m, 4H), 4.98 (s, 2H), 4.64 (s, 2H), 3.57 (s, 2H)
5-Hydroxy-6-(6-oxo-5-phenylmethanesulfonylmethyl-l,6-dihydro-pyrimidin-2-yl)- nicotinonitrile
[0388] 1H NMR (300 MHz, DMSO-d6+TFA) δ 8.66 (s, IH), 8.11 (s, 2H), 7.43-7.35 (m, 5H),
4.53 (s, 2H), 4.37 (s, 2H)
6-{5-[2-(3,4-Dihydro-lH-isoquinolin-2-yl)-2-oxo-ethyl]-6-oxo-l,6-dihydro-pyrimidin-2-yl}-5- hydroxy-nicotinonitrile
[0389] 1H NMR (300 MHz, DMSO-d6+TFA) δ 8.62 (s, IH), 8.07 (s, IH), 7.91 (s, IH), 7.17(s,
4H), 4.77 (s, IH), 4.60 (s, IH), 3.78 (t, J = 5.7 Hz, IH), 3.68-3.60 (m, 3H), 2.90 (t, J = 5.4 Hz,
IH), 2.77 (t, J = 5.7 Hz, IH)
5-Hydroxy-6- {4-[2-oxo-2-((R)-2-trifluoromethyl-pyrrolidin- 1 -yl)-ethyl] -thiazol-2-yl} - nicotinonitrile
[0390] 1H NMR (300 MHz, CDC13) δ 12.00 (s, IH), 8.38 (s, IH), 7.60 (s, IH), 7.49 (s, IH),
4.90-4.85 (m, IH), 4.01-3.98 (m, 2H), 3.72-3.68 (m, 2H), 2.27-2.06 (m, 4H)
6- {4-[2-(5-Bromo- 1 ,3-dihydro-isoindol-2-yl)-2-oxo-ethyl]-thiazol-2-yl} -5-hydroxy- nicotinonitrile
[0391] 1H NMR (300 MHz, DMSO-d6) d 12.05 (br s, IH), 8.56 (s, IH), 8.02 (s, IH), 7.82 (s,
IH), 7.59 (d, J = 3.6 Hz, IH), 7.49 (d, J = 8.1 Hz, IH), 7.32 (dd, J = 8.1 and 3.6 Hz, IH), 4.94 (d,
J = 12.3 Hz, 2H), 4.65 (d, J = 12.3 Hz, 2H), 4.07 (s, 2H)
5-Hydroxy-6-{4-[2-((S)-2-hydroxymethyl-pyrrolidin-l-yl)-2-oxo-ethyl]-thiazol-2-yl}- nicotinonitrile
[0392] 1H NMR (300 MHz, DMSO-d6) d 12.02 (br s, IH), 8.38 (t, J = 1.8 Hz, IH), 7.60 (d, J =
1.8 Hz, IH), 7.47 (s, IH), 4.51 (br s, IH), 4.30-4.24 (m, IH), 3.94 (s, 2H), 3.73-3.56 (m, 4H),
2.13-1.89 (m, 3H), 1.73-1.64 (m, IH) (S)-I -{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetyl}-pyrrolidine-2-carboxylic acid
[0393] 1H NMR (300 MHz, CDC13) d 8.36 (d, J = 1.5 Hz, IH), 7.60 (d, J = 1.5 Hz, IH), 7.50
(s, IH), 4.70-4.63 (m, IH), 3.99 (s, 2H), 3.74-3.61 (m, 2H), 2.17-2.04 (m, 4H)
6-{4-[2-(5-Amino-3,4-dihydro-lH-isoquinolin-2-yl)-2-oxo-ethyl]-thiazol-2-yl}-5-hydroxy- nicotinonitrile
[0394] 1H NMR (300 MHz, DMSO-d6, TFA) d 8.59 (s, IH), 8.04 (s, IH), 7.82-7.78 (m, IH),
7.26-7.18 (m, IH), 7.16-7.04 (m, 2H), 4.79 (s, IH), 4.66(s, IH), 4.14 (s, 2H), 3.84 (t, J = 5.7 Hz,
2H), 3.73 (t, J = 5.7 Hz, 2H), 2.78-2.66 (m, 2H)
(S)-2- {2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetyl} -1 ,2,3,4-tetrahydro- isoquinoline-3-carboxylic acid tert-butylamide
[0395] 1H NMR (300 MHz, DMSO-d6) d 12.08(br s, IH), 8.58 (d, J = 1.5 Hz, IH), 8.05 (s, IH), 7.83 (d, J = 31.2 Hz, IH), 7.41-7.15 (m, 4H), 4.85-4.4.65(m, 2H), 4.20-4.19 (m, IH), 4.05- 3.96 (m, IH), 3.22-3.01 (m, 3H), 1.11 (s, 9H)
6- [4-(2- Azetidin- 1 -yl-2-oxo-ethyl)-thiazol-2-yl] -5 -hydroxy-nicotinonitrile [0396] 1H NMR (300 MHz, CDC13) d 12.13 (s, IH), 8.38 (d, J = 1.8 Hz, IH), 7.60 (d, J = 1.8 Hz, IH), 7.50 (s, IH), 4.28 (t, J = 7.8 Hz, 2H), 4.09 (t, J = 7.8 Hz, 2H), 3.69 (s, 2H), 2.38-2.28 (m, 2H)
6- {4-[2-(4-Fluoro-l ,3-dihydro-isoindol-2-yl)-2-oxo-ethyl]-thiazol-2-yl} -5-hydroxy- nicotinonitrile
[0397] 1H NMR (300 MHz, CDC13) d 12.02 (br s, IH), 8.38 (d, J = 1.8 Hz, IH), 7.60 (d, J =
1.8 Hz, IH), 7.55 (d, J = 4.2 Hz, IH), 7.34-7.27 (m, IH), 7.12-6.98 (m, 2H), 4.99 (s, 2H), 4.89 (s,
2H), 4.03 (d, J = 5.1 Hz, 2H)
6- {4-[2-(5-Fluoro-l ,3-dihydro-isoindol-2-yl)-2-oxo-ethyl]-thiazol-2-yl} -5-hydroxy- nicotinonitrile
- I l l - [0398] 1H NMR (300 MHz, CDC13) d 12.05 (br s, IH), 8.38 (d, J = 1.8 Hz, IH), 7.60 (d, J = 1.8 Hz, IH), 7.55 (s, IH), 7.29-7.21 (m, IH), 7.06-6.97 (m, 2H), 4.93 (d, J = 6.9 Hz, 2H), 4.83 (d, J = 6.9 Hz, 2H), 4.02 (s, 2H)
6-{4-[2-(l,3-Dihydro-isoindol-2-yl)-2-oxo-ethyl]-5-methyl-thiazol-2-yl}-5-hydroxy- nicotinonitrile
[0399] 1H NMR (300 MHz, CDC13) δ 8.35 (d, J = 1.5 Hz, IH), 7.54 (d, J = 1.5 Hz, IH),
7.33-7.32 (m, 4H), 4.99 (s, 2H), 4.85 (s, 2H), 3.92 (s, 2H), 2.58 (s, 3H)
6-{5-[2-(4-Fluoro-l,3-dihydro-isoindol-2-yl)-2-oxo-ethyl]-6-oxo-l,6-dihydro-pyrimidin-2-yl}-5- hydroxy-nicotinonitrile
[0400] 1H NMR (300 MHz, DMSO-d6+TFA) δ 8.64 (s, IH), 8.09 (s, IH), 7.98 (s, IH), 7.38-
7.34 (m, IH), 7.22-7.10 (m, 2H), 5.05 (d, J = 6.0Hz, 2H), 4.69 (s, 2H), 3.67 (s, 2H)
[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-5-phenyl-thiazol-4-yl]-acetic acid
[0401] 1H NMR (300 MHz, DMSO-d6) d 8.60 (s, IH), 8.07 (s, IH), 7.61-7.48 (m, 5H), 3.89 (s,
2H)
5 -Hydroxy-6- [4-(2-oxo-2-pyrrolidin- 1 -yl-ethyl)-5 -phenyl-thiazol-2-yl] -nicotinonitrile [0402] 1H NMR (300 MHz, DMSO-d6) d 11.98 (s, IH), 8.60 (d, J = 1.5 Hz, IH), 8.07 (d, J = 1.5 Hz, IH), 7.64-7.61 (m, 2H), 7.54-7.49 (m, 3H), 3.91 (s, 2H), 3.50 (t, J = 6.6 Hz, 2H), 3.31 (t, J = 6.6 Hz, 2H), 1.90-1.76 (m, 4H)
6-{4-[2-(l,3-Dihydro-isoindol-2-yl) -2-oxo-ethyl]-5-phenyl-thiazol-2-yl}-5-hydroxy- nicotinonitrile
[0403] 1H NMR (300 MHz, DMSO-d6) d 11.95 (br s, IH), 8.58 (d, J = 1.5 Hz, IH), 8.02 (d, J
= 1.5 Hz, IH), 7.66-7.63 (m, 2H), 7.55-7.46 (m, 3H), 7.38-7.27 (m, 4H), 4.95 (s, 2H), 4.70 (s,
2H), 4.08 (s, 2H)
5 -Hydroxy-4-methyl-6- [4-(2-oxo-2-pyrroli din- 1 -yl-ethyl)-thiazol-2-yl] -nicotinonitrile [0404] 1H NMR (300 MHz, DMSO-d6) d 12.50 (s, IH), 8.51 (s, IH), 7.76 (s, IH), 3.93 (s, 2H), 3.52 (t, J = 6.6 Hz, IH), 3.32-3.29 (m, 2H), 2.44 (s, 3H), 1.92-1.76 (m, 4H)
6-{4-[2-(l,3-Dihydro-isoindol-2-yl)-2-oxo-ethyl]-thiazol-2-yl}-5-hydroxy-4-methyl- nicotinonitrile
[0405] 1H NMR (300 MHz, DMSO-d6) d 12.50 (s, IH), 8.52 (s, IH), 7.83 (s, IH), 7.38-7.28
(m, 4H), 4.96 (s, 2H), 4.68 (s, 2H), 4.09 (s, 2H), 2.43 (s, 3H)
l-{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetyl}-aziridine-2-carboxylic acid methyl ester
[0406] 1H NMR (300 MHz, CDCl3) δ 11.99 (br s, IH), 8.39 (d, J = 1.5 Hz, IH), 7.61 (d, J = 1.5 Hz, IH), 7.48 (s, IH), 4.02-4.00 (m, 2H), 3.79 (s, 3H), 3.23-3.20 (m, IH), 2.66-2.65 (m, IH), 2.59-2.57 (m, IH)
5-Hydroxy-6-{4-[2-oxo-2-((S)-2-trifluoromethyl-pyrrolidin-l-yl)-ethyl] -thiazol-2-yl}- nicotinonitrile
[0407] 1H NMR (300 MHz, CDC13) d 8.38 (d, J = 1.5 Hz, IH), 7.60 (d, J = 1.5 Hz, IH), 4.92-
4.84 (m, IH), 3.98 (s, 3H), 3.72-3.68 (m, 2H), 2.22-2.05 (m, 4H)
6- {5-[2-(5-Bromo- 1 ,3-dihydro-isoindol-2-yl)-2-oxo-ethyl]-6-oxo-l ,6-dihydro-pyrimidin-2-yl} - 5 -hydroxy-nicotinonitrile
[0408] 1H NMR (300 MHz, CDC13) δ 8.41 (s, IH), 7.98 (s, IH), 7.67 (s, IH), 7.56-7.38 (m, 3H), 5.15-4.93 (m, 2H), 4.82-4.71 (m, 2H), 3.62 (s, 2H)
5 -Hydroxy-6- [5 -methyl-4-(2-oxo-2-pyrrolidin- 1 -yl-ethyl)-thiazol-2-yl] -nicotinonitrile
[0409] 1H NMR (300 MHz, CDC13) d 8.34 (d, J = 1.8 Hz, IH), 7.55 (d, J = 1.8 Hz, IH), 3.79
(s, 2H), 3.62-3.48 (m, 4H), 2.55 (s, 3H), 2.06-1.86 (m, 4H)
6- [4-(2- Azetidin- 1 -yl-2-oxo-ethyl)-5 -methyl-thiazol-2-yl] -5 -hydroxy-nicotinonitrile
[0410] 1H NMR (300 MHz, CDC13) d 8.35 (d, J = 1.5 Hz, IH), 7.56 (d, J = 1.5 Hz, IH), 4.31-
4.02 (m, 4H), 3.60 (s, 2H), 2.55 (s, 3H), 2.37-2.27 (m, 2H) 6- [4-(2- Azetidin- 1 -yl-2-oxo-ethyl)-5 -phenyl -thiazol-2-yl] -5 -hydroxy-nicotinonitrile
[0411] 1H NMR (300 MHz, DMSO-d6) d 12.00 (br s, IH), 8.58 (s, IH), 8.05 (s, IH), 7.66-7.45
(m, 5H), 4.17 (t, J = 7.5 Hz, 2H), 3.88 (t, J = 7.5 Hz, 2H), 3.69 (s, 2H), 2.25-2.14 (m, 2H)
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-5-methyl-thiazol-4-yl]-N-(2-pyridin-2-yl-ethyl)- acetamide
[0412] 1H NMR (300 MHz, CDC13) δ 12.01 (br s, IH), 8.59-8.58 (m, IH), 8.34-8.27 (m, 2H),
7.93-7.53 (m, 3H), 3.81-3.75 (m, 4H), 3.60-3.45 (m, 2H), 2.50 (s, 3H)
5-Hydroxy-6-[4-(3-phenyl-[l,2,4]oxadiazol-5-ylmethyl)-thiazol-2-yl]-nicotinonitrile
[0413] 1H NMR (300 MHz, CDCl3) δ 8.39 (d, J = 1.8 Hz, IH), 8.10-8.07 (m, 2H), 7.63 (d, J =
1.8 Hz, IH), 7.56-7.48 (m, 4H), 4.58 (s, 2H)
2-[2-(5-Cyano-3-hydroxy-4-methyl-pyridin-2-yl)-5-methyl-thiazol-4-yl]- N-(2-pyridin-2-yl- ethyl)-acetamide
[0414] 1H NMR (300 MHz, CDCl3) δ 12.15 (br s, IH), 8.43 (s, IH), 8.29 (s, IH), 7.99-7.83
(m, IH), 7.53-7.24 (m, 2H), 3.79-3.72 (m, 4H), 3.32-3.17 (m, 2H), 2.51 (s, 3H), 2.49 (s, 3H)
2-[2-(5-Cyano-3-hydroxy-4-methyl-pyridin-2-yl)-5-phenyl-thiazol-4-yl]- N-(2-pyridin-2-yl- ethyl)-acetamide
[0415] 1H NMR (300 MHz, CDCl3) δ 12.13 (br s, IH), 8.45 (s, IH), 8.32 (s, IH), 8.05-7.92
(m, IH), 7.56-7.40 (m, 7H), 3.83-3.76 (m, 4H), 3.35-3.20 (m, 2H), 2.54 (s, 3H)
2-[2-(5-Cyano-3-hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl]-N-(2-pyridin-2-yl-ethyl)- acetamide
[0416] 1H NMR (300MHz, CDCl3):δ 8.58-8.56 (m, IH), 8.33-8.28 (m, 2H), 7.89 (br s, IH),
7.80 (d, J = 8.1 Hz, IH), 7.71 (t, J = 6.9 Hz, IH), 7.47 (s, IH), 3.84-3.80 (m, 4H), 3.53-3.49 (m,
2H), 2.53 (s, 3H) 2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-5-phenyl-thiazol-4-yl]-N-(2-pyridin-2-yl-ethyl)- acetamide
[0417] 1H NMR (300MHz, CDCl3):δ 11.59 (br s, IH), 8.61-8.60 (m, IH), 8.37-8.32 (m, 2H),
7.64-7.45 (m, 8H), 3.85-3.78 (m, 4H), 3.65-3.47 (m, 2H)
2-[2-(5-Cyano-3-hydroxy-4-methyl-pyridin-2-yl)-5-methyl-thiazol-4-yl]- N-(3-imidazol- 1 -yl- propyl)-acetamide
[0418] 1H NMR (300MHz, CDCl3+CD3OD):δ 9.17 (br s, IH), 8.25 (s, IH), 7.78 (br s, IH),
7.25 (br s, IH), 4.28-4.24 (m, 2H), 3.26-3.25 (m, 2H), 2.50 (s, 3H), 2.45 (s, 3H), 2.13-2.09 (m,
2H), 2.03-1.99 (m, 2H)
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl] -N-methyl-N-(2-pyridin-2-yl- ethyl)-acetamide
[0419] 1H NMR (300MHz, CDCl3):δ 12.25 (br s, IH), 8.80-8.59 (m, IH), 8.31-8.30 (m, IH),
7.66-7.63 (m, IH), 7.35-7.20 (m, 3H), 3.92-3.79 (m, 4H), 3.09-3.01 (m, 5H), 2.53 (s, 3H)
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl]-N-(3-morpholin-4-yl-propyl)- acetamide
[0420] 1H NMR (300MHz, CDCl3):δ 12.38 (br s, IH), 8.37 (s, IH), 7.69 (br s, IH), 7.45 (s,
IH), 4.32-4.21 (m, 2H), 4.04-3.98 (m, 2H), 3.87 (s, 2H), 3.54-3.37 (m, 4H), 3.15-3.01 (m, 2H),
2.98-2.80 (m, IH), 2.53 (s, 3H), 2.27-2.08 (m, 2H)
[2-(5-Cyano-3-hydroxy-pyridin-2-yl) -thiazol-4-yl]-carbamic acid butyl ester
[0421] 1H NMR (300MHz, CDC13):δ 8.36 (s, IH), 7.60 (s, IH), 6.35 (s, IH), 4.18 (t, J = 6.3
Hz, 2H), 1.86-1.79 (m, 2H), 1.57-1.50 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H)
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-cyclopropylmethyl-acetamide
[0422] 1H NMR (300MHz, DMSO-d6): d 12.05 (s, IH), 8.59 (s, IH), 8.24 (br.s, IH), 8.07 (s,
IH), 7.76 (s, IH), 3.72 (s, 2H), 2.95 (m, 2H), 0.96 (m, IH), 0.40 (m, 2H), 0.13 (m, 2H).
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-cyclopropyl-acetamide [0423] 1H NMR (300MHz, DMSO-d6): d 12.00 (br.s, IH), 8.57 (s, IH), 8.27 (br.s, IH), 8.05 (s, IH), 7.78 (s, IH), 3.65 (s, 2H), 3.06 (m, 2H), 0.83 (m, IH), 0.62 (m, 2H), .0.41 (m, 2H).
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl] -N-(2-diethylamino-ethyl)- acetamide
[0424] 1H NMR (300 MHz, CDCl3) δ 8.56 (br s, IH), 8.31 (s, IH), 7.52 (s, IH), 5.90 (br s,
IH), 3.91 (s, 2H), 3.79-3.62 (m, 2H), 3.16-3.14 (m, 6H), 2.53 (s, 3H), 1.43-1.40 (m, 6H)
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-5 -methyl-thiazol-4-yl] - N-(2-diethylamino- ethyl)-acetamide
[0425] 1H NMR (300 MHz, CDCl3) δ 8.29 (s, IH), 3.73 (s, 2H), 3.42-3.41 (m, 2H), 2.72-2.59
(m, 6H), 2.54 (s, 3H), 2.51 (s, 3H), 1.05-1.01 (m, 6H)
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl] -N-cyclopropylmethyl-acetamide [0426] 1H NMR (300 MHz, CDCl3) δ 12.16 (br s, IH), 8.33 (s, IH), 7.43 (s, IH), 5.82 (br s, IH), 3.80 (s, 2H), 3.18-3.14 (m, 2H), 2.55 (s, 3H), 0.99-0.96 (m, IH), 0.55-0.49 (m, 2H), 0.24-0.19 (m, 2H)
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl]-N-cyclopropyl-acetamide [0427] 1H NMR (300 MHz, CDCl3) δ 12.17 (br s, IH), 8.29 (s, IH), 7.40 (s, IH), 6.43 (br s, IH), 3.71 (s, 2H), 2.74-2.68 (m, IH), 2.51 (s, 3H), 0.78-0.72 (m, 2H), 0.52-0.47 (m, 2H)
2-[2-(5-Cyano-3-hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl]-N-(2,2,2-trifluoro-ethyl)- acetamide
[0428] 1H NMR (300 MHz, DMSO-d6) δ 12.37 (br s, IH), 8.88 (s, IH), 8.53 (s, IH), 7.79 (s,
IH), 4.01-3.84 (m, 4H)
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl]-N-ethyl-acetamide
[0429] 1H NMR (300 MHz, CDCl3) δ 8.33 (s, IH), 7.42 (s, IH), 5.66 (br s, IH), 3.78 (s, 2H),
3.36-3.32 (m, 2H), 2.55 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H) 2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-5 -methyl-thiazol-4-yl] - N-ethyl-acetamide [0430] 1H NMR (300 MHz, CDCl3) δ 8.32 (s, IH), 5.60 (br s, IH), 3.70 (s, 2H), 3.35-3.33 (m, 2H), 2.54 (s, 6H), 1.27-1.16 (m, 3H)
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-5 -methyl-thiazol-4-yl]- N-(2-pyrrolidin- 1 -yl- ethyl)-acetamide
[0431] 1H NMR (300 MHz, CDCl3) δ 8.29 (s, IH), 3.73 (s, 2H), 3.54-3.52 (m, 2H), 2.93-2.90
(m, 6H), 2.54 (s, 3H), 2.51 (s, 3H), 1.92-1.90 (m, 4H)
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl] -acetamide
[0432] 1H NMR (300MHz, DMSO-d6): d 12.51 (br.s, IH), 8.51 (s, IH), 7.75 (s, IH), 7.59
(br.s, IH), 7.05 (br.s, IH), 3.68 (s, 2H), 2.44 (s, 3H).
2-(5-Phenylmethanesulfonylmethyl-[l,2,4]oxadiazol-3-yl)-pyridin-3-ol
[0433] 1H NMR (SOO MHZ5 CDCI3) S-S I (d, J = 4.2 HZ, IH), 8.24 (d, J = 8.7 HZ, IH), 8.11-
8.06 (m, IH), 7.54-7.51 (m, 2H), 7.45-7.38 (m, 3H), 5.08 (s, 2H), 4.76 (s, 2H)
6-(5-Benzylsulfanylmethyl-[ 1 ,2,4]oxadiazol-3-yl)-5-hydroxy-nicotinic acid
[0434] 1H NMR (300 MHz, CD3OD) 8.34 (br s, IH), 8.01 (br s, IH), 7.41-7.37 (m, 2H), 7.32-
7.21 (m, 3H), 3.94 (s, 2H), 3.92 (s, 2H)
5-Hydroxy-6-(5-phenylmethanesulfonylmethyl-[ 1 ,2,4]oxadiazol-3-yl)-nicotinic acid
[0435] 1H NMR (300 MHz, DMSO-d6) 8.29 (s, IH), 7.86 (s, IH), 7.47-7.39 (m, 5H), 5.20 (s,
2H), 4.79 (s, 2H)
6-(5-Ethylsulfanylmethyl-[l,2,4]oxadiazol-3-yl)-5-hydroxy-nicotinic acid
[0436] 1H NMR (300 MHz, DMSO-d6) 8.21 (s, IH), 7.80 (s, IH), 4.15 (s, 2H), 2.66 (q, J = 7.2
Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H)
6-(5-Ethanesulfonylmethyl-[ 1 ,2,4]oxadiazol-3-yl)-5-hydroxy-nicotinic acid [0437] 1H NMR (300 MHz, DMSO-d6) 8.29 (s, IH), 7.86 (s, IH), 5.28 (s, 2H), 3.39 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H)
3-(3-Hydroxy-5-methyl-pyridin-2-yl) -[l,2,4]oxadiazole-5-carboxylic acid dimethylamide [0438] 1H NMR (300 MHz, CDCl3) 8.89 (s, IH), 8.22 (s, IH), 7.24 (s, IH), 3.25 (s, 3H), 3.18 (s, 3H), 2.38 (s, 3H)
5-Hydroxy-6-(5-phenylsulfanylmethyl-[ 1 ,2,4]oxadiazol-3-yl)-nicotinic acid
[0439] 1H NMR (300 MHz, DMSO-d6) 8.29 (d, J = 4.8 Hz, IH), 7.84 (d, J = 4.8 Hz, IH),
7.46-7.42 (m, 2H), 7.36-7.24(m, 3H), 4.69 (s, 2H)
6-(5-Benzenesulfonylmethyl-[ 1 ,2,4]oxadiazol-3-yl)-5-hydroxy-nicotinic acid
[0440] 1H NMR (300 MHz, DMSO-d6) 8.25 (s, IH), 7.90-7.87 (m, 2H), 7.82-7.76 (m, 2H),
7.69-7.64 (m, 2H), 5.51 (s, 2H)
2-[3-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-5-yl]-N,N-dimethyl-acetamide [0441] 1H NMR (300 MHz, CDCl3) 9.67 (s, IH), 8.62 (s, IH), 7.69 (s, IH), 4.21 (s, 2H), 3.16 (s, 3H), 3.03 (s, 3H)
3 - [3 -(5 -Cyano-3 -hydroxy-pyridin-2-yl)- [ 1 ,2,4]oxadiazol-5 -yl] -propionic acid
[0442] 1H NMR (300 MHz, CDCl3) 8.59 (d, J = 1.5 Hz, IH), 7.70 (d, J = 1.5 Hz, IH), 3.37 (t, J
= 6.9 Hz, 2H), 3.03 (t, J = 6.9 Hz, 2H)
6-[5-(2-Carboxy-ethyl)-[ 1 ,2,4]oxadiazol-3-yl]-5-hydroxy-nicotinic acid
[0443] 1H NMR (300 MHz, DMSO-d6) 8.62 (s, IH), 7.83 (s, IH), 3.27 (t, J = 6.9 Hz, 2H),
2.82 (t, J = 6.7 Hz, 2H)
2- [3 -(5 -Bromo-3 -hydroxy-pyridin-2-yl)- [ 1 ,2,4]oxadiazol-5 -yl] -N,N-dimethyl-acetamide [0444] 1H NMR (300 MHz, CDCl3) 9.42 (br s, IH), 8.44 (s, IH), 7.63 (s, IH), 4.18 (s, 2H), 3.15 (s, 3H), 3.03 (s, 3H) 2-[3-(5-Bromo-3-hydroxy-pyridin-2-yl)-[ 1 ,2,4]oxadiazol-5-yl]- 1 -pyrrolidin-1 -yl-ethanone [0445] 1H NMR (300 MHz, CDCl3) 9.44 (s, IH), 8.42 (s, IH), 7.62 (s, IH), 4.11 (s, 2H), 3.58- 3.48 (m, 4H), 2.07-1.88 (m, 4H)
N-Benzyl-2-[3-(5-bromo-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-5-yl]- acetamide
[0446] 1H NMR (300 MHz, CDCl3) 9.25 (s, IH), 8.44 (s, IH), 7.66 (s, IH), 7.36-7.25 (m, 5H),
6.51 (s, 1H),4.5O (d, J = 1.8 Hz, 2H), 4.07 (s, 2H)
N-Benzyl-2-[5-(5-cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]- acetamide
[0447] 1H NMR (300MHz, DMSO-d6) 11.73 (s, IH), 8.78 (t, J = 6.0 Hz, IH), 8.67 (d, J = 1.5
Hz, IH), 7.97 (d, J = 1.5 Hz, IH), 7.35-7.22 (m,, 5H), 4.31 (d, J = 5.7 Hz, 2H), 3.84 (s, 2H)
2- [5 -(5 -Cyano-3 -hydroxy-pyridin-2-yl)-[ 1 ,2,4]oxadiazol-3 -yl] -N-phenethyl-acetamide [0448] 1H NMR (300MHz, DMSO-d6) 11.72 (s, IH), 8.66 (d, J = 1.5 Hz, IH), 8.35 (t, J = 5.7 Hz, IH), 7.96 (d, J = 1.5 Hz, IH), 7.29-7.14 (m, 5H), 3.74 (s, 2H), 3.33-3.26 (m, 2H), 2.72 (t, J = 7.5 Hz, 2H)
2-[5-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]-N-(2-pyridin-2-yl-ethyl)- acetamide
[0449] 1H NMR (300MHz, DMSO-d6) 8.68 (s, 2H), 8.44 (t, J = 6.0 Hz, IH), 8.18-8.13 (m,
IH), 8.02 (s, IH), 7.69-7.59 (m, 2H), 3.72 (s, 2H), 3.53-3.47 (m, 2H), 3.05 (t, J = 6.3 Hz, 2H)
2-[5-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]-N-[2-(4-hydroxy-phenyl)-ethyl]- acetamide
[0450] 1H NMR (300MHz, DMSO-d6, TFA) 8.66 (s, IH), 8.32 (t, J = 6.0 Hz, IH), 7.97 (s,
IH), 6.99 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.4 Hz, 2H), 3.74 (s, 2H), 3.26-3.19 (m, 2H), 2.59 (t, J
= 6.9 Hz, 2H)
2- [5 -(5 -Cyano-3 -hydroxy-pyridin-2-yl)- [ 1 ,2,4]oxadiazol-3 -yl] -N-pyridin-2-ylmethyl-acetamide [0451] 1H NMR (300MHz, DMSO-d6) 8.88 (t, J = 5.4 Hz, IH), 8.66 (s, IH), 8.51-8.48 (m, IH), 7.96 (s, IH), 7.77-7.27 (m, IH), 7.36 (d, J = 7.5 Hz, IH) 7.27-7.23 (m, IH), 4.40 (d, J = 6.0 Hz, 2H), 3.89 (s, 2H)
2- [5 -(5 -Cyano-3 -hydroxy-pyridin-2-yl)- [ 1 ,2,4]oxadiazol-3 -yl] -N-pyridin-3 -ylmethyl-acetamide [0452] 1H NMR (300MHz, DMSO-d6) 8.48 (t, J = 6.0 Hz, IH), 8.65 (s, IH), 8.52-8.41 (m, 2H), 7.95 (s, IH), 7.70 (d, J = 8.1 Hz, IH), 7.36-7.33 (m, IH), 4.34 (d, J = 5.4 Hz, 2H), 3.85 (s, 2H),
2- [5 -(5 -Cyano-3 -hydroxy-pyridin-2-yl)- [ 1 ,2,4]oxadiazol-3 -yl] -N-pyridin-4-ylmethyl-acetamide [0453] 1H NMR (300MHz, DMSO-d6) 8.89 (t, J = 6.0 Hz, IH), 8.65 (s, IH), 8.48 (s, 2H), 7.95 (s, IH), 7.31 (d, J = 4.8 Hz, 2H), 4.34 (d, J = 5.4 Hz, 2H), 3.88 (s, 2H) and
[2-(3-Hydroxy-pyridin-2-yl)-thiazol-4-yl] -acetic acid
[0454] 1H NMR (300 MHz, CDC13) 8.17 (d, J=3.6Hz, IH), 7.39-7.24 (m, 3H), 3.95 (s,
2H)
Example 10: Test and Administration
Biological Test
[0455] Biological activity of the compounds according to the present invention may be evaluated using any of the conventional known methods. The suitable assays have been widely known in the art. The following assays are described for the purpose of illustration, but are in no way intended to limit the scope of the present invention. The compounds of the present invention show activities in at least one of the following assays.
Cell-based Assay for HIFα Stabilization
[0456] Human cells induced from various tissues were inoculated into 35-mm culture dishes, respectively, and grown in standard culture media, for example, DMEM supplemented with 10% FBS under conditions of 37 0C, 20% O2 and 5% CO2. Their cell layers grew into clusters, the media was replaced with OPTI-MEM media (Invitrogen Life Technologies, Carlsbad CA), and the cell layers were cultured at 37 0C for 24 hours under 20% O2 and 5% CO2 conditions. The compounds or 0. 013% DMSO were added to the existing media, and then cultured overnight. [0457] After culturing, the media was removed, centrifuged, and stored for future analysis (see the following VEGF and EPO assays). The cells were washed twice with cold phosphate buffer saline (PBS), and then dissolved in a solution of 1 ml of 10 mM tris (pH 7.4), 1 mM EDTA, 150 mM NaCI, 0.5% IGEPAL (Sigma- Aldrich, St. Louis MO) and protease inhibitor mix (Roche Molecular Biochemicals) for 15 minutes while being kept in ice. Cell lysates were centrifuged at 4 0C for 5 minutes at a rotary speed of 3,000 xg, and cytosol fractions (supernatant) were collected. Nuclei (pellets) were re-suspended and dissolved in a solution of 100 μl of 20 mM HEPES (pH 7.2), 400 mM NaCl, 1 mM EDTA, 1 mM dithiothreitol and protease mix (Roche Molecular Biochemicals), centrifuged at 4 0C for 5 minutes at a rotary speed of 13,000 xg, and then nuclear protein fractions (supernatant) were collected.
[0458] Nucleus fractions were analyzed for HIF- lα using a QU ANTIKINE immunoassay (R&D Systems, Inc., Minneapolis MN) according to the manufacturer's instructions.
HIF-PH2 (PHD2) Assay and HIF-PH3 (PHD3) Assay
Materials
[0459] HIF-PH2 (EGLNl) was expressed from E.coli cells, and purified using two process: an Ni-affinity chromatography column and a size-exclusion chromatography column.
[0460] HIF-PH3 (EGLN3) was expressed from E.coli cells, and purified using two process: an Ni-affinity chromatography column and a size-exclusion chromatography column
A. HIF-PH2 (PHD2) Analysis (Fluorescence Polarization Method)
[0461] To evaluate activities of an HIF PH2 inhibitor, HIF PH2 enzyme that was first overexpressed by genetic recombination and then purified was used to perform an enzyme reaction. First, 20OnM HIF PH2 enzyme reacted with 50 nM peptide substrate (FITC- ACA- DLDLEALAPYIPADDDFQLR; SEQ ID NO.:1) in a reaction buffer (20 mM Tris-Cl (pH8.0), 100 mM NaCl, 0.5 % Nonidet P40). At this time, 2 mM ascorbic acid and 5 mM ketoglutarate with 100 μM FeCl2 or without FeCl2, were used together with crude enzyme. A concentration of HIF PH2 inhibitor to be tested was treated and reacted at 30 0C for one hour. After the reaction, the resulting reaction product was boiled at 95 0C for one minute to suppress the enzyme reaction.
[0462] To determine whether prolyl hydroxylation occurs in the substrate as the secondary reaction, 500 nM GST-VBC (GST- VHL-Elongin B - Elongin C) protein was added to a reaction buffer (50 mM Tris-Cl (pH8.0), 120 mM NaCl, 0.5 % Nonidet P40), and a GST-VBC binding reaction was carried out at room temperature for 30 minutes. After the reaction was completed, fluorescence polarization was determined at a wavelength of 485nm/535 nm(ex/em) by using a Fusion-FP (Packard) system.
[0463] A fluorescence polarization value of a sample that is not treated with the HIF PH2 inhibitor was used as 100 % control, and the activities of the HIF PH2 inhibitor were measured as percentage of the remaining HIF PH2 enzyme activity in samples treated with a concentration of the HIF PH2 inhibitor to be tested. The remaining HIF PH2 enzyme activities after the treatment with increasing concentrations of the HIF PH2 inhibitor was measured to calculate IC50 of the HIF PH2 inhibitor, and then a concentration of the inhibitor was determined as IC50, the concentration at which 50 % of HIF PH2 enzyme activity is inhibited compared to the control. IC50 data is given in Table 1.
B. HIF-PH3 Analysis (Fluorescence Polarization Method)
[0464] To evaluate activities of an HIF PH inhibitor, HIF PH3 enzyme was overexpressed by genetic recombination in E. coli and then purified. Purified enzyme was used to perform the following enzyme reaction. First, 20OnM of HIF PH3 enzyme was reacted with 50 nM peptide substrate (FITC- ACA-DLDLEALAPYIP ADDDFQLR) in a reaction buffer (20 mM Tris-Cl (pH 8.0), 100 mM NaCl, and 0.5 % Nonidet P40). At this time, 2 mM ascorbic acid, 100 uM FeC12 and 5 mM ketoglutarate were used together with crude enzyme. A concentration of HIF PH inhibitor to be tested was treated and reacted at 30 0C for one hour. After the reaction, the resulting reaction product was boiled at 95 0C for one minute to suppress the enzyme reaction.
[0465] To determine whether prolyl hydroxylation occurs in the substrate as the secondary reaction, 500 nM GST-VBC (GST- VHL-Elongin B - Elongin C) protein was added to a reaction buffer (50 mM Tris-Cl (pH8.0), 120 mM NaCl, and 0.5 % Nonidet P40), and a GST-VBC binding reaction was carried out at room temperature for 30 minutes. After the reaction was completed, the fluorescence polarization was determined at a wavelength of 485nm/535nm(ex/em) by using a Fusion-FP (Packard) system.
[0466] A fluorescence polarization value of a sample that is not treated with the HIF PH inhibitor was used as 100 % control, and the activities of the HIF PH inhibitor were measured as percentage of the remaining HIF PH3 enzyme activity in samples treated with a concentration of the HIF PH inhibitor to be tested. The remaining HIF PH3 enzyme activities after the treatment with increasing concentrations of the HIF PH inhibitor was measured to calculate IC50 of the HIF PH inhibitor, and then a concentration of the inhibitor was determined as IC50, the concentration at which 50 % of HIF PH3 enzyme activity is inhibited compared to the control. Table 1 [0467] HIF PH2 inhibition activity
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
A = 0-100 μM; B = 101-300 μM; C = 301-500 μM; D = > 500 μM
Human EPO Immunoassay
[0468] Human cells derived from hepatocarcinoma (Hep3B) tissue (see, e.g., American Type Culture Collection, Manassas VA) were grown at 37°C, 20% 02, 5% CO2 in DMEM (GIBCO) + 10 % FBS, 4.5 g/L D-Glucose; L-Glutamate and l lOmg/L sodium pyruvate. Ninety-six well plates were seeded with 4 X 104 HEP3B cells/well. The media was removed and replaced with DMEM + 10% FBS. Compounds were added to wells at concentrations between lμM-lOOμM for a 24-hour incubation. Cell culture media was harvested and EPO concentration was determined using a Human Erythropoietin Quantikine IVD ELISA Kit (R&D Systems®, Minneapolis, MN) following the manufacturer's instructions for the benchtop assay. Cell-based assay for VEGF and EPO Reporters
[0469] A luciferase assay was used to determine the changes in transcription amount of EPO and VEGF genes in cells. For the luciferase assay, a human HIF lα gene was first cloned into an animal cell expression vector, pFlag-CMV, to prepare a pFlag-HIFlα vector, and a hypoxia responsible element (HRE) sequence of an EPO gene 3 '-enhancer domain was then cloned upstream of luciferase and TK promoter genes to prepare a pEPO HRE-Luc expression vector. Also, the promoter and luciferase domains of the VEGF gene were cloned into a pGL3-basic vector to prepare a pVEGF-Luc expression vector. HeLa cells were seed-cultured in a medium dish to grow to about 70-80% density one day before the HeLa cells were to be used. The HeLa cells were transfected with each of the prepared pEPO HRE-Luc and pVEGF-Luc expression vectors together with the pFlag-HIFlα and the Renilla luciferase expression vector (Promega, Madison, WI, USA), by using LipofectAMINE PLUS™ (Invitrogen Life Technologies, Carlsbad CA). Three hours after the transfection, the medium was exchanged with DMEM, 1% Penicillin- Streptomycin in 10% FBS supplemented with serum. At this time, cultured cells were treated with each of the compounds at the concentrations indicated. Then, the cells were cultured for 24 hrs in an incubator that was maintained under conditions of 37 0C, 20% O2 and 5% CO2. After culturing, cells were washed twice with cold phosphate buffer saline (PBS). Luciferase activity of the cells was measured using the dual luciferase assay system (Promega, Madison, WI, USA).

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula I:
Figure imgf000132_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, where
X1-X4 is each independently carbon or nitrogen, provided that at least one of X1-X4 is carbon; R1 is selected from the group consisting of hydrogen, optionally substituted alkyl, and cationic counterion;
R2-R5 is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -OR1S, -NO2, -N(RiS)2, -(CRi6Ri7)n-NHC(=O)Ris, -CH2NHRi5, -NH(SO2)Ri5, - CH2NH(SO2)Ri5, - (CRi6Ri7)n-C(=O)Ri5, and -(CRi6Ri7)n-C(=O)ORi5, , where n is an integer between 0 and 10, inclusive, provided that R2 does not exist when Xi is nitrogen, provided that R3 does not exist when X2 is nitrogen, provided that R4 does not exist when X3 is nitrogen, and provided that R5 does not exist when X4 is nitrogen; or
Xi and X2 are carbon and R2 and R3 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; or
X2 and X3 are carbon and R3 and R4 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; A is a moiety of Formula II, Formula HA, or Formula III:
Figure imgf000133_0001
where
Y1 is selected from the group consisting of nitrogen, oxygen, and sulfur, as valence allows; Y2 and Y3 is each independently selected from the group consisting of carbon, CH, oxygen, nitrogen, and sulfur; Y4 is carbon or nitrogen; R-6-R9 is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -OR15, -NO2,
-N(RiS)2, -NHC(=0)R15, -NHC(=0)0Ri5, -NH(SO2)Ri5, -(CR16Ri7VCC=O)OR15,
-(CRi6Ri7VSRi5, - (CRi6Ri7)nC(=O)N(Ri5)2, -
(CRi6Ri7)n-C(=O)NH-(CRi6Ri7)n-C(=O)ORi5, -
(CRi6Ri7)n-C(=O)NH-(CRi6Ri7)n-C(=O)Ri5 -CCR16R17VSC=O)R15, -
(CRi6Ri7)n-C(=O)Ri5, and -(CRi6Ri7)n-S(=O)2Ri5, where n is an integer between
0 and 10, inclusive, provided that R6 does not exist when Yi is oxygen or sulfur, and provided that R9 does not exist when Y4 is nitrogen; or Y2 and Y3 are carbon and R7 and Rs taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; bond a is single bond or double bond, such that Y2 and Y3 have a complete octet along with R7 and R8; Z1-Z5 is each independently carbon or nitrogen, provided that at least two of Z1-Z5 are carbon; R10-R14 is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -ORi5, -NO2, -N(R15)2, -NHC(=O)R15, -NH(SO2)Ar, - (CR16R17)n-C(=O)R15, -(CR16R17)n-C(=O)NH-(CR16R17)n-C(=O)OR15, (CR16R17)nC(=O)N(R15)2 -(CR16Ri7)n-S(=O)2R15, and -(CR16Ri7)n-C(=O)OR15, where Ar is an optionally substituted aryl, and where n is an integer between 0 and 10, inclusive, provided that R1O does not exist when Z1 is nitrogen, provided that R11 does not exist when Z2 is nitrogen, provided that R12 does not exist when Z3 is nitrogen, provided that R13 does not exist when Z4 is nitrogen, and provided that R14 does not exist when Z5 is nitrogen;
R15 is independently selected as it appears from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and
Ri6 and R17 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; or
Z3 and Z4 are carbon and R12 and R13 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring.
2. A compound of Formula I :
Figure imgf000134_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein
X1-X4 is each independently carbon or nitrogen, provided that at least one of X1-X4 is carbon; R1 is selected from the group consisting of hydrogen optionally substituted alkyl, and cationic counterion;
R2-R5 is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -OR15, -NO2, -N(Ri5)2, -NHC(=0)Ri5, -NH(SO2)Ar, and -(CRi6Ri7)n-C(=O)ORi5, wherein Ar is an optionally substituted aryl, and wherein n is an integer between 0 and 10, inclusive, provided that R2 does not exist when Xi is nitrogen, provided that R3 does not exist when X2 is nitrogen, provided that R4 does not exist when X3 is nitrogen, and provided that R5 does not exist when X4 is nitrogen; or
Xi and X2 are carbon and R2 and R3 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; or
X2 and X3 are carbon and R3 and R4 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; A is a moiety of Formula II or Formula III:
Figure imgf000135_0001
wherein
Yi is selected from the group consisting of nitrogen, oxygen, and sulfur;
Y2 and Y3 is each independently selected from the group consisting of carbon, CH, oxygen, and sulfur;
Y4 is carbon or nitrogen;
R6-R9 is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -ORi5, -NO2, -N(R15)2, -NHC(=O)R15, -NH(SO2)Ar, -(CR16R17)n-C(=O)OR15, (CR16R17)n-S(=O)R15, and -(CR16R17)n-S(=O)2R15, wherein Ar is an optionally substituted aryl, and wherein n is an integer between 0 and 10, inclusive, provided that R6 does not exist when Y1 is oxygen or sulfur, and provided that Rp does not exist when Y4 is nitrogen; or
Y2 and Y3 are carbon and R7 and R8 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring; bond a is single bond or double bond, such that Y2 and Y3 have a complete octet along with R7 and R8; Z1-Zs is each independently carbon or nitrogen, provided that at least two of Z1-Zs are carbon;
R1O-R14 is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -OR1S, -NO2, -N(R15)2, -NHC(=0)R15, -NH(SO2)Ar, and -(CR16R17)n-C(=O)OR15, wherein Ar is an optionally substituted aryl, and wherein n is an integer between 0 and 10, inclusive, provided that R1O does not exist when Z1 is nitrogen, provided that R11 does not exist when Z2 is nitrogen, provided that R12 does not exist when Z3 is nitrogen, provided that R13 does not exist when Z4 is nitrogen, and provided that R14 does not exist when Z5 is nitrogen;
Ris is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and
Ri6 and R17 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl.
3. The compound of claim 1, wherein R1 is hydrogen or an optionally substituted alkyl.
4. The compound of claim 1, wherein R1 is a cationic counterion.
5. The compound of claim 1, wherein R3 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -OR1S, -NO2, - (CR16Rn)n-C(O)OR15, -CH2NH(SO2)R15, and -(CR16R17)n-NHC(=O)R15.
6. The compound of claim 1, wherein R3 is -OR15 and R15 is hydrogen or an optionally substituted alkyl.
7. The compound of claim 6, wherein the alkyl is substituted with an aryl.
8. The compound of claim 1, wherein R3 is selected from the group consisting of hydrogen, bromo, cyano, phenyl, -NO2, -OH, and -OCH2C6H5.
9. The compound of claim 1, wherein R3 is -C(=0)0R15.
10. The compound of claim 9, wherein R15 is hydrogen.
11. The compound of claim 1 , wherein R3 is -(CR16Rn)nNHC(O)R15.
12. The compound of claim 11, wherein R15 is an optionally substituted alkyl.
13. The compound of claim 12, wherein the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
14. The compound of claim 1, wherein R3 is -CH2NH(SO2)R15.
15. The compound of claim 14, wherein R15 is selected from the group consisting of optionally substituted aryl and optionally substituted arylalkyl.
16. The compound of claim 5, wherein the alkyl is methyl.
17. The compound of claim 1, wherein R4 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, perhaloalkyl, - (CR16R17)Ii-C(O)R15, and -OR15.
18. The compound of claim 1, wherein R4 is selected from the group consisting of hydrogen, acetyl, chloro, bromo, and phenyl.
19. The compound of claim 1, wherein R2, R5, R6, R1O, Ro, and R14 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.
20. The compound of claim 1, wherein R2, R5, R6, R10, Ro, and R14 is each independently hydrogen.
21. The compound of claim 1, wherein X1 and X2 are carbon and R2 and R3 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring.
22. The compound of claim 1, wherein X1 and X2 are carbon and R3 and R4 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring.
23.. The compound of claim 1, wherein X1-X4 are carbon.
24. The compound of claim 1, wherein X1-X3 are carbon and X4 is nitrogen.
25. The compound of claim 1, wherein R7 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, -ORi5, -N(R15)2, -NHC(K))R15, and -(CR16Ri7VC(K))OR15.
26. The compound of claim 25, wherein Ri 5 is hydrogen or an optionally substituted alkyl.
27. The compound of claim 26, wherein the alkyl is substituted with an aryl.
28. The compound of claim 27, wherein R7 is selected from the group consisting of methyl, -OH, -OCH2C6H5, -C(O)OH, -C(O)CH3, -CH2CH2-C(O)OH, and -C(O)CH2CH3.
29. The compound of claim 1, wherein R7 is -(CRi6Ri7VSRi5, - (CRi6Rn)nC(O)N(RiS)2, - (CR16R17VC(K))R15, - (CR16R17VC(K))OR15, and
Figure imgf000138_0001
30. The compound of claim 29 where Ri5 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroalicyclyl, and optionally substituted arylalkyl.
31. The compound of claim 30, wherein the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
32. The compound of claim 30, wherein the heteroalicyclyl is selected from pyrrolidine.
33. The compound of claim 1, wherein R8 and R9 is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.
34. The compound of claim 1, wherein R8 and R9 is each independently hydrogen or methyl.
35. The compound of claim 1, wherein R8 is selected from the group consisting of, - C(R16R17)nN(R15)2, -CH2NH-C(=O)OR15, -(CR16R17)n-C(=O)R15 — (CRi6Ri7)n-C(=O)N-(CRi6Ri7)n-C(=O)ORi5, — (CRi6Ri7)n-C(=O)N-(CRi6Ri7)n-C(=O)Ri5, - (CRi6Ri7)nC(=O)N(Ri5)2, -(CR16Ri7)n-S(=O)2R15, and - (CRi6Ri7)n-C(=O)ORi5.
36. The compound of claim 35, wherein R8 is -CH2C(=O)OH.
37. The compound of claim 35, wherein R15 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl.
38. The compound of claim 37, wherein the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
39. The compound of claim 38, wherein the alkyl is substituted with one of more from the group consisting of optionally substituted aryl, hydroxy, optionally substituted heteroaryl, and dialkylamino.
40. The compound of claim 39, wherein the aryl is phenyl.
41. The compound of claim 37, wherein the cycloalkyl is cyclopropyl.
42. The compound of claim 37, wherein the heteroalicyclyl is selected from pyrrolidine, piperdine, piperazine, morpholine, , aziridine, and azetedine.
43. The compound of claim 37, wherein the heteroaryl is selected from pyridine, imidazol, indole, isoindole, oxadiazol and isoquinoline.
44. The compound of claim 35, wherein R8 is -(CR16R17)nC(=O)N(R15)2 and R15 is an optionally substituted arylalkyl. or optionally substituted heteroarylalkyl.
45. The compound of claim 44, wherein the arylalky is selected from phenylmethyl and phenylethyl and the heteroarylalkyl is selected from pyridinemethyl and pyridineethyl.
46. The compound of claim 1, wherein Y2 and Y3 are carbon and R7 and R8 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or optionally substituted heteroaryl ring.
47. The compound of claim 1 , wherein A is a moiety of Formula II and
(i) Y1 is sulfur; Y2 is carbon; Y3 is carbon; Y4 is nitrogen, and bond a is a double bond; (ii) Y1 is oxygen; Y2 is CH; Y3 is CH; Y4 is nitrogen, and bond a is a single bond;
(iii) Y1 is sulfur; Y2 is CH; Y3 is CH; Y4 is nitrogen, and bond a is a single bond; or
(iv) Y1 is nitrogen; Y2 is CH; Y3 is CH; Y4 is nitrogen, and bond a is a single bond.
48. The compound of claim 1, wherein A is a moiety of Formula II and
(i) Y1 is oxygen, Y2 is nitrogen, Y3 is carbon and Y4 is nitrogen, and bond a is a double bond;
(ii) Y1 is oxygen, Y2 is nitrogen, Y3 is carbon, and Y4 is nitrogen and bond a is double bond or;
(iii) Y1 is sulfur, Y2 is nitrogen, Y3 is carbon and Y4 is nitrogen, and bond a is a double bond.
49. The compound of claim 1, wherein A is a moiety of Formula IIA and Y1 is nitrogen, Y2 is carbon, Y3 is oxygen, and Y4 is nitrogen;
50. The compound of claim 1, wherein R11 is -(CR16R17)n-C(=O)OR15 and R1S is hydrogen or an optionally substituted alkyl.
51. The compound of claim 50, wherein R11 is selected from the group consisting of methyl, -C(=O)OH, -C(=O)CH3, and -C(=O)CH2CH3.
52. The compound of claim 1, wherein R11 is OR1S.
53. The compound of claim 52, wherein R1S is hydrogen.
54. The compound of claim 1, wherein R12 is selected from the group consisting of hydrogen, optionally substituted alkyl, and halo.
55. The compound of claim 1, wherein R12 is hydrogen or bromo.
56. The compound of claim 1, wherein R12 is selected from the group consisting of , - (CRi6Rn)n-C(O)Ri5, -(CRi6Rn)n-C(O)NH-(CRi6Rn)n-C(O)ORi5, -(CRi6Rn)n-C(O)NH-(CRi6Rn)n-C(O)Ri5, (CRi6Rn)nC(O)N(Ris)2, -(CRi6Rn)n-S(O)2Ri5, and -(CRi6Rn)n-C(O)ORi5.
57. The compound of claim 56, wherein R15 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl.
58. The compound of claim 57, wherein the alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
59. The compound of claim 57, wherein the cycloalkyl is cyclopropyl.
60. The compound of claim 57, wherein the heteroalicyclyl is selected from pyrrolidine, piperdine, or indole.
61. The compound of claim 57, wherein the heteroaryl is pyridine.
62. The compound of claim 57, wherein the aryl is phenyl.
63.. The compound of claim 1 , wherein
(i) Z1-Z4 are carbon and Z5 is nitrogen; or
(ii) Z2-Z4 are carbon and Z1 and Z5 are nitrogen.
64. The compound of claim 1, herein Z3 and Z4 are carbon and R12 and R13 taken together along with the carbon atoms to which they are attached form a six-membered optionally substituted aryl or six-membered optionally substituted heteroaryl.
65. The compound of claim 64, wherein the aryl ring formed is phenyl.
66. The compound of claim 1 selected from the group consisting of
Figure imgf000141_0001
67. The compound of claim 66 selected from the group consisting of
Figure imgf000142_0001
68. The compound of claim 1, wherein A is selected from the group consisting of
Figure imgf000143_0001
69. The compound of claim 68, wherein A is selected from the group consisting of
Figure imgf000143_0002
Figure imgf000144_0001
Figure imgf000144_0002
Figure imgf000145_0001
Figure imgf000146_0001
- 145-
Figure imgf000147_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
- 150-
Figure imgf000152_0001
Figure imgf000153_0001
70. The compound of claim 1 , wherein A is
Figure imgf000153_0002
71. The compound of claim 70, wherein A is selected from the group consisting of
Figure imgf000153_0003
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
72. The compound of claim 1 selected from the group consisting of
Figure imgf000156_0002
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein
A is a moiety selected from the group consisting of
Figure imgf000157_0001
R1 is selected from the group consisting of hydrogen optionally substituted alkyl, and cationic counterion; and
R2-Rs and R1O-Ro is each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, halo, cyano, perhaloalkyl, -OR15, -NO2, -N(R15)2, -NHC(=0)R15, -NH(SO2)R15, (CR16R17)n-C(=O)R15, -(CRi6R17)n-C(=O)NH-(CRi6R17)n-C(=O)ORi5,
-(CRi6R17)n-C(=O)NH-(CRi6R17)n-C(=O)Ri5, (CRi6R17)nC(=O)N(Ri5)2,
-(CR16R17)n-S(=O)2R15, and -(CR16R17)n-C(=O)OR15, wherein n is an integer between 0 and 10, inclusive.
73. The compound of claim 1, wherein the compound is a compound of Formula IV:
Figure imgf000157_0002
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, where
X is selected from the group consisting of oxygen, NH, and sulfur;
Ri8 and R^ is each independently selected from the group consisting of hydrogen, - (CRi6Ri7)n-S(=O)R20, and -(CRi6Ri7)n-S(=0)2R2o, n is an integer between 0 and 10, inclusive; R16 and R17 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted aryl;
R20 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OR15, and -N(R15)2; where R15 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and bond a is a single bond or a double bond.
74. A compound selected from the group consisting of 2-(2-Hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, 2-(2-Hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid, 2-(5-Bromo-2-hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, 2-(5-Bromo-2-hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid, 2-(2-Hydroxy-phenyl)-4,5-dihydro-oxazole-5-carboxylic acid, 2-(2-Hydroxy-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid, 2-(3-Hydroxy-naphthalen-2-yl)-4-methyl-thiazole-5-carboxylic acid, 2-(4-Hydroxy-biphenyl-3-yl)-4-methyl-thiazole-5-carboxylic acid ethyl ester, 2-(4-Hydroxy-biphenyl-3-yl)-4-methyl-thiazole-5-carboxylic acid, 2-(5-Bromo-2-hydroxy-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid, 2-(2-Hydroxy-4-nitro-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid, 2-(5-Acetyl-2-hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid, 2-(4-Bromo-2-hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid, 2-(5-Chloro-2-hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid, 2-(2-Hydroxy-4-nitro-phenyl)-4-methyl-thiazole-5-carboxylic acid, 2-(4-Bromo-2-hydroxy-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid, 2-(4-Bromo-2-hydroxy-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid methyl ester, 3-(4,5-Dihydro-lH-imidazol-2-yl)-naphthalen-2-ol,
2-(3-Hydroxy-naphthalen-2-yl)-4,5-dihydro-3H-imidazole-4-carboxylic acid, 2-(4,5-Dihydro-lH-imidazol-2-yl)-pyridin-3-ol, l-Chloro-3-(4,5-dihydro-lH-imidazol-2-yl)-isoquinolin-4-ol, 2-(5-Methyl-4,5-dihydro-lH-imidazol-2-yl)-pyridin-3-ol, 2-(2,4-Dihydroxy-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid, 5-Bromo-2-(3-hydroxy-pyridin-2-yl)-pyrimidine-4-carboxylic acid, 2-(4-Benzyloxy-2-hydroxy-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid, 2-(3-Hydroxy-pyridin-2-yl)-pyrimidine-4-carboxylic acid,
(R)-2-(3-Hydroxy-5-phenyl-pyridin-2-yl)-4,5-dihydro-thiazole-4-carboxylic acid, (R)-2-(3-Hydroxy-pyridin-2-yl)-4,5-dihydro-thiazole-4-carboxylic acid, (S)-2-(3-Hydroxy-pyridin-2-yl)-4,5-dihydro-thiazole-4-carboxylic acid, 2-(l-Hydroxy-naphthalen-2-yl)-4,5-dihydro-oxazole-5-carboxylic acid, 3'-Hydroxy-[2,2']bipyridinyl-4-carboxylic acid, 3-(lH-Benzoimidazol-2-yl)-l-chloro-isoquinolin-4-ol, (R)-2-(2-Hydroxy-4-nitro-phenyl)-4,5-dihydro-thiazole-4-carboxylic acid, (S)-2-(2-Hydroxy-4-nitro-phenyl)-4,5-dihydro-thiazole-4-carboxylic acid, 2-(l-Chloro-4-hydroxy-isoquinolin-3-yl)-lH-benzoimidazole-5-carboxylic acid, 4-Hydroxy-2-(3 -hydroxy-pyridin-2-yl)-pyrimidine-5 -carboxylic acid, 2-(6-Bromo-3-hydroxy-pyridin-2-yl)-4-hydroxy-pyrimidine-5-carboxylic acid, 2-(6-Bromo-3-hydroxy-pyridin-2-yl)-4-hydroxy-pyrimidine-5 -carboxylic acid ethyl ester, 3-(4,5-Dihydro-lH-imidazol-2-yl)naphthalen-2-ol, 4-Hydroxy-2-(3 -hydroxy-pyridin-2-yl)-pyrimidine-5 -carboxylic acid, 2-(6-Bromo-3-hydroxy-pyridin-2-yl)-4-hydroxy-pyrimidine-5 -carboxylic acid, 2-(2-Hydroxy-4-bromo-phenyl)-4,5-dihydro-thiazole-5-carboxylic acid, and 2-(3-Hydroxy-naphthalen-2-yl)-4,5-dihydro-3H-imidazole-4-carboxylic acid, rmaceutically acceptable salt, ester, amide, or prodrug thereof.
75. A compound selected from the group consisting of 2-(3-Hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-acetic acid, 2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo- 1 ,6-dihydro-pyrimidin-5-yl] -acetic acid, 6-(5-Carboxymethyl-6-oxo- 1 ,6-dihydro-pyrimidin-2-yl)-5-hydroxy-nicotinic acid, N-Benzyl-2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide, 2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl] -acetic acid butyl ester, 2-(3-Hydroxy-pyridin-2-yl)-thiazole-4-carboxylic acid benzyl amide, N-Benzyl-2-[2-(3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-acetamide,
{2-[2-(3-Hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-acetylamino} -acetic acid,
2-(3,5-Dihydroxy-pyridin-2-yl)-3H-quinazolin-4-one,
5-Hydroxy-6-(4-oxo-3,4-dihydro-quinazolin-2-yl)-nicotinonitrile,
5-Hydroxy-6-(4-oxo-3,4-dihydro-quinazolin-2-yl)-nicotinic acid,
5-Hydroxy-6-(6-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl)-nicotinonitrile,
5-Hydroxy-6-(6-methoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-nicotinonitrile,
5-Hydroxy-6-(6-hydroxy-4-oxo-3,4-dihydro-inazolin-2-yl)-nicotinonitrile,
N-Benzyl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide,
6-[6-(3,5-Dichloro-phenoxy)-4-oxo-3,4-dihydro-quinazolin-2-yl]-5-hydroxy- nicotinonitrile,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(3-fluoro-benzyl)-acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(4-fluoro-benzyl)-acetamide,
{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino} -acetic acid,
(S)-{2-[2-(5-Bromo-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino}-phenyl-acetic acid methyl ester,
(R)-{2-[2-(5-Bromo-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino}-phenyl-acetic acid methyl ester,
(S)-{2-[2-(5-Bromo-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino}-phenyl-acetic acid,
(R)-{2-[2-(5-Bromo-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino}-phenyl-acetic acid,
N-(2-Chloro-benzyl)-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide,
N-(3-Chloro-benzyl)-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide,
N-(4-tert-Butyl-benzyl)-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-(3 -trifluoromethyl-benzyl)- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-(4-dimethylamino-benzyl)- acetamide, 2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-( 1 -methyl- 1 -phenyl-ethyl)- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-pyridin-2-ylmethyl-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-pyridin-3 -ylmethyl-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-pyridin-4-ylmethyl-acetamide,
N-(4-Chloro-benzyl)-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-pyridin-2-yl-ethyl)-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-pyridin-3-yl-ethyl)-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(3-methoxy-benzyl)-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-pyridin-4-yl-ethyl)-acetamide,
N-Benzhydryl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-(I H-indol-5-ylmethyl)- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-phenethyl-acetamide,
N- {2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -acetyl} -methanesulfonamide,
N-{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetyl}-benzenesulfonamide,
N-{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetyl}-C-phenyl- methanesulfonamide,
N-(6-Chloro-pyridin-3-ylmethyl)-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]- acetamide,
{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetylamino} -acetic acid methyl ester,
(R)2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-((R)-2 -hydroxy- 1 -phenyl- ethyl)-acetamide,
(S)2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-((S)-2-hydroxy-l-phenyl- ethyl)-acetamide,
[2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -acetic acid,
{2-[5-(Acetylamino-methyl)-3-hydroxy-pyridin-2-yl]-thiazol-4-yl} -acetic acid,
{2-[5-(Benzenesulfonylamino-methyl)-3-hydroxy-pyridin-2-yl]-thiazol-4-yl} -acetic acid,
{2- [3 -Hydroxy-5 -(phenylmethanesulfonylamino-ethyl)-pyridin-2-yl] -thiazol-4-yl} -acetic acid, 2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-methyl-N-(2-pyridin-2-yl-ethyl)- acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(4-hydroxy-phenyl)-ethyl]- acetamide,
2-(2-(5-cyano-3-hydroxypyridin-2-yl)-thiazol-4-yl)-N-(4-sulfamoylphenethyl)- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-(3 -imidazol- 1 -yl-propyl)- acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(2-oxo-pyrrolidin-l-yl)-ethyl]- acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(lH-imidazol-4-yl)-ethyl]- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-morpholin-4-yl-ethyl)- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(3-morpholin-4-yl-propyl)- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-pyrrolidin-l-yl-ethyl)- acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(lH-indol-3-yl)-ethyl]- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-piperi din- 1-yl-ethyl)- acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[3-(2-oxo-pyrrolidin-l-yl)- propyl] -acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(3,4-dihydroxy-phenyl)- ethyl] -acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(5-hydroxy-lH-indol-3-yl)- ethyl] -acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-[2-(4-methyl-piperazin-l-yl)- ethyl] -acetamide, N-Benzyl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo- 1 ,6-dihydro-pyrimidin-5 -yl] -N-phenethyl- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-(3 -phenyl- propyl)-acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-[3-(2-oxo- pyrrolidin- 1 -yl)-propyl] -acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo- 1 ,6-dihydro-pyrimidin-5 -yl] -N-pyridin-3 - ylmethyl-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-(2-pyri din-
2-yl-ethyl)-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-(2-pyri din-
3 -yl-ethyl)-acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-[2-(3- trifluoromethyl-phenyl)-ethyl]-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo- 1 ,6-dihydro-pyrimidin-5 -yl] -N-phenyl- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl] -N- cyclopropyl-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]-N-(2-oxo-2- phenyl-ethyl)-acetamide,
N-Butyl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]- acetamide,
5-Hydroxy-6-[6-oxo-5-(2-oxo-2-pyrrolidin-l-yl-ethyl)-l,6-dihydro-pyrimidin-2-yl]- nicotinonitrile,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -N-((R)-2-hydroxy- 1 -phenyl-ethyl)- acetamide,
2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl] -acetic acid benzyl ester,
[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetic acid 2-pyridin-2-yl-ethyl ester, 5-Hydroxy-6-{5-[2-(2-methyl-2,3-dihydro-indol-l-yl)-2-oxo-ethyl]-6-oxo-l,6-dihydro- pyrimidin-2-yl} -nicotinonitrile,
5-Hydroxy-6-[6-oxo-5-(2-oxo-2-piperidin-l-yl-ethyl)-l,6-dihydro-pyrimidin-2-yl]- nicotinonitrile,
5 -Hydroxy-6- [4-(2-oxo-2-pyrrolidin- 1 -yl-ethyl)-thiazol-2-yl] -nicotinonitrile,
5 -Hydroxy-6-[4-(2-oxo-2-piperidin-l-yl-ethyl)-thiazol-2-yl] -nicotinonitrile,
N-Benzyl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-ethyl-acetamide,
N-Benzyl-2-[2-(5-cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-(2-dimethylamino- ethyl)-acetamide,
6-{4-[2-(6,7-Dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)-2-oxo-ethyl]-thiazol-2-yl}-5- hydroxy-nicotinonitrile,
5-Hydroxy-6-(4-phenylmethanesulfonylmethyl-thiazol-2-yl)-nicotinonitrile,
6-{4-[2-(2,6-Dimethyl-morpholin-4-yl)-2-oxo-ethyl]-thiazol-2-yl}-5-hydroxy- nicotinonitrile,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-N,N-diisopropyl-acetamide,
6-(4-Benzenesulfonylmethyl-thiazol-2-yl)-5-hydroxy-nicotinonitrile,
5 -Hydroxy-6- [4-(2-phenyl-ethanesulfonylmethyl)-thiazol-2-yl] -nicotinonitrile,
{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-6-oxo-l,6-dihydro-pyrimidin-5-yl]- acetylamino} -acetic acid,
5-Hydroxy-6- {4-[2-oxo-2-(4-phenyl-piperidin- 1 -yl)-ethyl]-thiazol-2-yl} -nicotinonitrile,
5 -Hydroxy-6- [6-oxo-5 -(2 -phenyl-ethanesulfonylmethyl)- 1 ,6-dihydro-pyrimidin-2-yl] - nicotinonitrile,
6-{4-[(Benzyl-ethyl-carbamoyl)-methyl]-thiazol-2-yl}-5-hydroxy-nicotinic acid,
6-{4-[2-(3-Diethylamino-pyrrolidin-l-yl)-2-oxo-ethyl]-thiazol-2-yl}-5-hydroxy- nicotinonitrile,
5-Hydroxy-6-{6-oxo-5-[2-oxo-2-(4-phenyl-piperidin-l-yl)-ethyl]-l,6-dihydro-pyrimidin-
2-yl} -nicotinonitrile,
6-(4-Benzenesulfonylmethyl-thiazol-2-yl)-5-hydroxy-nicotinic acid,
6-{4-[2-(5-Bromo-2-oxo-2H-pyridin-l-yl)-2-oxo-ethyl]-thiazol-2-yl}-5-hydroxy- nicotinonitrile,
5-Hydroxy-6-{4-[2-(4-methyl-piperazin-l-yl)-2-oxo-ethyl]-thiazol-2-yl} -nicotinonitrile, 6-[4-(2-[l,4']Bipiperidinyl-r-yl-2-oxo-ethyl)-thiazol-2-yl]-5-hydroxy-nicotinonitrile,
6-{4-[2-(l,3-Dihydro-isoindol-2-yl) -2-oxo-ethyl]-thiazol-2-yl}-5-hydroxy- nicotinonitrile,
6- {4-[2-(3 ,4-Dihydro- 1 H-isoquinolin-2-yl)-2-oxo-ethyl]-thiazol-2-yl} -5 -hydroxy- nicotinonitrile,
5-Hydroxy-6-[4-(2-indol-l-yl-2-oxo-ethyl)-thiazol-2-yl]-nicotinonitrile,
6-{5-[2-(l,3-Dihydro-isoindol-2-yl)-2-oxo-ethyl]-6-oxo-l,6-dihydro-pyrimidin-2-yl}-5- hydroxy-nicotinonitrile,
5-Hydroxy-6-(6-oxo-5-phenylmethanesulfonylmethyl-l,6-dihydro-pyrimidin-2-yl)- nicotinonitrile,
6-{5-[2-(3,4-Dihydro-lH-isoquinolin-2-yl)-2-oxo-ethyl]-6-oxo-l,6-dihydro-pyrimidin-2- yl } -5 -hydroxy-nicotinonitrile,
5-Hydroxy-6- {4-[2-oxo-2-((R)-2-trifluoromethyl-pyrrolidin- 1 -yl)-ethyl] -thiazol-2-yl} - nicotinonitrile,
6- {4-[2-(5-Bromo- 1 ,3-dihydro-isoindol-2-yl)-2-oxo-ethyl]-thiazol-2-yl} -5-hydroxy- nicotinonitrile,
5-Hydroxy-6-{4-[2-((S)-2-hydroxymethyl-pyrrolidin-l-yl)-2-oxo-ethyl]-thiazol-2-yl}- nicotinonitrile,
(S)-I- {2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetyl}-pyrrolidine-2- carboxylic acid,
6-{4-[2-(5-Amino-3,4-dihydro-lH-isoquinolin-2-yl)-2-oxo-ethyl]-thiazol-2-yl}-5- hydroxy-nicotinonitrile,
(S)-2- {2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetyl} -1 ,2,3,4-tetrahydro- isoquinoline-3-carboxylic acid tert-butylamide,
6- [4-(2-Azetidin-l-yl-2-oxo-ethyl)-thiazol-2-yl] -5 -hydroxy-nicotinonitrile,
6- {4-[2-(4-Fluoro-l ,3-dihydro-isoindol-2-yl)-2-oxo-ethyl]-thiazol-2-yl} -5-hydroxy- nicotinonitrile,
6- {4-[2-(5-Fluoro-l ,3-dihydro-isoindol-2-yl)-2-oxo-ethyl]-thiazol-2-yl} -5-hydroxy- nicotinonitrile,
6-{4-[2-(l,3-Dihydro-isoindol-2-yl)-2-oxo-ethyl]-5-methyl-thiazol-2-yl}-5-hydroxy- nicotinonitrile, 6-{5-[2-(4-Fluoro-l,3-dihydro-isoindol-2-yl)-2-oxo-ethyl]-6-oxo-l,6-dihydro-pyrimidin-
2-yl}-5-hydroxy-nicotinonitrile,
[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-5-phenyl-thiazol-4-yl]-acetic acid,
5 -Hydroxy-6- [4-(2-oxo-2-pyrrolidin- 1 -yl-ethyl)-5 -phenyl-thiazol-2-yl] -nicotinonitrile,
6-{4-[2-(l,3-Dihydro-isoindol-2-yl) -2-oxo-ethyl]-5-phenyl-thiazol-2-yl}-5-hydroxy- nicotinonitrile,
5 -Hydroxy-4-methyl-6- [4-(2-oxo-2-pyrrolidin- 1 -yl-ethyl)-thiazol-2-yl] -nicotinonitrile,
6-{4-[2-(l,3-Dihydro-isoindol-2-yl)-2-oxo-ethyl]-thiazol-2-yl}-5-hydroxy-4-methyl- nicotinonitrile, l-{2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetyl}-aziridine-2-carboxylic acid methyl ester,
5 -Hydroxy-6- {4- [2-oxo-2-((S)-2-trifluoromethyl-pyrrolidin-l-yl)-ethyl] -thiazol-2-yl}- nicotinonitrile,
6-{5-[2-(5-Bromo-l,3-dihydro-isoindol-2-yl)-2-oxo-ethyl]-6-oxo-l,6-dihydro-pyrimidin-
2-yl}-5-hydroxy-nicotinonitrile,
5 -Hydroxy-6- [5 -methyl-4-(2-oxo-2-pyrrolidin- 1 -yl-ethyl)-thiazol-2-yl] -nicotinonitrile,
6- [4-(2- Azetidin- 1 -yl-2-oxo-ethyl)-5 -methyl-thiazol-2-yl] -5 -hydroxy-nicotinonitrile,
6- [4-(2-Azetidin-l-yl-2-oxo-ethyl)-5 -phenyl-thiazol-2-yl] -5 -hydroxy-nicotinonitrile,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-5-methyl-thiazol-4-yl]-N-(2-pyridin-2-yl-ethyl)- acetamide,
5-Hydroxy-6-[4-(3-phenyl-[l,2,4]oxadiazol-5-ylmethyl)-thiazol-2-yl]-nicotinonitrile,
2-[2-(5-Cyano-3-hydroxy-4-methyl-pyridin-2-yl)-5-methyl-thiazol-4-yl]- N-(2-pyridin-2- yl-ethyl)-acetamide,
2-[2-(5-Cyano-3-hydroxy-4-methyl-pyridin-2-yl)-5-phenyl-thiazol-4-yl]- N-(2-pyridin-2- yl-ethyl)-acetamide,
2-[2-(5-Cyano-3-hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl]-N-(2-pyridin-2-yl-ethyl)- acetamide,
2-[2-(5-Cyano-3-hydroxy-pyridin-2-yl)-5-phenyl-thiazol-4-yl]-N-(2-pyridin-2-yl-ethyl)- acetamide,
2-[2-(5-Cyano-3-hydroxy-4-methyl-pyridin-2-yl)-5-methyl-thiazol-4-yl]- N-(3-imidazol-
1 -yl-propyl)-acetamide, 2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl] -N-methyl-N-(2-pyridin-2- yl-ethyl)-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl] -N-(3 -morpholin-4-yl- propyl)-acetamide,
[2-(5-Cyano-3-hydroxy-pyridin-2-yl) -thiazol-4-yl]-carbamic acid butyl ester,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-cyclopropylmethyl-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-pyridin-2-yl)-thiazol-4-yl]-N-cyclopropyl-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl]-N-(2-diethylamino-ethyl)- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-5-methyl-thiazol-4-yl]- N-(2- diethylamino-ethyl)-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl] -N-cyclopropylmethyl- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl]-N-cyclopropyl-acetamide,
2-[2-(5-Cyano-3-hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl]-N-(2,2,2-trifluoro-ethyl)- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl]-N-ethyl-acetamide,
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-5-methyl-thiazol-4-yl]- N-ethyl- acetamide,
2- [2-(5 -Cyano-3 -hydroxy-4-methyl-pyridin-2-yl)-5-methyl-thiazol-4-yl]- N-(2- pyrrolidin- 1 -yl-ethyl)-acetamide.
2-[2-(5-Cyano-3-hydroxy-4-methyl-pyridin-2-yl)-thiazol-4-yl]-acetamide.
2-(5-Phenylmethanesulfonylmethyl-[l,2,4]oxadiazol-3-yl)-pyridin-3-ol,
6-(5-Benzylsulfanylmethyl-[ 1 ,2,4]oxadiazol-3-yl)-5-hydroxy-nicotinic acid,
5-Hydroxy-6-(5-phenylmethanesulfonylmethyl-[ 1 ,2,4]oxadiazol-3-yl)-nicotinic acid,
6-(5-Ethylsulfanylmethyl-[l,2,4]oxadiazol-3-yl)-5-hydroxy-nicotinic acid,
6-(5-Ethanesulfonylmethyl-[ 1 ,2,4]oxadiazol-3-yl)-5-hydroxy-nicotinic acid,
3-(3-Hydroxy-5-methyl-pyridin-2-yl) -[1 ,2,4]oxadiazole-5-carboxylic acid dimethylamide,
5-Hydroxy-6-(5-phenylsulfanylmethyl-[ 1 ,2,4]oxadiazol-3-yl)-nicotinic acid,
6-(5-Benzenesulfonylmethyl-[ 1 ,2,4]oxadiazol-3-yl)-5-hydroxy-nicotinic acid, 2-[3-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-5-yl]-N,N-dimethyl-acetamide,
3 - [3 -(5 -Cyano-3 -hydroxy-pyridin-2-yl)- [ 1 ,2,4]oxadiazol-5 -yl] -propionic acid,
6-[5-(2-Carboxy-ethyl)-[ 1 ,2,4]oxadiazol-3-yl]-5-hydroxy-nicotinic acid,
2-[3-(5-Bromo-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-5-yl]-N,N-dimethyl-acetamide,
2- [3 -(5 -Bromo-3 -hydroxy-pyridin-2-yl)- [ 1 ,2,4]oxadiazol-5-yl]- 1 -pyrrolidin-1 -yl- ethanone,
N-Benzyl-2-[3-(5-bromo-3-hydroxy-pyridin-2-yl)-[ 1 ,2,4]oxadiazol-5-yl]- acetamide,
N-Benzyl-2-[5-(5-cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]- acetamide,
2-[5-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]-N-phenethyl-acetamide,
2-[5-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]-N-(2-pyridin-2-yl-ethyl)- acetamide,
2-[5-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]-N-[2-(4-hydroxy-phenyl)- ethyl] -acetamide,
2-[5-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]-N-pyridin-2-ylmethyl- acetamide,
2-[5-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]-N-pyridin-3-ylmethyl- acetamide, and
2-[5-(5-Cyano-3-hydroxy-pyridin-2-yl)-[l,2,4]oxadiazol-3-yl]-N-pyridin-4-ylmethyl- acetamide or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
76. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, and a physiologically acceptable carrier, diluent, or excipient.
77. A method of modulating a level of HIF in a subject comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, sufficient to modulate the level of HIF in the subject.
78. A method of modulating an amount of HIF in a cell comprising administering to the cell, or contacting the cell with, an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, sufficient to modulate the amount of HIF in the cell.
79. The method of claim 78, wherein the amount of HIF in the cell is increased.
80. A method of inhibiting hydroxylation of HIF α in a subject comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, sufficient to inhibit the hydroxylation of HIF α in the subject.
81. A method of modulating expression of HIF -regulated genes in a subject comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, sufficient to modulate expression of HIF- regulated genes in the subject.
82. A method of modulating HIF levels or HIF activity in a subject comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, an amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, sufficient to modulate HIF levels or HIF activity in the subject.
83. A method of treating a disorder in a subject where it is desired to modulate HIF activity or levels, the method comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
84. A method of treating a disorder in a subject comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein the disorder is selected from the group consisting of ischemic disorders, hypoxic disorders, anemic disorders (including, but not limited to, anemia associated with autoimmune diseases, rheumatoid arthritis, systemic lupus, chronic infections such as, without limitation, HCV, and HIV, inflammatory bowel disease, chemotherapy-induced, chronic heart disease, chronic kidney disease, chronic obstructive pulmonary disease (COPD), end stage renal disease, prematurity, hypothyroidism, malnutrition, blood disorders, including but not limited to, sickle cell anemia, and β-thalassemia, malignancies), stenocardia, neurological disorders, stroke, epilepsy, neurodegenerative disease, myocardial infarction, liver ischemia, renal ischemia, chronic kidney disease, peripheral vascular disorders, ulcers, burns, chronic wounds, pulmonary embolism, ischemic-reperfusion injury, ischemic-reperfusion injuries associated with surgeries and organ transplantations, respiratory distress syndrome, prevention of broncho-pulmonary dysplasia in pre-maturity, pulmonary hypertension, auto-immune diseases, side effects of diabetes, diabetic retinopathy, macular degeneration, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, Eales' disease, Behcet's disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndrome, toxoplasmosis, trauma and post-laser complications, diseases associated with rubeosis, metabolic disorders, proliferative vitreoretinopathy, and depression.
85. The method of claim 84, wherein the anemic disorder is selected from the group consisting of autoimmune disorders, chronic infections, inflammatory bowel disease, chronic heart disease, chronic kidney disease, chronic obstructive pulmonary disease (COPD), end stage renal disease, blood disorders, chemotherapy-induced, prematurity, hypothyroidism, malnutrition and malignancies.
86. The method of claim 85, wherein the blood disorder is sickle cell anemia or β- thalassemia.
87. The method of claim 85, wherein the chronic infection is HCV, or HIV.
88. The method of claim 85, wherein the autoimmune disorder is rheumatoid arthritis or systemic lupus.
89. A method of modulating the activity of a hydroxylase enzyme which modifies the alpha subunit of hypoxia inducible factor comprising contacting the enzyme with at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
90. A method of modulating levels of endogenous EPO in a subject comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
91. A method of regulating or modulating angiogenesis in a subject comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
92. A method for vascularizing ischemic tissue in a subject comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
93. A method for promoting the growth of skin graft replacements comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
94. A method for promoting tissue repair in the context of guided tissue regeneration (GTR) procedures comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
95. A method for treating anemia in a subject comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
96. A method for regulating anemia in a subject comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
97. A method for preventing anemia in a subject comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
98. A method of treating ischemia in a subject comprising identifying a subject in need thereof and administering to the subject, or contracting the subject with a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof
99. A method of treating a hypoxic-related disorder in a subject comprising identifying a subject in need thereof and administering to the subject, or contracting the subject with a therapeutically effective amount of at least one compound of Formula I, or pharmaceutically acceptable salt, ester, amide, or a prodrug thereof.
100. A method of treating inflammatory disorders in a subject comprising identifying a subject in need thereof and administering to the subject, or contracting the subject with, a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
101. A method of treating depression disorders in a subject comprising identifying a subject in need thereof and administering to the subject, or contracting the subject with, a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
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