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WO2025174820A1 - Inhibiteurs d'hétéroaryle topoisomérase et leurs utilisations - Google Patents

Inhibiteurs d'hétéroaryle topoisomérase et leurs utilisations

Info

Publication number
WO2025174820A1
WO2025174820A1 PCT/US2025/015508 US2025015508W WO2025174820A1 WO 2025174820 A1 WO2025174820 A1 WO 2025174820A1 US 2025015508 W US2025015508 W US 2025015508W WO 2025174820 A1 WO2025174820 A1 WO 2025174820A1
Authority
WO
WIPO (PCT)
Prior art keywords
methoxy
fluoro
piperidin
ethyl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/015508
Other languages
English (en)
Inventor
Mark MITTON-FRY
Joshua Powell
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ohio State Innovation Foundation
Original Assignee
Ohio State Innovation Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ohio State Innovation Foundation filed Critical Ohio State Innovation Foundation
Publication of WO2025174820A1 publication Critical patent/WO2025174820A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the term “substantially” means that the subsequently described event or circumstance completely occurs or that the subsequently described event or circumstance generally, typically, or approximately occurs. Still further, the term “substantially” can, in some aspects, refer to at least about 90 %, at least about 91 %, at least about 92 %, at least about 93 %, at least about 94 %, at least about 95 %, at least about 96 %, at least about 97 %, at least about 98 %, at least about 99 %, or about 100 % of the stated property, component, composition, or other condition for which substantially is used to characterize or otherwise quantify an amount.
  • a point of attachment bond denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond.
  • XY indicates that the chemical entity “XY” is bonded to another chemical entity via the point of attachment bond.
  • the specific point of attachment to the non-depicted chemical entity can be specified by inference.
  • C 1 -C 6 alkyl indicates an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species
  • C1-C4alkyl indicates an alkyl group having 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species.
  • Alkynyl is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain, for example, C 2 - C 4 alkynyl or C 2 -C 6 alkynyl (i.e., having 2, 3, 4, 5, or 6 carbons).
  • the specified ranges, as used herein, indicate an alkynyl group, with each member of the range described as an independent species, as described above for the alkyl moiety.
  • alkynyl examples include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl.
  • the alkynyl group is optionally substituted as described herein.
  • Aryl indicates an aromatic group containing only carbon in the aromatic ring or rings.
  • the aryl group contains 1 to 3 separate or fused rings and is 6 to 14 or 18 ring atoms, without heteroatoms as ring members.
  • such aryl groups may be further substituted with carbon or non-carbon atoms or groups.
  • Such substitution may include the fusion to a 4- to 7- or 5- to 7-membered saturated or partially unsaturated cyclic group that optionally contains 1, 2, or 3 heteroatoms independently selected from N, O, B, P, Si, and S, to form, for example, a 3,4-methylenedioxyphenyl group.
  • Aryl groups include, for example, Attorney Docket No.103361-644WO1 phenyl and naphthyl, including 1-naphthyl and 2-naphthyl.
  • aryl groups are pendant.
  • An example of a pendant ring is a phenyl group substituted with a phenyl group.
  • the aryl group is optionally substituted as described herein.
  • heterocycle refers to saturated and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from N, O, and S.
  • heterocycle includes monocyclic 3-12 members rings, as well as bicyclic 5-16 membered ring systems (which can include fused, bridged, or spiro bicyclic ring systems). It does not include rings containing -O-O-, -O-S-, and -S-S- portions.
  • partially saturated heterocycle radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.
  • partially saturated and saturated heterocycle groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2- dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a
  • heterocycle group is optionally substituted as described herein.
  • Attorney Docket No.103361-644WO1 “Heteroaryl” refers to a stable monocyclic, bicyclic, or multicyclic aromatic ring that contains from 1 to 4, or in some aspects 1, 2, or 3 heteroatoms selected from N, O, S, B, and P (and typically selected from N, O, and S) with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5, 6, or 7 membered aromatic ring which contains from 1 to 4, or in some aspects from 1 to 3 or from 1 to 2, heteroatoms selected from N, O, S, B, or P, with remaining ring atoms being carbon.
  • the only heteroatom is nitrogen.
  • the only heteroatom is oxygen. In one aspect, the only heteroatom is sulfur.
  • Monocyclic heteroaryl groups typically have from 5 to 6 ring atoms.
  • bicyclic heteroaryl groups are 8- to 10-membered heteroaryl groups, that is groups containing 8 or 10 ring atoms in which one 5-, 6-, or 7-membered aromatic ring which contains from 1 to 4 heteroatoms selected from N, O, S, B, or P is fused to a second aromatic or non-aromatic ring, wherein the point of attachment is an aromatic ring.
  • the total number of S and O atoms in the heteroaryl ring exceeds 1, these heteroatoms are not adjacent to one another within the ring.
  • the total number of S and O atoms in the heteroaryl ring is not more than 2. In another aspect, the total number of S and O atoms in the heteroaryl ring is not more than 1.
  • heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, is
  • a “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, pharmaceutically acceptable, acid or base addition salts thereof.
  • the salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like) or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like
  • Salts of the present Attorney Docket No.103361-644WO1 compounds further include solvates of the compounds and of the compound salts.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include salts that are acceptable for human consumption and the quaternary ammonium salts of the parent compound formed, for example, from inorganic or organic salts.
  • examples of such salts include but are not limited to, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC
  • Suitable counterions found in pharmaceutically acceptable salts described herein include but are not limited to, cations such as calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, meglumine, potassium, procaine, sodium, triethylamine, and zinc, and anions such as acetate, aspartate, benzenesulfonate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamo
  • the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compound.
  • substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), nuclear magnetic resonance (NMR), gel electrophoresis, high- Attorney Docket No.103361-644WO1 performance liquid chromatography (HPLC) and mass spectrometry (MS), gas- chromatography mass spectrometry (GC-MS), and similar, used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance.
  • TLC thin layer chromatography
  • NMR nuclear magnetic resonance
  • HPLC high- Attorney Docket No.103361-644WO1 performance liquid chromatography
  • MS mass spectrometry
  • GC-MS gas- chromatography mass spectrometry
  • a substantially chemically pure compound may, however, be a mixture of stereoisomers.
  • Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art.
  • the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers, such as Sigma-Aldrich (formally MilliporeSigma, Burlington, MA) or Thermo Fisher Scientific Inc.
  • a compound is provided of Formula I-A or Formula I-B: or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.
  • the dashed line represents a bond that can be present or absent, and when the bond is present, R 1 and R 2 can be cis or trans.
  • A can be a fused bicyclic aryl or bicyclic heteroaryl ring optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • a and R 1 can be brought together with the carbon to which they are attached to form a tricyclic ring optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • B can be a five- to six-membered heteroaryl ring having 1, 2, or 3 ring heteroatoms selected from N, O, and S, wherein B can be optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • R 1 and R 2 can be independently selected from H, OH, Cl, F, Br, I, CN, NO 2 , NH 2 , CF 3 , CO 2 H, OC(O)NH 2 , OC(O)NHR 3 , CO 2 R 3 , C(O)R 3 , C(O)NH2, C(O)NHR 3 , oxo, and C1-C6 alkyl or C1-C6 alkoxyl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • R 1 can be a C1-C3 alkyl or C2-C3 alkenyl, optionally substituted with R 9 , also bound to A as allowed by valency.
  • each R 3 can be independently selected from C1-C6 alkyl, C1-C6 cycloalkyl, C5-C15 aryl, C4-C15 heteroaryl, C3-C15 heterocycloalkyl, and C1- C15 heteroalkyl, any of which can be optionally substituted with one or more (for example, 1, 2, 3, or 4) groups selected from Z as allowed by valency.
  • R 9 can be H, Cl, F, Br, I, CN, OH, NO2, NH2, CF3, CO2H, CO2NH2, CO2NHR 3 , CO2R 3 , C(O)R 3 , C(O)NH2, C(O)NHR 3 , or C1-C6 alkyl or C1- C 6 alkoxyl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups selected from Z as allowed by valency.
  • Z can be independently selected at each occurrence from halo, nitro, cyano, azido, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 8-membered monocyclic or bicyclic heterocycle, 6- to 10-membered monocyclic or bicyclic aryl, 5- to 10-membered monocyclic or bicyclic heteroaryl, R x O-, R x S-, (R x R y N)-, R x O-C(O)-, R x S-C(O)-, (R x R y N)-C(O)-, R x O-S(O)2-, (R x R y N)-S(O) 2 -, R z
  • R x and R y can be independently selected at each occurrence from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 7 cycloalkyl, 4- to 6-membered heterocycle, 5- to 10-membered monocyclic or bicyclic aryl, 5- to 10-membered monocyclic or bicyclic heteroaryl.
  • R z can be independently selected at each occurrence from hydrogen, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C7cycloalkyl, 4- to 6-membered heterocycle, 5- to 10-membered monocyclic or bicyclic aryl, 5- to 10-membered monocyclic or bicyclic heteroaryl, -OR x , -SR x , and -NR x R y .
  • the dashed line represents a bond and thus can be represented by a formula selected from: wherein all variables are as defined herein.
  • the dashed line is absent and thus can be represented by the following formula: , wherein all variables are as defined herein.
  • Attorney Docket No.103361-644WO1 In some aspects of Formula I-B, the dashed line represents a bond and thus can be represented by a formula selected from: wherein all variables are as defined herein. In some aspects of Formula I-B, the dashed line is absent and thus can be represented by the following formula: , wherein all variables are as defined herein.
  • the compound can be of a formula selected from:
  • B can be a five-membered heteroaryl ring having 1, 2, or 3 ring heteroatoms selected from N, O, and S, wherein B can be optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • B can be selected from furanyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, isoxazolyl, and triazolyl, each of which may be optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • B can be furanyl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • B can be pyrrolyl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • B can be pyrazolyl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • B can be oxazolyl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • B can be imidazolyl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • B can be isoxazolyl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • B can be triazolyl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • R 4 and R 5 can be independently selected from H, Cl, F, Br, I, CN, OH, NO 2 , NH 2 , CF 3 , CO 2 H, OC(O)NH 2 , OC(O)NHR 3 , CO 2 R 3 , C(O)R 3 , C(O)NH 2 , C(O)NHR 3 , and C 1 -C 6 alkyl or C 1 -C 6 alkoxyl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups selected from Z as allowed by valency.
  • R 4 and R 5 can be independently selected from H, Cl, F, Br, I, CN, OH, and unsubstituted C 1 -C 6 alkyl or C 1 -C 6 alkoxy. In some aspects of Formula II, R 4 and R 5 can be independently selected from H, Cl, F, CN, OH, and methoxy. In some aspects of Formula II, R 4 and R 5 can be independently selected from F and methoxy.
  • each X in Formula II can be CH. In some aspects of Formula II, one X can be CH and the other two X’s can be N. In some aspects of Formula II, two X’s can be CH and the other X can be N.
  • all X’s can be N.
  • A can be , wherein all variables are as defined herein.
  • Attorney Docket No.103361-644WO1 In some aspects of Formula I-A or Formula I-B, A can be , wherein all variables are as defined herein.
  • A can be a fused bicyclic aryl or bicyclic heteroaryl ring having Formula III: III wherein all variables are as defined herein.
  • X can be independently CH or N.
  • R 4 can be selected from H, Cl, F, Br, I, CN, OH, NO2, NH2, CF 3 , CO 2 H, OC(O)NH 2 , OC(O)NHR 3 , CO 2 R 3 , C(O)R 3 , C(O)NH 2 , C(O)NHR 3 , and C 1 -C 6 alkyl or C1-C6 alkoxyl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • R 4 can be selected from H, Cl, F, Br, I, CN, OH, and unsubstituted C 1 -C 6 alkyl or C 1 -C 6 alkoxy. In some aspects of Formula III, R 4 can be selected from H, Cl, F, CN, OH, and methoxy. In aspects of Formula III, R 4 can be selected from F and methoxy. In some aspects of Formula III, each X can be N. In some aspects of Formula III, two X’s can be CH and the other X can be N. In some aspects of Formula III, two X’s can be N and the other X can be CH.
  • A can be a bicyclic aryl or bicyclic heteroaryl that together with R 1 forms a tricyclic ring.
  • R 1 is a CH 2
  • this can be represented by Formula IX, X, XI, or XII.
  • Attorney Docket No.103361-644WO1 In some aspects of Formula I-A or Formula I-B, A can be Formula IX: wherein all variables are as defined herein.
  • X can be CH, N, or CR 8 .
  • R 4 and R 5 can be independently selected from H, Cl, F, Br, I, CN, OH, NO 2 , NH 2 , CF 3 , CO 2 H, OC(O)NH 2 , OC(O)NHR 3 , CO 2 R 3 , C(O)R 3 , C(O)NH 2 , C(O)NHR 3 , and C1-C6 alkyl or C1-C6 alkoxyl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • R 8 can be Cl, F, CN, OH, OCH 3 , CH 3 , or NH 2 .
  • R 9 can be H, Cl, F, Br, I, CN, OH, NO2, NH2, CF3, CO2H, OC(O)NH2, OC(O)NHR 3 , CO2R 3 , C(O)R 3 , C(O)NH2, C(O)NHR 3 , or C1-C6 alkyl or C1-C6 alkoxyl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • A can be Formula X: wherein all variables are as defined herein.
  • each X can be independently CH, N, or CR 8 .
  • R 4 and R 5 can be independently selected from H, Cl, F, Br, I, CN, OH, NO2, NH2, CF3, CO2H, OC(O)NH2, OC(O)NHR 3 , CO2R 3 , C(O)R 3 , C(O)NH2, C(O)NHR 3 , and C 1 -C 6 alkyl or C 1 -C 6 alkoxyl optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • R 8 can be independently Cl, F, CN, OH, OCH3, CH3, or NH2.
  • R 9 can be H, Cl, F, Br, I, CN, OH, NO 2 , NH 2 , CF 3 , CO 2 H, OC(O)NH 2 , OC(O)NHR 3 , CO 2 R 3 , C(O)R 3 , C(O)NH 2 , C(O)NHR 3 , or C 1 -C 6 alkyl or C 1 -C 6 alkoxy optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • A is , wherein all variables are as defined herein.
  • A can be , wherein all variables are as defined herein.
  • A can be Attorney Docket No.103361-644WO1 , wherein all variables are as defined herein.
  • A can be , wherein all variables are as defined herein.
  • A can be Formula XI: wherein all variables are as defined herein.
  • each X can be independently CH, N, or CR 8 .
  • R 4 and R 5 can be independently selected from H, Cl, F, Br, I, CN, OH, NO2, NH2, CF3, CO2H, OC(O)NH2, OC(O)NHR 3 , CO2R 3 , C(O)R 3 , C(O)NH2, C(O)NHR 3 , and C 1 -C 6 alkyl or C 1 -C 6 alkoxy optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • each R 8 can be independently Cl, F, CN, OH, OCH3, CH3, or NH2.
  • R 9 can be H or C 1 -C 6 alkyl.
  • A can be Formula XII: XII wherein all variables are as defined herein.
  • each X can be independently CH, N, or CR 8 .
  • R 4 and R 5 can be independently selected from H, Cl, F, Br, I, CN, OH, NO 2 , NH 2 , CF 3 , CO 2 H, OC(O)NH 2 , OC(O)NHR 3 , CO 2 R 3 , C(O)R 3 , C(O)NH 2 , C(O)NHR 3 , and C 1 -C 6 alkyl or C 1 -C 6 alkoxy optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • each R 8 can be independently Cl, F, CN, OH, OCH3, CH3, or NH 2 .
  • R 9 can be H or C1-C6 alkyl.
  • A can be wherein each of R 4 , R 5 , R 8 , and R 9 can be independently selected from Cl, F, CN, OH, OCH 3 , CH3, or NH2.
  • R 9 is H or CH3.
  • A can be Attorney Docket No.103361-644WO1 , wherein all variables are as defined herein.
  • A can be , wherein all variables are as defined herein.
  • A can be , wherein all variables are as defined herein.
  • R 5 can be F.
  • A is selected from: Attorney Docket No.103361-644WO1
  • R 1 and R 2 are independently selected from H, F, OH, and NH2.
  • R 2 is NH2.
  • R 2 is H or OH.
  • R 1 is H or OH.
  • Incorporation of a hydroxyl substituent (at R 1 or R 2 ) reduces lipophilicity by ca. 1.5 CLogP units and has been shown in some cases to impact hERG inhibition and other properties.
  • D is aryl or heteroaryl ring having Formulae IV-VIII or XIII. Attorney Docket No.103361-644WO1 VIII XIII wherein all variables are as defined herein.
  • each X can be independently selected from CH or N.
  • each Y can be independently selected from O, S, NH, or CH 2 .
  • R 6 and R 7 can be independently selected from H, Cl, F, Br, I, CN, OH, NO2, NH2, CF3, CO2H, OC(O)NH2, OC(O)NHR 3 , CO2R 3 , C(O)R 3 , C(O)NH 2 , C(O)NHR 3 , and C 1 -C 6 alkyl or C 1 -C 6 alkoxy optionally substituted with one or more (for example, 1, 2, 3, or 4) groups independently selected from Z as allowed by valency.
  • R 6 and R 7 can be independently selected from H, Cl, F, Br, I, CN, OH, and unsubstituted C 1 -C 6 alkyl or C 1 -C 6 alkoxy. In some aspects of Formulae IV-VIII or XIII, R 6 and R 7 can be independently selected from H, Cl, F, CN, OH, and methoxy. In some aspects of Formulae IV-VIII or XIII, R 6 and R 7 can be independently selected from F and methoxy. In some aspects of Formulae IV-VIII or XIII, R 6 and R 7 can be both H. In some aspects of Formulae IV-VIII or XIII, both Y can be O.
  • D can be , wherein all variables are as defined herein.
  • D can be , Attorney Docket No.103361-644WO1 wherein all variables are as defined herein.
  • D can be , wherein all variables are as defined herein.
  • D can be , wherein all variables are as defined herein.
  • D can be , wherein all variables are as defined herein.
  • D can be selected from:
  • Z can be selected from fluoro, chloro, bromo, and iodo.
  • Z can be cyano.
  • Z can be azido.
  • Z can be oxo.
  • Z can be selected from pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphth
  • Z can be (R x R y N)-, wherein R x and R y can be independently selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
  • Z can be R x O-C(O)-, wherein R x can be selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
  • Z can be R x S-C(O)-, wherein R x can be selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
  • Z can be (R x R y N)-C(O)-, wherein R x and R y can be independently selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
  • Z can be R x O-S(O) 2 -, wherein R x can be selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
  • Z can be (R x R y N)-S(O) 2 -, wherein R x and R y can be independently selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
  • Z can be R z C(O)-O-, wherein R z can be selected from hydrogen, chloro, bromo, -OH, -NH 2 , methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
  • Z can be R z C(O)-(R x N)-, wherein R x can be selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, and wherein R z is selected from hydrogen, chloro, bromo, -OH, -NH2, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
  • Z can be R z S(O)2-O-, wherein R z can be selected from hydrogen, chloro, bromo, -OH, -NH2, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
  • Z can be R z S(O)2-(R x N)-, wherein R x can be selected from hydrogen, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, and wherein R z is selected from hydrogen, chloro, bromo, -OH, -NH 2 , methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
  • Z can be R z S(O)-, wherein R z can be selected from hydrogen, chloro, bromo, -OH, -NH2, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl.
  • a compound selected from: 7-fluoro-2-methoxy-8-(2-(4-(5-(p-tolyl)furan-2-yl)piperidin-1-yl)ethyl)-1,5-naphthyridine (example 1); 8-(2-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)furan-2-yl)piperidin-1-yl)ethyl)-7-fluoro-2- methoxy-1,5-naphthyridine (example 2); 6-(5-(1-(2-(3-fluoro-6-methoxy-1,5-naphthyridin-4-yl)ethyl)piperidin-4-yl)furan-2-yl)-2H- benzo[b][1,4]oxazin-3(4H)-one (example 3); 7-fluoro-2-me
  • the present disclosure also includes compounds described herein with at least one desired isotopic substitution of an atom at an amount above the natural abundance of the isotope, i.e., enriched.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 15 N, 17 O, 18 O, 18 F, 31 P , 32 P, 35 S, 36 Cl, and 125 I, respectively.
  • isotopically labeled compounds can be used in metabolic studies (with 14 C), reaction kinetic studies (with, for example, 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug and substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F-labeled compound may be particularly desirable for PET or SPECT studies.
  • Attorney Docket No.103361-644WO1 Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed herein by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • isotopes of hydrogen for example, deuterium ( 2 H) and tritium ( 3 H), may optionally be used anywhere in described structures that achieve the desired result.
  • isotopes of carbon e.g., 13 C and 14 C, may be used.
  • the isotopic substitution is replacing hydrogen with deuterium at one or more locations on the molecule to improve the performance of the molecule as a drug, for example, the pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, T max , C max , etc.
  • solvate refers to a molecular complex of a compound of the present disclosure (including a salt thereof) with one or more solvent molecules.
  • solvents are water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents.
  • hydrate refers to a molecular complex comprising a disclosed compound and water.
  • solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D 2 O, d 6 -acetone, or d 6 - DMSO.
  • a solvate can be in a liquid or solid form.
  • a “prodrug,” as used herein, means a compound that, when administered to a host in vivo, is converted into a parent drug.
  • the term “parent drug” means any of the presently described compounds herein.
  • Prodrugs can be used to achieve any desired effect, including to enhance the properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent, including increasing the half-life of the drug in vivo.
  • non-limiting aspects include the use of a divalent linker moiety such as a dicarboxylic acid, amino acid, diamine, hydroxycarboxylic acid, hydroxyamine, di-hydroxy compound, or other compounds that have at least two functional groups that can link the parent compound with another prodrug moiety and are typically biodegradable in vivo.
  • a divalent linker moiety such as a dicarboxylic acid, amino acid, diamine, hydroxycarboxylic acid, hydroxyamine, di-hydroxy compound, or other compounds that have at least two functional groups that can link the parent compound with another prodrug moiety and are typically biodegradable in vivo.
  • 2, 3, 4, or 5 prodrug biodegradable moieties are covalently bound in a sequence, branched, or cyclic fashion to the parent compound.
  • Non- limiting examples of prodrugs according to the present disclosure are formed with: a carboxylic acid on the parent drug and a hydroxylated prodrug moiety to form an ester; a carboxylic acid on the parent drug and an amine prodrug to form an amide; an amino on the parent drug and a carboxylic acid prodrug moiety to form an amide; an amino on the parent drug and a sulfonic acid to form a sulfonamide; a sulfonic acid on the parent drug and an amino on the prodrug moiety to form a sulfonamide; a hydroxyl group on the parent drug and a carboxylic acid on the prodrug moiety to form an ester; a hydroxyl on the parent drug and a hydroxylated prodrug moiety to form an ester; a phosphonate on the parent drug and a hydroxylated prodrug moiety to form a phosphonate ester; a phosphoric acid on the parent drug and
  • a prodrug is provided by attaching a natural or non-natural amino acid to an appropriate functional moiety on the parent compound, for example, oxygen, nitrogen, or sulfur, and typically oxygen or nitrogen, usually in a manner such that the amino acid is cleaved in vivo to provide the parent drug.
  • the amino acid can be used alone or covalently linked (straight, branched, or cyclic) to one or more other prodrug moieties to modify the parent drug to achieve the desired performance, such as increased half-life, lipophilicity, or other drug delivery or pharmacokinetic properties.
  • the amino acid can be any compound with an amino group and a carboxylic acid, which includes an aliphatic amino acid, alkyl amino acid, aromatic amino acid, heteroaliphatic amino acid, heteroalkyl amino acid, heterocyclic amino acid, or heteroaryl amino acid.
  • Pharmaceutical Compositions The compounds as described herein can be administered by any suitable method and technique presently or prospectively known to those skilled in the art.
  • the active components described herein can be formulated in a physiologically- or pharmaceutically-acceptable form and administered by any suitable route known in the art, including, for example, oral and parenteral routes of administering.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrasternal administration, such as by injection.
  • Administration of the active components of their compositions can be a single administration or at continuous and distinct intervals as can be readily determined by a person skilled in the art.
  • Compositions, as described herein, comprising an active compound and a pharmaceutically acceptable carrier or excipient of some sort may be useful in a variety of medical and non- medical applications.
  • pharmaceutical compositions comprising an active compound and an excipient may be useful for the treatment or prevention of an infection in a subject in need thereof.
  • “Pharmaceutically acceptable carrier” (sometimes referred to as a “carrier”) means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic and includes a carrier that is acceptable for veterinary and/or human pharmaceutical or therapeutic use.
  • carrier or “pharmaceutically acceptable carrier” can include, but are not limited to, phosphate-buffered saline solution, water, emulsions (such as an oil/water or water/oil emulsion) and/or various types of wetting agents.
  • excipients include but are not limited to, any non-toxic, inert solid, semisolid, or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type.
  • the excipients may be chosen based on what the composition is useful for.
  • the choice of the excipient will depend on the route of administration, the agent being delivered, the time course of delivery of the agent, etc., and can be administered to humans and/or to animals, orally, rectally, parenterally, intracisternally, intravaginally, intranasally, intraperitoneally, topically (as by powders, creams, ointments, or drops), buccally, or as an oral or nasal spray.
  • the active compounds disclosed herein are administered topically.
  • Representative diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, Attorney Docket No.103361-644WO1 sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof.
  • Representative granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof.
  • crospovidone cross-linked poly(vinyl-pyrrolidone)
  • sodium carboxymethyl starch sodium starch glycolate
  • Representative surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g.
  • natural emulsifiers e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin
  • colloidal clays e.g. bentonite [aluminum silicate] and Veegum [magnes
  • stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol
  • carbomers e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer
  • carrageenan cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
  • Representative binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, Attorney Docket No.103361-644WO1 lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes
  • Representative chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid monohydrate
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Representative antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Representative alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Representative acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated Attorney Docket No.103361-644WO1 hydroxyanisol (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.
  • the preservative is an anti- oxidant.
  • the preservative is a chelating agent.
  • Representative buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-
  • Representative lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.
  • Representative natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckt
  • Representative synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.
  • Attorney Docket No.103361-644WO1 Additionally, the composition may further comprise a polymer.
  • Representative polymers contemplated herein include, but are not limited to, cellulosic polymers and copolymers, for example, cellulose ethers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methylhydroxyethylcellulose (MHEC), methylhydroxypropylcellulose (MHPC), carboxymethyl cellulose (CMC) and its various salts, including, e.g., the sodium salt, hydroxyethylcarboxymethylcellulose (HECMC) and its various salts, carboxymethylhydroxyethylcellulose (CMHEC) and its various salts, other polysaccharides and polysaccharide derivatives such as starch, dextran, dextran derivatives, chitosan, and alginic acid and its various salts, carageenan, varoius gums, including xanthan gum, guar gum, gum arabic, gum karaya,
  • composition may further comprise an emulsifying agent.
  • emulsifying agents include, but are not limited to, a polyethylene glycol (PEG), a polypropylene glycol, a polyvinyl alcohol, a poly-N-vinyl pyrrolidone and copolymers thereof, poloxamer nonionic surfactants, neutral water-soluble polysaccharides (e.g., dextran, Ficoll, celluloses), non-cationic poly(meth)acrylates, non-cationic polyacrylates, such as poly (meth) acrylic acid, and esters amide and hydroxy alkyl amides thereof, natural emulsifiers (e.g.
  • acacia agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid Attorney Docket No.103361-644WO1 derivatives, high molecular weight alcohols (e.g.
  • stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol
  • carbomers e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer
  • carrageenan cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
  • Cremophor polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl- pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
  • the emulsifying agent is cholesterol.
  • Liquid compositions include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid composition may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable compositions for example, injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be an injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents for pharmaceutical or cosmetic compositions that may be employed are water, Ringer's solution, U.S.P., and Attorney Docket No.103361-644WO1 isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the particles are suspended in a carrier fluid comprising 1% (w/v) sodium carboxymethyl cellulose and 0.1% (v/v) Tween 80.
  • the injectable composition can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • Compositions for rectal or vaginal administration may be in the form of suppositories which can be prepared by mixing the particles with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the particles.
  • Solid compositions include capsules, tablets, pills, powders, and granules.
  • the particles are mixed with at least one excipient and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • Tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • compositions examples include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in Attorney Docket No.103361-644WO1 soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • Compositions for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active compound is admixed with an excipient and any needed preservatives or buffers as may be required.
  • the ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the nanoparticles in a proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or by dispersing the particles in a polymer matrix or gel.
  • the compounds disclosed herein can be administered in combination or alternation with one or more additional therapeutic agents. In some aspects, the compounds may be administered in combination with one or more additional therapeutic agents in the same pharmaceutical composition or may be administered as separate dosage forms.
  • therapeutic agent includes any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (either human or a nonhuman animal), induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action.
  • the term therefore, encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals, including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs, and the like.
  • therapeutic agents are described in well-known literature references such as the Merk Index (14 th Edition), the Physician’s Desk Reference (64 th Edition), and The Attorney Docket No.103361-644WO1 Pharmacological Basis of Therapeutics (12 th Edition), and they include, without limitation, medicaments; vitamins; mineral supplements, substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
  • the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiandrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics, antispasmodics, cardiovascular preparations (including calcium channel blockers, beta blockers, and
  • the agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas.
  • the disclosed compounds can be administered in combination with one or more additional antimicrobial agents.
  • the disclosed compounds can be combined with one or more of Acedapsone; Acetosulfone Sodium; Alamecin; Alexidine; Amdinocillin; Amdinocillin Pivoxil; Amicycline; Amifloxacin; Amifloxacin Mesylate; Amikacin; Amikacin Sulfate; Aminosalicylic acid; Aminosalicylate sodium; Amoxicillin; Amphomycin; Ampicillin; Ampicillin Sodium; Apalcillin Sodium; Apramycin; Aspartocin; Astromicin Sulfate; Avilamycin; Avoparcin; Azithromycin; Azlocillin; Azlocillin Sodium; Bacampicillin Hydrochloride; Bacitracin; Bacitracin Methylene Dis
  • the disclosed compounds can be administered in combination with one or more foaming agents such as sodium laureth ether sulfate (SLES), sodium lauryl dodecyl sulfate (SDS), disodium laureth sulfosuccinate, ammonium lauryl sulfate (ALS), sodium pareth sulfate, and sodium coceth sulfate.
  • foaming agents can be present from about 1% to about 70%, about 5% to about 50%, about 10 % to about 30%, or about 1% to about 5% by weight.
  • the disclosed compounds can be administered in combination with one or more antibiotics.
  • antibiotics examples include amikacin, gentamicin, kanamycin, neomycin, streptomycin, tobramycin, bacitracin, clindamycin, daptomycin, lincomycin, linezolid, metronidazole, polymyxin, rifaximin, vancomycin, penicillin, cephalosporin, cephazolin, cephalexin, erythromycin, azithromycin, ciprofloxacin, levofloxacin, sulfadiazine, minocycline, tetracycline, and rifampin.
  • the proportion of antibiotics can be about 0.001% to about 10%, about 0.01% to about 5%, about 0.1 % to about 10%, or about 1% to about 5% by weight.
  • the disclosed compounds administered in combination with one or more therapeutic agents selected from as acyclovir, cephradine, malphalen, procaine, ephedrine, adriamycin, dauno, mycin, plumbagin, atropine, quinine, digoxin, and quinidine, cephradine, cephalothin, cishydroxy-L-proline, melphalan, nicotinic acid, nitric oxide, nitroglycerin, chemodeoxycholic acid, chlorambucil, paclitaxel, sirolimus, 5-flurouracil, paclitaxel, mercaptoethanesulfonate, verapamil, or antifungal agents.
  • the proportion of these additional agents can be about 0.001% to about 10%, about 0.01% to about 5%, about 0.1 % to about 10%, or about 1% to about 5% by weight.
  • the disclosed compounds can be administered in combination with one or more anti-inflammatory agents.
  • Representative infections that can be treated include, but are not limited to, Actinobacter, Actinomycetes, Bacilli, Bortedellen, Clostridia, Corynebacteria, Enterobacter, Enterococci, Helicobacter, Haemophilus, Klebsiella, Listeria, Mycobacteria, Neisseria, Shigella, Salmonella, Streptococci, Staphylococci, tuberculosis bacteria, and Yersinia.
  • the disclosed compounds can be used to treat infections caused by resistant Gram-positive bacteria, such as Methicillin Resistant Staphylococcus aureus (MRSA).
  • MRSA Methicillin Resistant Staphylococcus aureus
  • the CDC characterizes MRSA as a serious threat, its second-highest level of concern.
  • These disclosed methods can involve administering a compound disclosed herein to the infected human or animal or the human or animal at risk of being infected.
  • the infected individual has cystic fibrosis.
  • the disclosed compounds can be used to treat infections caused by resistant Gram-negative pathogens such as P. aeruginosa. Infections caused by Gram-negative bacteria in general, and MDR P. aeruginosa in particular (Wagner, S., et al. J. Med.
  • Chem.2016, 59, 5929 represent a key need in antibacterial drug discovery that is currently underrepresented by approaches in clinical development.
  • the additional permeability barrier imposed by the outer membrane of Gram-negative organisms (Zgurskaya, H. I., et al. ACS Infect. Dis.2015, 1, 512), as well as other resistance mechanisms, such as robust multidrug efflux transporters, make the identification of potential new therapies particularly challenging.
  • These disclosed methods can involve administering a compound disclosed herein to the infected human or animal or the human or animal at risk of being infected.
  • the disclosed compounds can be used to treat infections by M. tuberculosis, M. avium, or M. abscessus.
  • the disclosed compounds can be used to treat infections caused by Enterococcus faecium, Klebsiella pneumoniae, Acinetobacter baumannii, various Enterobacter, and Neisseria gonorrhoeae.
  • Further examples include the following diseases include: tuberculosis; Pneumonia; Typhoid; Paratyphoid; Syphilis, Gastritis; Gastroenteritis; Ruhr; Pestilence; Enteritis; extraintestinal infections, peritonitis and appendicitis with E.
  • coli Attorney Docket No.103361-644WO1 and intestinal infections with EHEC, EPEC, ETEC and EIEC; Cholera, Legionnaires' disease, whooping cough, brucellosis, Lyme disease, leptospirosis, typhus, trachoma, gonorrhea, meningitis, septicemia, leprosy etc.
  • these methods can involve administering a compound disclosed herein to the infected human or animal or the human or animal at risk of being infected.
  • methods of treating an infection in a patient comprising administering to the patient a therapeutically effective amount of any of the compounds disclosed herein.
  • livestock honey, cows, pigs, sheep, goats, etc.
  • poultry and companion animals
  • dogs dogs, cats, rabbits, etc.
  • the compositions or organisms can be administered alone or in combination with other therapeutics or nutritional supplements.
  • the composition can be combined into a feed.
  • the active ingredient may be administered in such amounts, time, and route deemed necessary in order to achieve the desired result.
  • the exact amount of the active ingredient will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the medical disorder, the particular active ingredient, its mode of administration, its mode of activity, and the like.
  • the active ingredient is preferably formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the active ingredient will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the active ingredient may be administered by any route.
  • the active ingredient is administered via a variety of routes, including oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), Attorney Docket No.103361-644WO1 mucosal, nasal, bucal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • the most appropriate route of administration will depend upon a variety of factors, including the nature of the active ingredient (e.g., its stability in the environment of the gastrointestinal tract), the condition of the subject (e.g., whether the subject is able to tolerate oral administration), etc.
  • the exact amount of an active ingredient required to achieve a therapeutically or prophylactically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • Useful dosages of the active agents and pharmaceutical compositions disclosed herein can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice and other animals to humans are known to the art.
  • the dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms or disorder are affected.
  • the dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like.
  • the dosage will vary with the age, condition, sex, and extent of the disease in the patient and can be determined by one of skill in the art.
  • the dosage can be adjusted by the individual physician in the event of any counterindications.
  • Dosage can vary and can be administered in one or more dose administrations daily for one or several days.
  • the disclosed compounds can be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • the dose of each compound can be either the same or differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • administration and variants thereof (e.g., “administering” a compound) in reference to a compound of the disclosure means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • “administration” and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • active agents Attorney Docket No.103361-644WO1
  • “administration” and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • the disclosed compounds and compositions containing them can be accomplished by any suitable method and technique presently or prospectively known to those skilled in the art.
  • the disclosed compounds can be formulated in a physiologically- or pharmaceutically-acceptable form and administered by any suitable route known in the art, including, for example, oral, nasal, rectal, topical, and parenteral routes of administration.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrasternal administration, such as by injection.
  • Administration of the disclosed compounds or compositions can be a single administration or at continuous or distinct intervals as can be readily determined by a person skilled in the art.
  • the compounds disclosed herein and compositions comprising them can also be administered utilizing liposome technology, slow-release capsules, implantable pumps, and biodegradable containers. These delivery methods can, advantageously, provide a uniform dosage over an extended period of time.
  • the compounds can also be administered in their salt derivative forms or crystalline forms.
  • the compounds disclosed herein can be formulated according to known methods for preparing pharmaceutically acceptable compositions.
  • Formulations suitable for administration include, for example, aqueous sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and nonaqueous sterile suspensions, which can include suspending agents and thickening agents.
  • the formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the condition of the sterile liquid carrier, for example, water for injections, prior to use.
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powder, granules, tablets, etc.
  • compositions disclosed herein can include other conventional agents in the art, having regard to the type of formulation in question.
  • Compounds disclosed herein and compositions comprising them can be delivered to a cell either through direct contact with the cell or via a carrier means.
  • Carrier means for delivering compounds and compositions to cells are known in the art and include, for example, encapsulating the composition in a liposome moiety.
  • Another means for delivery of compounds and compositions disclosed herein to a cell comprises attaching the compounds to a protein or nucleic acid that is targeted for delivery to the target cell.
  • Aspect 2 The compound of aspect 1, wherein B is a five-membered heteroaryl ring having 1, 2, or 3 ring heteroatoms selected from N, O, and S, wherein B is optionally substituted with one or more groups independently selected from Z.
  • Aspect 3 The compound of aspect 1 or aspect 2, wherein B is selected from furanyl, pyrrolyl, pyrazolyl, oxazolyl, imidazolyl, isoxazolyl, and triazolyl is optionally substituted with one or more groups independently selected from Z.
  • Aspect 4. The compound of any one of aspects 1-3, wherein R 1 and R 2 are independently selected from from H, F, CN, OH, and NH2.
  • Aspect 5 The compound of any one of aspects 1-3, wherein R 1 and R 2 are independently selected from from from H, F, CN, OH, and NH2.
  • Aspect 15 The compound of aspect 14, wherein R 6 and R 7 are independently selected from H, Cl, F, Br, I, CN, OH, and unsubstituted C1-C6 alkyl or C1-C6 alkoxyl.
  • Aspect 16 The compound of aspect 14, wherein R 6 and R 7 are independently selected from H, Cl, F, CN, OH, and methoxy.
  • Aspect 17. The compound of aspect 14, wherein R 6 and R 7 are both H.
  • Aspect 18 The compound any one of aspects 14-17, wherein each Y is O.
  • Aspect 19 The compound of any one of aspects 14-17, wherein one Y is S and the other is O.
  • Aspect 20 The compound of any one of aspects 14-17, wherein one Y is NH and the other is O.
  • Aspect 25 The compound of any one of aspects 1-24, wherein the compound is a type II topoisomerase inhibitor.
  • Aspect 26. A pharmaceutical composition comprising a compound of any one of aspects 1- 25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • Aspect 27. A method of treating an infection in a subject in need thereof comprising administering a compound of any one of aspects 1-25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of aspect 26.
  • Aspect 28. The method of aspect 27, wherein the infection is a Staphylococcus aureus infection.
  • Aspect 29. The method of aspect 27, wherein the infection is a methicillin-resistant Staphylococcus aureus (MRSA) infection.
  • MRSA methicillin-resistant Staphylococcus aureus
  • reaction was then heated to 60°C and allowed to stir overnight under a nitrogen atmosphere. Upon return, reaction was cooled to room temperature and diluted with ethyl acetate and water. The ethyl acetate was separated, and the water layer was extracted from 5x15 mL ethyl acetate. Then organics were combined and dried over sodium sulfate. Then organics were concentrated by rotary evaporation and purified by flash chromatography. TMS-deprotection. TMS-protected starting material (1 eq), potassium carbonate (2 eq), and methanol (0.244M) were all added to a round bottom flask. This was allowed to stir for 1-4 hours, monitoring for the disappearance of starting material by TLC.
  • reaction was diluted with methanol and quenched, slowly, with aqueous sodium carbonate. Then reaction was further diluted with DCM, and organics were separated from the aqueous layer. Aqueous layer was further extracted with 5 x 10% methanol in DCM. Organics were collected, dried over sodium sulfate, and concentrated by rotary evaporation to afford crude mixtures. Crude mixtures were purified by flash chromatography. Imidazole synthesis. Tert-butyl 4-formylpiperidine-1-carboxylate (1 eq) was added to RBF and dissolved in t-butanol (0.1 M).
  • reaction Upon return, reaction was cooled to room temperature, and filtered through a celite plug washing with excess ethyl acetate. Then organics were concentrated by rotary evaporation. Then crude mixture was purified by flash chromatography. 15. Racemic Dihydroxylation. 8-ethenyl-7-fluoro-2-methoxy-1,5-naphthyridine (1 eq), potassium osmate (0.02 eq), N-methylmorpholine N-oxide (1.1eq), chloroform (0.33M), and water (1M) were added to a round bottom flask. Reaction was heated to 60°C and allowed to stir overnight.
  • Trimethyl orthoacetate was added and Attorney Docket No.103361-644WO1 allowed to stir for 1.5 hours.
  • TMS-chloride (3 eq) was added and allowed to stir overnight.
  • reaction was concentrated by rotary evaporation.
  • mixture was dissolved in methanol (0.114M) and potassium carbonate (5 eq) was added to the reaction. This was allowed to stir for 1 hour.
  • Reaction was then quenched with saturated, aqueous ammonium chloride.
  • reaction was diluted with water and DCM. DCM was separated, and water layer was extracted from 3x10 mL DCM. Organics were dried over sodium sulfate and concentrated by rotary evaporation to afford crude mixture. This was purified by flash chromatography.
  • Example 22 7-fluoro-2-methoxy-8-(2-(4-(5-(p-tolyl)-1H-imidazol-2-yl)piperidin-1- yl)ethyl)-1,5-naphthyridine
  • Title compound was synthesized from 2-(3-fluoro-6-methoxy-1,5-naphthyridin-4- yl)acetaldehyde and 4-(5-(p-tolyl)-1H-imidazol-2-yl)piperidine using General Procedure 3.
  • Example 45 6-(4-(1-(2-(3-fluoro-6-methoxy-1,5-naphthyridin-4-yl)ethyl)piperidin-4-yl)- 1H-1,2,3-triazol-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one Attorney Docket No.103361-644WO1
  • the title compound was synthesized from 2-(3-fluoro-6-methoxy-1,5-naphthyridin-4- yl)acetaldehyde and 6-(4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-2H-benzo[b][1,4]oxazin- 3(4H)-one according to General Procedure 3.
  • the reaction was stirred overnight then diluted with water, becoming bright yellow and cloudy.
  • the mixture was extracted 5x15 mL ethyl acetate (discarded), and the aqueous layer was extracted 5x15 mL dichloromethane.
  • the combined organic layers contained a precipitate which was collected by filtration.
  • the precipitate was washed with 100 mL 50% DCM/MeOH, and the filtrate was concentrated to afford the crude product as an orange solid (70 mg). This solid was dissolved in methanol (2.5 mL), and sodium methoxide (13.4 mg, 2 equiv) was added. After stirring overnight, the reaction was diluted with 1M aqueous NaOH and stirred an additional 15 minutes.
  • compositions and method steps disclosed herein are specifically described, other combinations of the compositions and method steps are also intended to fall within the scope of the appended claims, even if not Attorney Docket No.103361-644WO1 specifically recited.
  • a combination of steps, elements, components, or constituents may be explicitly mentioned herein; however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated.

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Abstract

La présente invention concerne des composés représentés par la formule (I-A) ou la formule (I-B) utiles en tant qu'inhibiteurs de topoisomérase et des compositions pharmaceutiques les comprenant. L'invention concerne également des procédés de fabrication et d'utilisation des composés décrits.
PCT/US2025/015508 2024-02-12 2025-02-12 Inhibiteurs d'hétéroaryle topoisomérase et leurs utilisations Pending WO2025174820A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4352811A (en) * 1981-11-12 1982-10-05 Hoechst-Roussel Pharmaceuticals Inc. 3-(1-Substituted-4-piperidyl)-1,2-benzisoxazoles
US5668148A (en) * 1995-04-20 1997-09-16 Merck & Co., Inc. Alpha1a adrenergic receptor antagonists
WO2003074522A1 (fr) * 2002-03-05 2003-09-12 Ferrer Internacional, S.A. Procede de preparation de 3-(2-(4-(6-fluorobenzo(d) isoxazol-3-yl)-piperidin-1yl)-ethyl)-2-methyl-6,7,8,9-tetrahydro-4h-pyrido-(1,2-a) pyrimidin-4-one
US20030191112A1 (en) * 2001-10-12 2003-10-09 Dorwald Florencio Zaragoza Novel substituted piperidines

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4352811A (en) * 1981-11-12 1982-10-05 Hoechst-Roussel Pharmaceuticals Inc. 3-(1-Substituted-4-piperidyl)-1,2-benzisoxazoles
US5668148A (en) * 1995-04-20 1997-09-16 Merck & Co., Inc. Alpha1a adrenergic receptor antagonists
US20030191112A1 (en) * 2001-10-12 2003-10-09 Dorwald Florencio Zaragoza Novel substituted piperidines
WO2003074522A1 (fr) * 2002-03-05 2003-09-12 Ferrer Internacional, S.A. Procede de preparation de 3-(2-(4-(6-fluorobenzo(d) isoxazol-3-yl)-piperidin-1yl)-ethyl)-2-methyl-6,7,8,9-tetrahydro-4h-pyrido-(1,2-a) pyrimidin-4-one

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