(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`21 June 2007 (21.06.2007)
`
`{4
`
`|
`
` (10) International Publication Number
`
`WO 2007/070359 A2
`
`(51) International Patent Classification:
`
`Notclassified
`
`(21) International Application Number:
`PCT/US2006/046785
`
`(22) International Filing Date:
`8 December 2006 (08.12.2006)
`
`Camarillo, California 93010 (US). KURZEJA, Robert
`[US/US]; 4012 Barcelona Place, Newbury Park, California
`91320 (US). YU, Violeta [CA/US]; 4086 Weeping Wil-
`low, Moorpark, California 93021 (US). DAO, Jennifer
`[US/US]; 6838 Poppyview Drive, Oak Park, California
`91377 (US).
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(74) Agent: GARRETT,Arthur, S.; FINNEGAN, HENDER-
`SON, FARABOW, GARRETT & DUNNER LLP, 901
`New York Avenue, Nw, Washington, District Of Columbia
`20001-4413 (US).
`
`(30) Priority Data:
`60/748,577
`60/785,358
`
`9 December 2005 (09.12.2005)
`24 March 2006 (24.03.2006)
`
`US
`US
`
`(71) Applicant(for all designated States except US): AMGEN
`INC.[US/US]; One Amgen Center Drive, Thousand Oaks,
`California 91320-1799 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): ALLEN, Jennifer
`R. [US/US]; 5255 Via Capote, Newbury Park, California
`91320 (US). TEGLEY, Christopher M. [US/US]; 478
`Thunderhead Street, Thousand Oaks, California 91360
`(US). BISWAS,Kaustav[IN/US]; 26003 B Alizia Canyon
`Drive, Calabasas, California 91302 (US). BURLI, Roland
`[CH/US]; 479 S. Hudson Avenue, Pasadena, California
`91101 (US). MULLER, Kristine M.
`[CA/US]; 2520
`Vista Wood Circle #33, Thousand Oaks, California 91362
`(US). FROHN, Michael J. [US/US]; 2808 Cedar Wood
`Place, Thousand Oaks, California 91362 (US). GOLDEN,
`Jennifer E. [US/US]; 3168 Tecopa Springs Lane, Simi
`Valley, California 93063 (US). MERCEDE, Stephanie
`J. [US/US]; 22301 Haynes Street, Woodland Hills, Cal-
`ifornia 91303 (US). NEIRA, Susana C. [CL/US]; 3277
`Sunset Hills Blvd., Thousand Oaks, California 91362
`(US). PETERKIN, Tanya A. N. [JM/US]; 6130 Nevada
`Ave., #311, WoodlandHills, California 91367 (US). HUN-
`GATE, Randall W. [US/US]; 640 W. Highland Drive,
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
`GB, GD, GE, GH, GM, GT, HN, HR, HU,ID,IL,IN,IS,
`JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS,
`LT, LU,LV, LY, MA, MD, MG, MK, MN, MW, Mx, MY,
`MZ, NA, NG, NI, NO, NZ, OM,PG, PH, PL, PT, RO, RS,
`RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN,
`TR,TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, 7M,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK,EE,ES, FI,
`FR, GB, GR, HU,IE,IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`without international search report and to be republished
`upon receipt of that report
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes and Abbreviations" appearing at the begin-
`ning of each regular issue of the PCT Gazette.
`
`(54) Title: QUINOLONE BASED COMPOUNDSEXHIBITING PROLYL HYDROXYLASE INHIBITORY ACTIVITY, AND
`COMPOSITIONS, AND USES THEREOF
`
`(57) Abstract: This invention relates to new quinolone based compounds that exhibit prolyl hydroxylase inhibitory activity. This
`invention also relates to methodsof increasing HIF levels oractivity in a subject or treating a condition associated with HIF levels or
`activity in a subject by administering to the subject at least one quinolone based compound. This inventionfurther involves assays
`for the detection of a hydroxyproline residuc in a HIF moleculc.
`
`
`
`
`
`
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`WO2007/070359A2|IMMNNINNINITNTMIATAIITAKAT
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`WO 2007/070359
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`PCT/US2006/046785
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`QUINOLONE BASED COMPOUNDS EXHIBITING PROLYL HYDROXYLASE
`INHIBITORY ACTIVITY, AND COMPOSITIONS,
`AND USES THEREOF
`
`This application claims the benefit of priority of U.S. Provisional Patent Application
`No. 60/748,577, filed December 9, 2005, and U.S. Provisional Patent Application No.
`60/785,358, filed March 24, 2006.
`
`The cellular transcription factor HIF (Hypoxia Inducible Factor) occupies a central
`
`position in oxygen homeostasis in a wide range of organismsandis a key regulator of
`
`responses to hypoxia. The genes regulated by HIF transcriptional activity can playcritical
`
`roles in angiogenesis, erythropoiesis, hemoglobin F production, energy metabolism,
`
`inflammation, vasomotorfunction, apoptosis and cellular proliferation. HIF can also play a
`
`role in cancer, in which it is commonly upregulated, and in the pathophysiological responses
`to ischemia and hypoxia.
`
`The HIF transcriptional complex comprises an af heterodimer: HIF-B is a
`
`constitutive nuclear protein that dimerizes with oxygen-regulated HIF-« subunits. Oxygen
`
`regulation occurs through hydroxylation of the HIF-o subunits, which are then rapidly
`
`destroyed by the proteasome. In oxygenated cells, the von Hippel-Lindau tumor suppressor
`
`protein (pVHL) binds to. hydroxylated HIF-o subunits, thereby promoting their ubiquitin
`
`dependentproteolysis. This process is suppressed under hypoxic conditions, stabilizing
`
`HIF-a and promoting transcriptional activation by the HIF ap complex. See, e.g., U.S.
`
`Patent 6,787,326.
`
`Hydroxylation ofHIF-o subunits can occur on proline and asparagine residues and
`can be mediated by a family of 2-oxoglutarate dependent enzymes. This family includes the
`
`HIF prolyl hydroxylase isozymes (PHDs), which hydroxylate Pro 402 and Pro 564 of human
`
`HIF1a, as well as Factor Inhibiting HIF (FIN), which hydroxylates Asn 803 of human
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`WO 2007/070359
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`HIFla. Inhibition of FIH or the PHDsleads to HIF stabilization and transcriptional
`activation. See, e.g., Schofield and Ratcliffe, Nature Rev. Mol. Cell Biol., Vol 5, pages 343-
`354 (2004).
`
`Provided herein is at least one compound chosen from compoundsof Formula I:
`
`Ry
`
`Re
`
`oO
`
`Rg Rg
`
`Re
`
`a pharmaceutically acceptable salt thereof, a solvate thereof, a chelate thereof, a non-covalent
`complex thereof, a prodrug thereof, and mixtures of any of the foregoing, wherein:
`nis 1 to 6;
`R, is chosen from H, lower alkyl and substituted lower alkyl;
`Rais chosen from H, lower alky! and substituted lower alkyl;
`R3 and R4 are independently chosen from H, lower alkyl, substituted lower alkyl,
`lower haloalkyl, substituted lower haloalkyl, or R3 and Rg can join together to form a 3 to 6
`membered ring or a substituted 3 to 6 membered ring;
`Rs is chosen from OH, SH, NH, lower alkyl, substituted lower alkyl, lower alkoxy,
`substituted lower alkoxy, and sulfany];
`Rg is chosen from H, OH, SH, NHb, NHSO)R, and sulfonyl;
`each of R7, Rg, Ro and Rio is independently chosen from H, alkyl, substituted alkyl,
`alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, NR3Ru,
`C(O)OH, ORj3, SRiz, SO2R13, CN, NO, halo,aryl, substituted aryl, heteroaryl, substituted
`heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, substituted
`heterocycloalkyl, alkylsilyl, substituted alkylsilyl, alkynylsilyl, substituted alkynylsilyl,
`alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, and -X-Rj2, wherein:
`R3 and Ry are defined above;
`X is chosen from —N(R1,)-Y- and -Y-N(Rip-3
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`WO 2007/070359
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`ah
`
`Y is chosen from C(O), SQz, alkylene, substituted alkylene, alkenylene, substituted
`alkenylene, alkynylene, and substituted alkynylene;
`Ry is chosen from H, lower alkyl, and substituted lower alkyl,
`Riz is chosen from H, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted
`aryl, heteroaryl, and substituted heteroaryl; and
`Rj is chosen from H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,
`substituted alkynyl and NR3Ru;
`wherein at least one of adjacent pairs Rg and R7, R7 and Rg, Rg and Ro, Ro and Ryo,
`and Rig and Rj, can join together to form a 4 to 7 membered ring or a substituted 4 to 7
`memberedring.
`Also provided herein is a pharmaceutical composition comprising at least one
`pharmaceutically acceptable carrier, and a therapeutically effective amount ofat least one
`
`compound described herein.
`
`Further provided are pharmaceutical compositions comprisingat least one
`pharmaceutically acceptable carrier, and a therapeutically effective amountofat least one
`
`compound described herein in combination with at least one additional compound such as an
`erythropoiesis stimulating agent or chemotherapeutic agent.
`
`Additionally provided herein is a method of increasing HIF levels or activity in a
`subject by administering to the subjectat least one compound describedherein.
`
`Further provided is a method of treating a condition where it is desired to modulate
`
`HIF activity comprising administering to a subject at least one compounddescribed herein.
`
`Also provided is a methodoftreating a hypoxic or ischemic related disorderin a
`subject comprising administering to a subjectat least one compound described herein.
`Also provided is a method oftreating anemiain a subject comprising administering to
`a subject at least one compounddescribedherein.
`
`Further provided is a method of modulating the amount of HIF in a cell comprising
`contacting the cell with at least one compound described herein.
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`ta
`
`Additionally provided is a method of increasing the amount of hemoglobin Fina
`
`subject comprising administering to the subject at least one compounddescribed herein.
`
`Also providedis a method of modulating angiogenesis in a subject comprising
`
`administering to the subject at least one compound described herein.
`
`Additionally provided is a methodof treating at least one diseasein a patient in need
`
`of such treatment comprising administering to the patient a therapeutically effective amount
`
`of at least one compound described herein.
`
`Also provided is a methodof inhibiting HIF hydroxylation in a subject comprising
`
`administering to the subject at least one compounddescribedherein.
`
`Further provided is an assay for the detection of HIF1a hydroxyproline residues
`
`comprising incubating a fluorochrome-labeled HIF1a polypeptide or fragmentthereof with a
`
`VCB complex labeled with a rare earth element and detecting the binding of the VCB
`
`complex to HIF1a by homogeneous time-resolved FRET.
`
`Also provided is an assay for the detection of HIF1a hydroxyproline residues
`
`comprising incubating a HIF1o polypeptide or fragment thereof with a VCB complex labeled
`
`with ruthenium and detecting the binding of the VCB complex to HIF1a by
`
`electrochemiluminescence.
`
`Additional embodimentsof the invention are set forth in the description which
`
`follows, or may be learned by practice of the invention.
`
`Figure 1 illustrates the ratio of fluorescence signal to background generated by the
`
`interaction of Eu-VCB with streptavidin-APC-hydroxyprolyl HIF1o peptide.
`
`Figure 2 illustrates the ratio of HTRF signal generated by the interaction of Eu-VCB
`
`with streptavidin-APC-hydroxyprolyl HIFla peptide over backgroundsignal generated by
`
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`the interaction of Eu-VCB with streptavidin-APC-HIF1o peptide (nonhydroxylated). Panel
`
`A illustrates a 0-125 nM peptide range. Panel B illustrates a 0-10 nM peptide range.
`
`Figure 3 illustrates VCB binding and HTRF detection for determining HIF PHD2
`
`hydroxylation of a HIF1& peptide. PanelA illustrates a time course forthe hydroxylation of
`
`the HIF1o. peptide with increasing amounts of HIF PHD2 enzyme. Panel B illustratesinitial
`
`rates with increasing enzyme concentrations.
`
`Figure 4 illustrates the Ru-VCB/biotin-HIF-OH binding curve and linear range
`
`determination by ECL detection.
`
`Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction
`conditions, and so forth usedin the specification and claims are to be understood as being
`modified in all instances by the term “about.” Accordingly, unless indicated to the contrary,
`the numerical parameters set forth in the following specification and attached claims are
`
`approximations that may vary depending uponthe standard deviation foundin their
`
`respective testing measurements,
`
`As used herein, when any variable occurs more than onetimein a chemical formula,
`
`its definition on each occurrenceis independentofits definition at every other occurrence.
`
`Whenthe chemical structure and chemical name conflict, the chemical structure is
`
`determinative of the identity of the compound. The compoundsof the present disclosure may
`contain one or more chiral centers and/or double bondsandtherefore, may exist as
`Stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or
`
`diastereomers. Accordingly, any chemical structures within the scopeofthe specification
`depicted, in whole orin part, with a relative configuration encompassall possible
`enantiomers and stereoisomersoftheillustrated compoundsincluding the stereoisomerically
`pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and
`enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be
`
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`resolved into the component enantiomers or stereoisomers using separation techniques or
`chiral synthesis techniques well knowntothe skilled artisan.
`
`Compounds of Formula I include, but are not limited to optical isomers of compounds
`of FormulaI, racemates, and other mixtures thereof. In those Situations, the single
`enantiomersor diastereomers,i.e., optically active forms, can be obtained by asymmetric
`
`synthesis or by resolution of the racemates. Resolution of the racemates can be
`
`accomplished, for example, by conventional methods such as crystallization in the presence
`of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid
`chromatography (HPLC) column. In addition, compounds of Formula I include Z- and E-
`
`forms (or cis- and trans- forms) of compounds with double bonds. Where compounds of
`Formula I exists in various tautomeric forms, chemical entities of the present invention
`
`includeall tautomeric forms of the compound.
`
`Compoundsofthe present disclosure include, but are not limited to compounds of
`Formula J and all pharmaceutically acceptable forms thereof. Pharmaceutically acceptable
`forms of the compoundsrecited herein include pharmaceutically acceptablesalts, solvates,
`crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes,
`prodrugs, and mixtures thereof. In certain embodiments, the compounds described herein are
`in the form of pharmaceutically acceptablesalts. As used henceforth, the term “compound”
`encompasses not only the compounditself, but also a pharmaceutically acceptable salt
`thereof, a solvate thereof, a chelate thereof, a non-covalent complex thereof, a prodrug
`thereof, and mixtures of any of the foregoing.
`
`As noted above, prodrugsalsofall within the scope of chemical entities, for example,
`ester or amide derivatives of the compounds of Formula L The term “prodrugs”includes any
`compoundsthat become compounds of Formula I when administered to a patient, e.g., upon
`metabolic processing of the prodrug. Examples of prodrugs include, but are notlimited to,
`
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`acetate, formate, and benzoate andlike derivatives of functional groups (such as alcohol or
`
`amine groups) in the compounds of FormulaI.
`
`The term “solvate”refers to the compound formedbythe interaction of a solvent and
`
`acompound, Suitable solvates are pharmaceutically acceptable solvates, such as hydrates,
`
`|
`including monohydrates and hemi-hydrates.
`“Alkeny!”refers to an unsaturated branched,straight-chain or cyclic alkyl group
`
`having at least one carbon-carbon double bond derived by the removal of one hydrogen atom
`
`from a single carbon atom of a parent alkene. The group maybein either the Z- and E-
`
`forms(orcis or trans conformation) about the double bond(s). Typical alkenyl groups
`include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,
`
`prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop~1-en-1-yl; cycloprop-2-en-1-yl; butenyls
`
`such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl,
`
`but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,
`
`cyclobuta-1,3-dien-1-yl; and the like. In certain embodiments, an alkenyl group has from 2
`to 20 carbon atomsand in other embodiments, from 2 to 6 carbon atoms,i.e. “lower alkenyl.”
`
`“Alkynyl” refers to an unsaturated branched orstraight-chain havingat least one
`carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon
`
`atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl;
`
`propynyl; butenyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like. In certain
`
`embodiments, an alkynyl group has from 2 to 20 carbon atomsand in other embodiments,
`
`from 2 to 6 carbon atoms,i.e. “lower alkynyl.”
`
`“Alkoxy”refers to a radical -OR where R represents an alkyl, substituted alky],
`
`substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl
`
`group as defined herein. Representative examples include, but are not limited to, methoxy,
`
`ethoxy, propoxy, butoxy, cyclohexyloxy, and thelike.
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`“Alkoxycarbonyl”refers to a radical ~C(O)— OR whereR is as defined herein.
`
`“Alkyl” refers to a saturated, branched orstraight-chain monovalent hydrocarbon
`
`group derived by the removal of one hydrogen atom from a single carbon atom of a parent
`alkane. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyls such as
`
`propan-1-yl, propan-2-yl, and cyclopropan-1-yl, butyls such as butan-1-yl, butan-2-yl,
`2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, tert-butyl, and the like, In
`
`certain embodiments,an alkyl group comprises from 1 to 20 carbon atoms. As used herein
`
`the term “loweralkyl” refers to an alkyl group comprising from | to 6 carbon atoms.
`
`“Aryl”refers to a monovalent aromatic hydrocarbon group derived by the removal of
`
`one hydrogen atom from a single carbon atom of a parent aromatic ring system. Aryl
`
`encompasses 5- and 6-membered carbocyclic aromatic rings, for example, benzene;bicyclic
`ring systems wherein at least one ringis carbocyclic and aromatic, for example, naphthalene,
`indane,and tetralin; and tricyclic ring systems wherein at least onering is carbocyclic and
`
`aromatic, for example, fluorene. For example, aryl includes 5- and 6-membered carbocyclic
`aromatic rings fused to a 5- to 7-membered heterocycloalky! ring containing 1 or more
`heteroatoms chosen from N,O, and S. In certain embodiments, an aryl group can comprise
`from 6 to 10 carbon atoms. Aryl, however, does not encompass or overlap in any way with
`heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings is
`fused with a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl, not aryl,
`as defined herein.
`
`“Arylalky!”or “aralkyl” refers to an acyclic alkyl group in which one of the hydrogen
`atoms bondedto a carbon atom,typically a terminal or Sp3 carbon atom, is replaced with an
`aryl group. Typical arylalkyl groups include, but are not limited to, benzyl,
`2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-y],
`2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-y! and the like. Where
`
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`specific alkyl moieties are intended, the nomenclaturearylalkyl, arylalkenyl, and/or
`
`arylalkynyl is used. In certain embodiments, an arylalkyl group can be (C¢-30) arylalkyl, e.g.,
`the alkyl group of the arylalkyl group can be (C)-19) andthe aryl moiety can be (Cs5-29).
`
`“Carbonyl”refers to a radical -C(O) group.
`
`“Carboxy”refers to the radical -C(O)OH.
`
`“Cyano”refers to the radical -CN.
`
`“Cycloalky!”refers to a saturated or unsaturated cyclic alkyl group. Where a specific
`
`level of saturation is intended, the nomenclature “cycloalkany!”or “cycloalkenyl”is used.
`
`Typical cycloalkyl groups include, but are notlimitedto, groups derived from cyclopropane,
`cyclobutane, cyclopentane, cyclohexane,and the like. In certain embodiments, the cycloalkyl
`group can be C3-19 cycloalkyl, such as, for example, C3-6 cycloalkyl.
`
`“Heterocycloalky!”refers to a saturated or unsaturated, but non-aromatic, cyclic alkyl
`
`group in which one or more carbon atoms (and any associated hydrogen atoms) are
`
`independently replaced with the same or different heteroatom and its associated hydrogen
`
`atoms, where appropriate. Typical heteroatomsto replace the carbon atom(s) include, but are
`
`not limited to, N, P, O, S, and Si. Where a specific level of saturation is intended, the
`
`nomenclature “heterocycloalkanyl” or “heterocycloalkenyl” is used. Typical
`
`heterocycloalkyl groups include,but are notlimited to, groups derived from epoxides,
`imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine,
`tetrahydrofuran, tetrahydropyran andthe like. Substituted heterocycloalkyl also includes ring
`
`systems substituted with one or more oxo (=0) or oxide (-O/) substituents, such as piperidinyl
`N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.
`
`“Disease” refers to any disease, disorder, condition, symptom,orindication.
`
`“Halo”refers to a fluoro, chloro, bromo, or iodo group.
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`“Heteroaryl” refers to a monovalent heteroaromatic group derived by the removal of
`
`one hydrogen atom from a single atom ofa parent heteroaromatic ring system. Heteroaryl
`
`encompasses:
`
`5- to 7-membered aromatic, monocyclic rings containing one or more, for example,
`
`from1to 4,or in certain embodiments, from 1 to 3, heteroatoms chosen from N,O,and S,
`
`with the remaining ring atoms being carbon; and
`
`polycyclic heterocycloalkyl rings containing one or more, for example, from 1 to 4, or
`
`in certain embodiments, from 1 to 3, heteroatoms chosen from N,O, and S, with the
`
`remaining ring atoms being carbon and whereinat least one heteroatom is present in an
`
`aromatic ring.
`
`For example, heteroaryl includes a 5- to 7J-membered heteroaromatic ring fused to a 5-
`
`to 7-membered cycloalkyl ring and a 5- to 7-membered heteroaromatic ring fused to a 5- to 7-
`
`membered heterocycloalkyl ring. For such fused, bicyclic heteroaryl ring systems wherein
`
`only one ofthe rings contains one or more heteroatoms, the point of attachment maybeat the
`
`heteroaromatic ring or the cycloalkyl ring. When the total number of S and O atomsin the
`
`heteroaryl group exceeds 1, those heteroatomsare not adjacent to one another. In certain
`
`embodiments, the total number of S and O atomsin the heteroaryl group is not more than 2.
`
`In certain embodiments, the total number of S and O atoms in the aromatic heterocycle is not
`
`more than 1. Heteroaryl does not encompassor overlap with aryl as defined above. Typical
`
`heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole,
`
`carbazole, B-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole,-
`
`indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,
`
`isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine,
`phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,
`
`pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine,
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`quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, xanthene, andthe like. In
`
`certain embodiments,the heteroaryl group can be between 5 to 20 membered heteroaryl, such
`
`as, for example, a 5 to 10 membered heteroaryl. In certain embodiments, heteroaryl groups
`
`can be those derived from thiophene, pyrrole, benzothiophene, benzofuran,indole, pyridine,
`
`quinoline, imidazole, oxazole, and pyrazine.
`
`“Heteroarylalkyl” or “heteroaralkyl”refers to an acyclic alkyl group in which one of
`
`the hydrogen atoms bondedto a carbon atom,typically a terminal or sp’ carbon atom,is
`
`replaced with a heteroaryl group. Where specific alkyl moieties are intended, the
`
`nomenclature heteroarylalkanyl, heteroarylalkenyl, and/or heteroarylalkyny] is used. In
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`certain embodiments,the heteroarylalkyl group can be a 6 to 30 membered heteroarylalkyl,
`
`e.g., the alkanyl, alkenyl or alkynyl! moiety ofthe heteroarylalkyl can be 1 to 10 membered
`
`and the heteroaryl moiety can be a 5 to 20-membered heteroaryl.
`
`“Sulfonyl” refers to a radical -S(O)2R where R is an alkyl, substituted alkyl,
`
`substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl
`
`group as defined herein. Representative examplesinclude, but arenot limited to
`
`methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfony], andthe like.
`
`“Sulfanyl” refers to a radical -SR whereRis an alkyl, substituted alkyl, substituted
`
`cycloalkyl, substituted heterocycloalkyl, substituted aryl, or substituted heteroaryl group as
`defined herein that may be optionally substituted as defined herein. Representative examples
`include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.
`“Pharmaceutically acceptable”refers to generally recognized for use in animals, and
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`moreparticularly in humans.
`
`“Pharmaceutically acceptable salt” refers to a salt of a compoundthatis
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`pharmaceutically acceptable and that possesses the desired pharmacological activity of the
`
`parent compound. Suchsalts include: (1) acid addition salts, formed with inorganic acids
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`such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and
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`the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid,
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`cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic
`
`acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, 3-(4-
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`hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the
`
`like; or (2) salts formed whenan acidic proton presentin the parent compoundeitheris
`
`replaced by a metal ion,e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or
`
`coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-
`
`methylglucamine, dicyclohexylamine,and the like.
`
`“Pharmaceutically acceptable excipient,” “pharmaceutically acceptable carrier,” or
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`“pharmaceutically acceptable adjuvant”refer, respectively, to an excipient, carrier or
`
`adjuvant with which at least one compoundof the present disclosure is administered.
`
`“Pharmaceutically acceptable vehicle”refers to any of a diluent, adjuvant, excipient or carrier
`
`with which at least one compoundofthe present disclosure is administered.
`
`“Stereoisomer”refers to an isomerthat differs in the arrangement of the constituent
`
`atoms in space. Stereoisomersthat are mirror images of each other and optically active are
`
`termed “enantiomers,” and stereoisomers that are not mirror images of one anotherand are
`
`optically active are termed “diastereoisomers.”
`
`“Subject” includes mammals and humans. The terms “human” and “subject” are used
`
`interchangeably herein.
`
`“Substituted” refers to a group in which one or more hydrogen atoms are each
`
`independently replaced with the sameordifferent substituent(s). Typical substituents
`include, but are not limited to, —X, —R33, -OH, =O, “ORn, -SR33, -SH, =S,
`-NR33R34, =NR33, ~CX3, —CF3, -CN,-NO2,-S(O)2R33, -OS(O2)OH, —OS(O)sR33,
`
`—OP(O)(OR33)(OR34), -C(O)R33, -C(S)R33, —C(O)OR33, -C(O)NR33Ra4, ~C(O)OH,
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`—C(S)OR33, -NR3sC(O)NRaaR34, -NR3sC(S)NRa3R34, -NR3sC(NR33)NRaaRaa,
`
`—C(NR33)NR33Ra4, ~S(O)2NRa3R34, -NR3sS(O)2R33, -NR3sC(O)R3s, and —S(O)R33 where
`
`each X is independently a halo; each R33 and Raq are independently hydrogen,alkyl,
`
`substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted
`
`cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl,
`
`heteroarylalkyl, substituted heteroarylalkyl, -NR3s5R3.6, -C(O)R35 or —S(O)eR3s5 or optionally
`
`R33 and R34 together with the atom to which R33 and R34 are attached form one or more
`
`heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl rings; and
`
`R3s and Rag are independently hydrogen,alkyl, substituted alkyl, aryl, substituted aryl,
`
`arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl,
`
`substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted
`
`heteroarylalkyl, or optionally R35 and R3g together with the nitrogen atom to which R35 and
`
`Rag are attached form one or more heterocycloalkyl, substituted heterocycloalkyl, heteroaryl,
`or substituted heteroaryl rings. In certain embodiments, a tertiary amine or aromatic nitrogen
`
`may be substituted with on or more oxygen atomsto form the correspondingnitrogen oxide.
`
`“Therapeutically effective amount”refers to the amountof a compoundthat, when
`
`administered to a subject for treating a disease, or at least oneofthe clinical symptoms of a
`
`disease or disorder,is sufficient to affect such treatment for the disease, disorder, or
`
`symptom. The “therapeutically effective amount” can vary depending on the compound,the
`
`disease, disorder, and/or symptomsof the disease or disorder, severity of the disease,
`
`disorder, and/or symptomsof the disease or disorder, the age of the subjectto be treated,
`
`and/or the weight of the subject to be treated. An appropriate amountin any given instance
`
`can be readily apparent to those skilled in the art or capable of determination by routine
`
`experimentation.
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`“Treating”or “treatment” of any disease or disorder refers to arresting or
`
`ameliorating a disease, disorder, or at least one ofthe clinical symptomsof a disease or
`
`disorder, reducing the risk of acquiring a disease, disorder, or at least one of the clinical
`
`symptomsof a disease or disorder, reducing the developmentofa disease, disorderorat least
`
`one of the clinical symptomsofthe disease or disorder, or reducingthe risk of developing a
`
`disease or disorderorat least oneof the clinical symptomsof a disease or disorder.
`“Treating”or “treatment” also refersto inhibiting the disease or disorder, either physically,
`(e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical
`
`parameter), or both, or inhibiting at least one physical parameter which maynot be
`
`discernible to the subject. Further, “treating” or “treatment”refers to delaying the onset of
`
`the disease or disorder or at least symptomsthereofin a subject which may be exposedto or
`
`predisposed to a disease or disorder even thoughthat subject does not yet experience or
`
`display symptomsofthe disease or disorder.
`
`Reference will now be madein detail to embodiments of the present disclosure.
`
`While certain embodiments of the present disclosure will be described,it will be understood
`
`that it is not intended to limit the embodiments of the present disclosure to those described
`
`embodiments. To the contrary, reference to embodiments ofthe present disclosure is
`
`intended to coveralternatives, modifications, and equivalents as may be included within the
`
`spirit and scope of the embodiments of the present disclosure as defined by the appended
`
`claims.
`
`Embodimentsof the present invention are directed to at least one compound of
`
`Formula I:
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`a pharmaceutically acceptable salt thereof, a solvate thereof, a chelate thereof, a non-covalent
`complex thereof, a prodrug thereof, and mixtures ofanyof the foregoing, wherein:
`nis I to 6;
`
`R,is chosen from H, lower alkyl and substituted loweralkyl;
`Ry is chosen from H,loweralkyl and substituted lower alkyl;
`R3 and Ry are independently chosen from H, lower alkyl, substituted loweralkyl,
`lower haloalkyl, substituted lower haloalkyl, or R3 and R4 can join together to form a 3 to 6
`membered ring or a substituted 3 to 6 memberedring;
`Rs is chosen from OH, SH, NHp, loweralkyl, substituted lower alkyl, lower alkoxy,
`substituted lower alkoxy, and sulfanyl;
`;
`Rg is chosen from H, OH, SH, NH2, NHSOQ2R, and sulfonyl;
`each of R7, Rg, Ro