EP1328534A2 - 6-o substituierte erythromycinderivate mit verbesserter gastrointestinale toleranz - Google Patents

6-o substituierte erythromycinderivate mit verbesserter gastrointestinale toleranz

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Publication number
EP1328534A2
EP1328534A2 EP01981637A EP01981637A EP1328534A2 EP 1328534 A2 EP1328534 A2 EP 1328534A2 EP 01981637 A EP01981637 A EP 01981637A EP 01981637 A EP01981637 A EP 01981637A EP 1328534 A2 EP1328534 A2 EP 1328534A2
Authority
EP
European Patent Office
Prior art keywords
hydrogen
formula
compound
diyl
isoxazol
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.)
Withdrawn
Application number
EP01981637A
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English (en)
French (fr)
Inventor
Zhenkun Ma
Ly Tam Pham
Richard F. Clark
Souming Zhang
Stevan Djuric
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.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
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Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP1328534A2 publication Critical patent/EP1328534A2/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • 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

Definitions

  • This invention relates to novel semi-synthetic erythromycin derivatives having antibacterial activity, compositions containing the compounds, and methods of treatment using the compounds. These compounds have a lower incidence of GI irritation than the erythromycin derivatives of the prior art.
  • the instant invention provides a series of 6-O- substituted ketolides with an unexpectedly improved gastrointestinal tolerability profile, the ketolides having structural formula (I)
  • X is selected from hydrogen and fluoride
  • Y 1 is selected from isoxazole, oxazole, isothiazole, dihydroisoxazole, and dihydro-oxazole;
  • A is selected from aryl and heteroaryl; and R 1 is selected from hydrogen and R p wherein R p is a hydroxyl protecting group.
  • the invention provides any compound, including metabolic precursors of the inhibitor compounds, which contain an essential inhibitory group as disclosed herein.
  • These inhibitory groups can be in masked form or in therapeutically effective prodrug form and can be converted or released by metabolic or other processes after administration to a patient.
  • compositions comprising the compounds in combination with a therapeutically acceptable excipient.
  • the invention provides a method of treating bacterial infections the method comprising administering a therapeutically effective amount of a compound having structural formula (I)
  • X is selected from hydrogen and fluoride
  • Y is selected from isoxazole, oxazole, isothiazole, dihydroisoxazole, and dihydro-oxazole;
  • a 1 is selected from aryl and heteroaryl
  • R is selected from hydrogen and R p wherein R p is a hydroxyl protecting group.
  • the invention provides a method for the preparation of the compounds of formula (la)
  • X is selected from hydrogen and fluoride
  • Y 1 is selected from isoxazole, oxazole, isothiazole, and isothiazole;
  • A is selected from aryl and heteroaryl;
  • R 1 is selected from hydrogen and R p wherein R p is a hydroxyl protecting group, the method comprising:
  • X is selected from hydrogen and fluoride
  • R 1 is selected from hydrogen and R p wherein R p is a hydroxyl protecting group, with a compound of formula (vii)
  • Y is selected from isoxazole, oxazole, and isothiazole, and A 1 is selected from aryl and heteroaryl, a base, a coupling catalyst, and, optionally, an additive; and
  • step (b) optionally deprotecting the product of step (a).
  • the invention provides a method for the preparation of the compounds of formula (lb)
  • X is selected from hydrogen and fluoride
  • A is selected from aryl and heteroaryl
  • R 1 is selected from hydrogen and R p wherein R p is a hydroxyl protecting group, the method comprising:
  • X is selected from hydrogen and fluoride
  • R 1 is selected from hydrogen and R p wherein R p is a hydroxyl protecting group, with a compound of formula (ii)
  • a 1 is selected from aryl and heteroaryl, and a base
  • step (b) optionally deprotecting the product of step (a).
  • X and R are hydrogen;
  • X is hydrogen and R 1 is R p wherein R p is acetyl; X is hydrogen and R 1 is R p wherein R p is benzoyl; X is fluoride and R 1 is hydrogen; X is fluoride and R is R p wherein R p is acetyl; and X is fluoride and R is R p wherein R p is benzoyl.
  • Each variable substituent at C-2 is represented by X.
  • X is hydrogen or fluoride. In a particularly preferred embodiment, X is fluoride.
  • D can also vary without departing from the intent ofthe invention and can be C 2 - alkynylene or C -alkenylene, the latter of which provides geometric isomers ofthe compounds.
  • the invention contemplates the various geometric isomers and mixtures thereof which result from the disposal of substituents around a carbon-carbon double bond.
  • Substituents around a carbon-carbon double bond are designated as being of Z or E configuration, wherein the term “Z” refers to higher order substituents on the same side ofthe carbon-carbon double bond, and the term “E” refers to higher order substituents on opposite sides ofthe carbon-carbon double bond.
  • Z refers to higher order substituents on the same side ofthe carbon-carbon double bond
  • E refers to higher order substituents on opposite sides ofthe carbon-carbon double bond.
  • D is C 2 - alkynylene, as exemplified by compounds of formula (la).
  • the compounds further comprise substituted heteroarylene or heterocyclene rings, represented by Y 1 , connected to the parent molecular group through groups represented by D 1 and substituted by groups represented by A 1 .
  • the groups represented by Y 1 are stable, 5- membered, diradical rings containing one nitrogen atom, one atom selected from oxygen and sulfur, and the remaining atoms are carbon. The rings are connected to D 1 and are substituted by A 1 through substitutable carbons.
  • the heteroatoms i.e. non-carbon atoms
  • the heteroatoms can be in adjacent or non-adjacent positions.
  • the heteroatoms are in adjacent positions.
  • the rings can contain one or two double bonds.
  • Y is a five membered ring with two double bonds and a nitrogen and oxygen atom in adjacent positions, i.e. isoxazole, the structure and atom numbering of which is shown directly below for illustrative purposes.
  • the isoxazole ring is substituted by A and D on the C-3 and C-5 positions, respectively, to provide a isoxazol-3,5-diyl. Accordingly, taking the listing of preferred substituents and combinations thereof, it will be appreciated by a skilled practioner that compounds of formula (lb)
  • A can also vary considerably without departing from the intent ofthe invention and can be aryl or heteroaryl.
  • Preferred embodiments of A 1 include unsubstituted or substituted monocyclic, aromatic groups such as phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl, tetrazolyl, and the like, and unsubstituted or substituted bicyclic, aromatic groups such as quinolinyl, benzothienyl, imidazo(2,l-b)thiazolyl, and the like.
  • Each ofthe aformentioned groups, represented by A are connected to Y through substitutable carbon atoms in the ring.
  • Y substituents such as, for instance, and by way of example only, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, and the like, are contemplated as being within the scope ofthe invention.
  • a preferred embodiment for the practice ofthe invention is unsubstituted pyridyl, and a particularly preferred embodiment is unsubstituted pyrid-2-yl. Accordingly, taking the listing of preferred substituents and combinations thereof, it will be appreciated by a skilled practioner that compounds of formula (Ii)
  • prodrugs can be prepared from the compounds by attaching thereto a prodrug-forming group such as, but not limited to, include carboxyl, hydroxyl, and amino protecting groups. These prodrugs can then be rapidly transformed in vivo to the parent compound, such as, for example, by hydrolysis in blood.
  • a prodrug-forming group such as, but not limited to, include carboxyl, hydroxyl, and amino protecting groups.
  • These prodrugs can then be rapidly transformed in vivo to the parent compound, such as, for example, by hydrolysis in blood.
  • the term "therapeutically acceptable prodrug,” means those prodrugs ofthe compounds which are suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, wherein possible, ofthe compounds.
  • additive means monodentate phosphorus-containing ligands of formulas P(R C ) 3 (phosphines), P(OR d ) 3 (phosphites) and As(R c ) 3 (arsines), wherein each R c is independently hydrogen; alkyl such as methyl, ethyl, and tert-butyl; cycloalkyl such as cyclopropyl and cyclohexyl; optionally substituted aryl such as phenyl, naphthyl, and ortho- tolyl; and optionally substiuted heteroaryl such as furyl and pyridyl; and wherein each R is independently alkyl such as methyl, ethyl, and tert-butyl; cycloalkyl such as cyclopropyl and cyclohexyl; optionally substituted aryl such as phenyl, naphth
  • additives include tri(alkyl)phosphines such as trimetliylphosphine, triethylphosphine, tributylphosphine, and the like; tri(cycloalkyl)phosphines such as tricyclopropylphosphine, tricyclohexylphosphine, and the like; tri(aryl)phosphines such as triphenylphosphine, trinaphthylphosphine, and the like; tri(heteroaryl)phosphines such as tri(fury-2-yl)phosphine, tri(pyrid-3-yl)phosphine, and the like; tri(alkyl)phosphites such as trimethylphosphite, triethylphosphite, tributylphosphite, and the like; tri(cycloalkyl)-phosphites such as tricyclopropylphosphit
  • additive also means bidentate phosphines such as 1,4- bis(diphenylphosphino)butane (dppb), l,2-bis(diphenyl-phosphino)ethane (dppe), 1,1- bis(diphenylphosphino)methane (dppm), l,2-bis(dimethyl-phosphino)ethane (dmpe), 1,1'- bis(diphenylphosphino)ferrocene (dppf), and the like.
  • the te ⁇ n "additive,” also means copper salts such as copper(I) iodide and copper(I) chloride.
  • alkanoyl means an alkyl group attached to the parent molecular group through a carbonyl group.
  • alkanoyloxy means an alkanoyl group attached to the parent molecular group through an oxygen atom.
  • alkoxy means an alkyl group attached to the parent molecular group through an oxygen atom.
  • alkoxy carbonyl means an alkoxy group attached to the parent molecular group through a carbonyl group.
  • alkoxyalkoxy means an alkoxy group to which attached at least one other alkoxy group.
  • alkyl means a straight or branched chain saturated hydrocarbon radical having from one to six carbon atoms.
  • alkenyl means a straight or branched chain hydrocarbon radical having from two to six carbon atoms and at least one carbon-carbon double bond.
  • C 2 -alkenylene means a diradical formed by the removal of a hydrogen atom from each carbon atom of ethylene.
  • alkynyl means a straight or branched chain hydrocarbon radical having from two to six carbon atoms and at least one carbon-carbon triple bond.
  • C 2 -alkynylene means a diradical formed by the removal of both hydrogen atoms from acetylene.
  • amino means -NH 2 or derivatives thereof formed by independent replacement of one or both hydrogen atoms thereon with a substituent or substituents independently selected from alkyl, alkanoyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, and an amino protecting group.
  • aminoalkyl means an alkyl group, as defined herein, to which is attached at least one amino substituent.
  • amino protecting group or “nitrogen protecting group,” mean selectively introducible and removable groups which protect amino groups against undesirable side reactions during synthetic procedures. Examples of amino protecting groups include
  • aryl means an aromatic, carbocyclic ring containing six carbon atoms.
  • the aryl group can be optionally fused to another aryl group, a cycloalkyl group, or a cycloalkenyl group.
  • Aryl groups ofthe invention are exemplified by phenyl, naphthyl, indenyl, indanyl, dihydronaphthyl, tetrahydronaphthyl, and the like.
  • the aryl groups are connected to the parent molecular group through a substitutable carbon.
  • the aryl groups of the invention can be optionally substituted with 1-5 substituents independently selected from alkyl, alkenyl, alkynyl, alkoxyalkoxy, amino, aminoalkyl, cyano, cyanoalkyl, halo, haloalkyl, nitro, perfluoroalkyl, perfluoroalkoxy, oxo, -(CH 2 ) a C(O)R 5 , -(CH 2 ) a C(O)OR 5 , -(CH 2 ) a N(R 5 )C(O)R 5 , -(CH 2 ) a C(O)N(R 5 ) 2 , -(CH 2 ) a N(R 5 )C(O)N(R 5 ) 2 , -(CH 2 ) a OR 5 , -(CH 2 ) a SO 2 R 5 , -(CH 2 ) a SR 6 , and -(CH 2
  • R is selected from hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocyclyl;
  • R is selected from unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocyclyl; and R is selected from unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heterocyclyl;
  • substituted alkyl means an alkyl group substituted with 1-3 substituents independently selected from alkoxy, alkanoyloxy, alkoxycarbonyl, amino, unsubstituted phenyl
  • substituted aryl means an aryl substituted with 1-5 substituents independently selected from unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkanoyloxy, alkoxycarbonyl, amino, carboxamido, carboxy, cyano, cycloalkyl, halo, hydroxy, nitro, perfluoroalkyl, oxo, and thioalkoxy.
  • substituted cycloalkyl means a cycloalkyl group substituted with one to four substituents independently selected from unsubstituted alkyl, alkoxy, alkanoyloxy, alkoxycarbonyl, amino, unsubstituted phenyl, carboxamido, carboxy, cyano, halo, hydroxy, nitro, perfluoroalkyl, oxo, and thioalkoxy.
  • substituted heteroaryl means a heteroaryl substituted with one to four substituents independently selected from unsubstituted alkyl, alkenyl, alkoxy, alkanoyloxy, alkoxycarbonyl, amino, carboxamido, carboxy, cyano, cycloalkyl, halo, hydroxy, nitro, perfluoroalkyl, oxo, and thioalkoxy.
  • substituted heterocyclyl means a heterocyclyl group substituted with one to four substituents independently selected from unsubstituted alkyl, alkenyl, alkoxy, alkanoyloxy, alkoxycarbonyl, amino, unsubstituted phenyl, carboxamido, carboxy, cyano, halo, hydroxy, nitro, perfluoroalkyl, oxo, and thioalkoxy.
  • arylalkyl means an alkyl group to which is attached at least one aryl group.
  • bases means reagents capable of accepting protons during the course of a chemical reaction.
  • bases include carbonates such as lithium carbonate, lithium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, and the like; phosphates such as potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, and the like; trialkylamines such as triethylamine, diisopropylethylamine, N,N,N,N-tetramethyl-l,8-naphthalenediamine (Proton-Sponge ), and the like; heterocyclic amines such as imidazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like; and bicyclic amines such as l,5-diazabicyclo[4.3.0]non-5- ene (DBN), l,8-diazabicyclo[5.4.0]undec-7-
  • the base chosen for a particular conversion depends on the nature ofthe starting materials, the solvent or solvents in which the reaction is conducted, and the temperature at which the reaction is conducted.
  • carbonyl means -C(O)-.
  • carboxy means -CO 2 H.
  • carboxy protecting group means selectively introducible and removable groups which protect carboxy groups against undesirable side reactions during synthetic procedures and includes all conventional carboxy protecting groups.
  • carboxy protecting groups include methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl (trityl), para- nitrobenzyl, para-methoxybenzyl, acetylmethyl, benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl, 2-tetrahydropyranyl 2-tetrahydrofuranyl, 2,2,2 -trichloroethyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, arylalk
  • Carboxy protecting groups can also be used as prodrug-forming groups.
  • the term "coupling catalyst” means palladium(O) complexes such as tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), allylpalladium chloride dimer, dipalladium tris(dibenzylidine acetone), and the like; palladium(II) salts such as palladium acetate, palladium chloride, and the like; palladium(II) complexes such as dichlorobis(triphenylphosphine)palladium(II), (1,1 - bis(diphenylphosphino)ferrocene)dichloropalladium(II), bis(acetato)bis(triphenylphosphine)palladium(II), bis(acetonitrile)dichloropalladium(II), and the like; nickel(O
  • cyano means -CN.
  • cyanoalkyl means an alkyl group to which is attached at least one cyano substituent.
  • cycloalkyl means a monovalent saturated cyclic or bicyclic hydrocarbon of three to fifteen carbons.
  • cycloalkylalkyl means an alkyl group to which is attached at least one cycloalkyl group.
  • halo means F (fluoride), Cl (chloride), Br (bromide), and I (iodide).
  • haloalkyl means means an alkyl group to which is attached at least one halo substituent.
  • heteroaryl means cyclic, aromatic five- and six-membered groups, wherein at least one atom is selected from the group consisting of nitrogen, oxygen, and sulfur, and the remaining atoms are carbon.
  • the five-membered rings have two double bonds, and the six-membered rings have three double bonds.
  • Heteroaryls are exemplified by furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, triazinyl, and the like.
  • the heteroaryl groups ofthe invention are connected through a substitutable carbon or nitrogen (for imidazolyl or pyrrolyl) in the ring.
  • heteroaryl groups ofthe invention can be fused to an aryl group, a heterocyclyl, or another heteroaryl.
  • Fused heteroaryls are exemplified by quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, indolyl, imidazo(2,l-b)(l,3)thiazolyl, and the like.
  • heteroaryl groups ofthe invention can be optionally substituted with 1-4 substituents independently selected from alkyl, alkenyl, alkynyl, alkoxyalkoxy, amino, aminoalkyl, alkylsulfanyl, alkylsulfonyl, cyano, cyanoalkyl, halo, haloalkyl, nitro, perfluoroalkyl, perfluoroalkoxy, oxo, -(CH 2 ) a C(O)R 5 , -(CH 2 ) a C(O)OR 5 ,
  • heteroarylalkyl means an alkyl group to which is attached at least one heteroaryl group.
  • heteroarylene means a diradical formed by the removal of two hydrogen atoms from a heteroaryl, as defined directly above. Heteroarylenes are exemplified by isoxazol-3,4-diyl, isoxazol-3,5-diyl, isothiazol-3,4-diyl, isothiazol-3,5-diyl, oxazol-2,4-diyl, oxazol-2,5-diyl, oxazol-4,5-diyl, and the like.
  • heterocyclyl means cyclic or bicyclic, non-aromatic, four-, five-, six-, or seven-membered rings containing at least one atom selected from the group consisting of oxygen, nitrogen, and sulfur.
  • the four-membered rings have zero double bonds, the five- membered rings have zero or one double bonds, the six- and seven-membered rings have zero, one, or two double bonds; and the bicyclic heterocyclyls have zero to two double bonds.
  • Heterocyclyls ofthe invention are exemplified by dihydropyranyl, dihydropyridinyl, 1,3- dioxolanyl, 1,4-dioxanyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyridinyl, thiomorpholinyl, and the like.
  • the heterocyclyl groups ofthe invention can be fused to an aryl group, a heteroaryl, or another heterocyclyl.
  • Fused heterocyclyls are exemplified by 1,3-benzodioxole, 2,3-dihydro-l,4-benzodioxine, and the like.
  • the heterocyclyl groups ofthe invention are connected through a substitutable carbon or nitrogen atom in the ring.
  • the heterocyclyl groups ofthe invention can be optionally substituted with 1-5 substituents independently selected from alkyl, alkenyl, alkynyl, alkoxyalkoxy, amino, aminoalkyl, alkylsulfanyl, alkylsulfonyl, cyano, cyanoalkyl, halo, haloalkyl, nitro, perfluoroalkyl, perfluoroalkoxy, oxo,
  • heterocyclene means a diradical formed by the removal of two hydrogen atoms from a heterocyclyl, as defined directly above.
  • Heterocyclenes are exemplified by pyrrolidin-2,4-diyl, l,3-dioxolan-2,4-diyl, and the like.
  • hydroxy protecting group means selectively introducible and removable groups which protect hydroxy groups against undesirable side reactions during synthetic procedures.
  • hydroxy protecting groups include benzyloxycarbonyl, 4- nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxy carbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trimethylsilyl (TMS), triethylsilyl, 2-(trimethylsilyl)- ethoxycarbonyl, 2-f ⁇ rrfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, tert-butyl, 2,2,2- trichloroethy
  • oxo means a group formed by the replacement of two hydrogen atoms on the same carbon atom with a single oxygen atom.
  • perfluoroalkyl means an alkyl group in which all ofthe hydrogen atoms have been replaced by fluoride atoms.
  • substituents such as -(CH 2 ) a C(O)R 5 represent -CH 2 C(O)H, and -CH 2 C(O)CH 3 ; and substituents such as -(CH 2 ) a N(R 5 )C(O)N(R 5 ) 2 represent CH 2 CH 2 N(H)C(O)N(CH 3 )(C 3 H 7 ) and -CH 2 N(CH 3 )C(O)NH(CH 3 ), and the like.
  • the compounds ofthe invention can exist as therapeutically acceptable salts.
  • therapeutically acceptable salt means salts or zwitterionic forms ofthe compounds of the invention which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic response, which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
  • the salts can be prepared during the final isolation and purification ofthe compounds or separately by reacting an amino group with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethansulfonate (isethionate), lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetic, trifluoroacetic, phosphate,
  • amino groups in the compounds ofthe invention can be quatemized with as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; benzyl and phenethyl bromides.
  • acids which can be employed to form therapeutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, sulphuric, and phosphoric and organic acids such as oxalic, maleic, succinic, and citric.
  • Basic addition salts can be prepared during the final isolation and purification ofthe compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary or tertiary amine.
  • Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
  • the compounds of this invention can exist as therapeutically acceptable prodrugs.
  • therapeutically acceptable prodrug represents those prodrugs of the compounds of this invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, ofthe compounds of this invention.
  • prodrug represents compounds, which are rapidly transformed in vivo to the parent compound ofthe above formula, for example, by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 ofthe A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.
  • a 1 is thien-2-yl, X is hydrogen, and R 1 is hydrogen; j) a compound of formula (I) wherein D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl,
  • a 1 is thiazol-2-yl, X is hydrogen, and R 1 is hydrogen; k) a compound of formula (I) wherein D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl,
  • a 1 is 3,4-difluorophenyl, X is hydrogen, and R 1 is hydrogen;
  • a 1 is 3-(trifluoromethyl)phenyl, X is hydrogen, and R 1 is hydrogen; m) a compound of formula (I) wherein D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl, A 1 is 3,4-dichlorophenyl, X is hydrogen, and R 1 is hydrogen; n) a compound of formula (I) wherein D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl,
  • a 1 is 3-cyanophenyl, X is hydrogen, and R 1 is hydrogen; o) a compound of formula (I) wherein D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl,
  • a 1 is 4-cyano-3-(methylsulfanyl)pyrid-2-yl, X is hydrogen, and R 1 is hydrogen; p) a compound of formula (I) wherein D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl,
  • a 1 is thiazol-5-yl, X is hydrogen, and R 1 is hydrogen; q) a compound of formula (I) wherein D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl,
  • a 1 is 6-chloroimidazo(2,l-b)thiazol-5-yl, X is fluoride, and R 1 is hydrogen; r) a compound of formula (I) wherein D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl, A 1 is thiazol-5-yl, X is fluoride, and R 1 is hydrogen; s) a compound of formula (I) wherein D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl,
  • a 1 is thiazol-2-yl, X is fluoride, and R 1 is hydrogen; t) a compound of formula (I) wherein D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl,
  • a 1 is 3,4-dichlorophenyl, X is fluoride, and R 1 is hydrogen; u) a compound of formula (I) wherein D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl,
  • a 1 is pyrimidin-5-yl, X is fluoride, and R 1 is hydrogen; v) a compound of formula (I) wherein D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl,
  • a 1 is 2-methyl-2H-tetrazol-5-yl, X is hydrogen, and R 1 is hydrogen; w) a compound of formula (I) wherein D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl, A 1 is 2-methyl-2H-tetrazol-5-yl; X is fluoride; and R 1 is hydrogen; x) a compound of formula (I) wherein D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl,
  • a 1 is 2-chloroquinol-3-yl, X is hydrogen, and R 1 is hydrogen; y) a compound of formula (I) wherein D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl,
  • a 1 is 3-methylbenzo(b)thien-2-yl, X is hydrogen, and R 1 is hydrogen; z) a compound of formula (I) wherein D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl,
  • a 1 is pyrid-2-yl, X is hydrogen, and R 1 is hydrogen; aa) a compound of formula (I) wherein D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl, A 1 is quinol-3-yl, X is fluoride, and R 1 is hydrogen.
  • a 1 is represented by aryl or heteroaryl. More specifically A 1 is phenyl, substituted phenyl, pyridyl, pyrimidinyl, thienyl, thiazolyl, quinolyl, benzothienyl, or imidazo (2,1-b) thiazolyl, in which any of said heterocycles may be further substituted. Even more particuslarly, A 1 is pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-2-yl, pyrimidin-4-yl or pyrimidin-5-yl.
  • the compounds can be administered alone to achieve an antibacterial effect or in combination with other antibacterial agents.
  • the therapeutically effective dose level depends on factors such as the disorder being treated and the severity of the disorder; the activity ofthe compound used; the composition employed; the age, body weight, general health, sex, and diet ofthe patient; the time of administration; the route of administration; the rate of excretion ofthe compound; the duration of treatment; and drugs used in combination with or coincidentally with the compounds.
  • the compounds can be administered orally, parenterally, nasally, rectally, vaginally, or topically in unit dosage formulations containing therapeutically acceptable excipients such as carriers, adjuvants, diluents, vehicles, or combinations thereof.
  • parenteral includes infusion, subcutaneous, intravenous, intramuscular, and intrasternal injection.
  • the antibacterial effect of parenterally administered compounds can be controlled by slowing their absorption, such as, for example, by administration of injectable suspensions of crystalline, amorphous, or otherwise water-insoluble forms ofthe compounds; administration ofthe compounds as oleaginous solutions or suspensions; or administration of microencapsulated matrices ofthe compounds trapped within liposomes, microemulsions, or biodegradable polymers.
  • the ratio of compound to excipient and the nature of the excipient influences the rate of release ofthe compound.
  • Transdermal patches also provide controlled delivery of compounds using rate-controlling membranes.
  • absorption enhancers can be used to increase absorption ofthe compounds.
  • Solid dosage forms for oral administration ofthe compounds include capsules, tablets, pills, powders, and granules. These compositions can contain diluents, lubricants, and buffering agents. Tablets and pills can be prepared with release-controlling coatings, and sprays can optionally contain propellants.
  • Liquid dosage forms for oral administration ofthe compounds include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. These compositions can also contain adjuvants such as wetting, emulsifying, suspending, sweetening, flavoring, and perfuming agents.
  • Topical dosage forms ofthe compounds include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, and inhalants.
  • Suppositories for rectal or vaginal administration comprise compounds with a suitable nonirritating excipient.
  • Ophthalmic formulations such as eye drops and eye are also contemplated as being within the scope of this invention.
  • the total daily dose ofthe compounds administered to a patient in single or divided doses can be in amounts from about 0J to about 200 mg/kg body weight or preferably from about 0.25 to about 100 mg/kg body weight.
  • Single dose compositions contain these amounts or submultiples thereof to make up the daily dose.
  • Representative compounds were assayed in vitro for antibacterial activity as follows: twelve petri dishes containing successive aqueous dilutions ofthe test compound and 10 mL of sterilized Brain Heart Infusion (BHI) agar (Difco 0418-01 -5) were prepared. Each plate was inoculated with 1:100 (or 1:10 for slow-growing Streptococcus strains) dilutions ofthe nine microorganisms shown in Table 1 using a Steers replicator block. The inoculated plates were incubated at about 35-37 °C for 20-24 hours. A control plate, using BHI agar containing no test compound, was also prepared and incubated at the beginning and end of each test. Finally, a plate containing Erythromycin A was prepared and incubated as another control and to provide test-to-test comparability.
  • BHI Brain Heart Infusion
  • the minimum inhibitory concentration (MIC) was defined as the lowest concentration of drug yielding no growth, a slight haze, or sparsely isolated colonies on the inoculum spot as compared to the growth control.
  • the compounds inhibited the growth of these bacteria with MIC's in a range of about 0.004 ⁇ g/mL to about 128 ⁇ g/mL; in a more preferred range, the compounds inhibited the growth of bacteria with MIC's in a range of about 0.004 ⁇ g/mL to about 2 ⁇ g/mL; and in a most preferred range, the compounds inhibited the growth of bacteria with MIC's in a range of about 0.004 ⁇ g/mL to about 4 ⁇ g/mL.
  • Example 3 and three reference compounds were investigated for their ability to produce nausea and emesis in conscious ferrets using the method as described in Drugs,
  • This enhanced gastrointestinal tolerability represents a significant advantage for the compounds of this invention.
  • These compounds will have an improved side effect profile when compared with the erythromycin derivatives ofthe prior art. Patients consuming these compounds will experience a reduced incidence of nausea, vomiting, gastrointestinal discomfort, cramping, and other GI side effects typically associated with erythromycin therapy.
  • "enhanced gastrointestinal tolerance” refers to a reduced incidence of GI side effects in a patient population, and not to a total absence of GI side effects. As is well known to those skilled in the art, even placebo dosage forms made of sugar produce some measurable incidence of side effects. Thus an enhanced profile must be interpreted in light ofthe relevant art.
  • THF for tetrahydrofuran
  • DMF for N,N-dimethylformamide
  • DME for 1,2-dimethoxy ethane
  • LDA lithium diisopropylamide
  • DDQ 2,3-dichloro-5,6- dicyanobenzoquinone
  • the compounds can be prepared by employing reactions shown in Schemes 1-10. It will be readily apparent to one of ordinary skill in the art that the compounds can be synthesized by substitution ofthe appropriate reactants in these syntheses, and that the steps themselves can be conducted in varying order. It will also be apparent that protection and deprotection steps can be performed to successfully complete the syntheses ofthe compounds. A thorough discussion of protecting groups is provided in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). The groups X, A , D , Y , R 1 , and R p are defined hereinabove and the groups R, W 1 , and X are defined hereinbelow. Scheme 1
  • Conversion of compounds of formula (i) to compounds of formula (iv) can be achieved by in situ treatment of compounds of formula (ii), prepared as described above, with compounds of formula (iii) (R is C C alkyl) and a base.
  • bases include sodium bicarbonate, sodium carbonate, triethylamine, and N-N-diisopropylethylamine.
  • Solvents useful for the reaction include DMF, THF, ethyl acetate, and mixtures thereof.
  • the temperatures at which the reactions are conducted typically range from about 25 °C to about 40 °C; and reaction times are typically from about 12 hours to about 48 hours.
  • Conversion of compounds of formula (iv) to compounds of formula (v) can be achieved by treatment ofthe former with iodine.
  • Solvents useful for the reaction include THF, 1 ,4-dioxane, toluene, and mixtures thereof.
  • the temperature at which the reactions are conducted is typically ambient; and reaction times are typically from about 2 hours to about 4 hours.
  • compounds of formula (vi), wherein X is hydrogen can be intraconverted to compounds of formula (vi), wherein X is fluoride, by treatment ofthe former with a fluorinating agent and, optionally, a base.
  • fluorinating agents include 3,5-dichloro-l-fluoropyridinium tetrafluoroborate, N-fluorobenzenesulfonimide, 3,5- dichloro-1-fluoropyridinium triflate, and N-fluorobenzenesulfonimide, N-fluoro-N-methyl- para-toluenesulfonamide, N-fluoropyridinium triflate, or N-fluoroperfluoropiperidine and a base.
  • bases include sodium hydride, potassium hydride, LDA, triethylamine, and N,N-diisopropylethylamine.
  • Solvents useful for the reaction include THF, diethylether, and mixtures thereof. The temperatures at which the reactions are conducted typically range from about -78 °C to about 0 °C; and reaction times are typically from about 2 hours to about 24 hours.
  • compounds of formula (vi) can be converted to compounds of formula (la) by treatment ofthe former with compounds of formula (vii), a base, a coupling catalyst, and, optionally, an additive.
  • bases include triethylamine and N,N- diisopropylethylamine.
  • coupling catalysts include dichlorobis(triphenylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), and dichlorobis(triphenylphosphine)nickel(II) .
  • additives include triphenylphosphine, triphenylarsine, copper(I) iodide, and mixtures thereof.
  • Solvents useful for the reaction include acetonitrile, THF, triethylamine, and mixtures thereof.
  • the temperatures at which the reactions are conducted typically range from about 50 °C to about 80 °C; and reaction times are typically from about 12 hours to about 48 hours.
  • the compounds of formula (vi) can be treated with compounds of formula (v) to provide compounds of formula (lb).
  • reduction catalysts include Lindlar catalyst and palladium on barium sulfate.
  • An example of an additive is quinoline.
  • Solvents useful for the reaction include C,-C 4 alcohols such as methanol, ethanol, propanol, butanol, wo-propanol, tert-butanol, and the like, acetonitrile, THF, ethyl acetate, and mixtures thereof.
  • the temperature at which the reactions are conducted is typically ambient; and reaction times are typically from about 1 hour to about 6 hours.
  • coupling catalysts include dichlorobis(triphenylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), and dichlorobis(triphenylphosphine)nickel(II).
  • bases include sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, and N,N-diisopropylethylamine.
  • additives include triphenylphosphine, tributylphosphine, and triphenylarsine.
  • Solvents useful for the reaction include acetonitrile, THF, DMF, DME, and mixtures thereof. The temperatures at which the reactions are conducted typically range from about 50 °C to about 80 °C; and reaction times are typically from about 12 hours to about 48 hours.
  • the compounds of formula (viii) can be treated with compounds of formula (v) to provide compounds of formula E-(Id).
  • conversion of compounds of formula (vi) to compounds of formula (ix) can be achieved by treatment ofthe former with l-iodo-2- (trimethylsilyl)acetylene, a base, a coupling catalyst, and, optionally, an additive.
  • bases include triethylamine and N-N-diisopropylethylamine.
  • coupling catalysts include dichlorobis(triphenylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), and dichlorobis(triphenylphosphine)nickel(II).
  • additives include copper(I) iodide, triphenylphosphine, and triphenylarsine.
  • Solvents useful for the reaction include acetonitrile, triethylamine, THF, and mixtures thereof.
  • the temperatures at which the reactions are conducted typically range from about 25 °C to about 80 °C; and reaction times are typically from about 6 hours to about 24 hours.
  • Conversion of compounds of formula (ix) to compounds of formula (x) can be achieved by treatment ofthe former with a base.
  • bases include potassium carbonate and sodium carbonate.
  • Solvents useful for the reaction include methanol or ethanol, and mixtures thereof. The temperature at which the reactions are conducted is typically ambient; and the reaction times are typically about 5-15 minutes.
  • Conversion of compounds of formula (x) to compounds of formula (lb) can be achieved by treatment ofthe former with compounds of formula (ii) and a base.
  • bases include sodium bicarbonate, sodium carbonate, triethylamine, and N,N- diisopropylethylamine.
  • Solvents useful for the reaction include DMF, THF, ethyl acetate, and mixtures thereof.
  • the temperatures at which the reactions are conducted typically range from about 25 °C to about 40 °C; and reaction times are typically from about 12 hours to about 48 hours.
  • conversion of compounds of formula (vi) to compounds of formula (xi) can be achieved by treatment ofthe former with vinyl bromide, a base, a coupling catalyst, and, optionally, an additive.
  • bases include triethylamine and N-N-diisopropylethylamine.
  • coupling catalysts include dichlorobis(triphenylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), and dichlorobis(triphenylphosphine)nickel(II).
  • additives examples include triphenylphosphine, triphenylarsine, and copper(I) iodide.
  • Solvents useful for the reaction include acetonitrile, THF, triethylamine, and mixtures thereof.
  • the temperatures at which the reactions are conducted typically range from about 25 °C to about 80 °C; and reaction times are typically from about 12 hours to about 48 hours.
  • Conversion of compounds of formula (xi) to compounds of formula (Ie) can be achieved by treatment ofthe former with compounds of formula (ii) and a base.
  • bases include sodium bicarbonate, sodium carbonate, triethylamine, and N,N- diisopropylethylamine.
  • Solvents useful for the reaction include DMF, THF, ethyl acetate, and mixtures thereof.
  • the temperatures at which the reactions are conducted typically range from about 25 °C to about 40 °C; and reaction times are typically from about 12 hours to about 48 hours.
  • Conversion of compounds of formula (Ie) to compounds of formula (lb) can be achieved by treatment ofthe former with oxidizing agents.
  • oxidizing agents include manganese dioxide, barium manganate, and DDQ.
  • Solvents useful for the reaction include THF, 1,4-dioxane, and mixtures thereof.
  • the temperatures at which the reactions are conducted typically range from about 50 °C to about 100 °C; and reaction times are typically from about 12 hours to about 96 hours.
  • compounds of formula (x) can be converted to compounds of formula (xii) by treatment ofthe former with comopunds of formula X 1 -C(O)-A 1 , wherein X 1 is Br or Cl, a coupling catalyst, a base, and, optionally, an additive.
  • coupling catalysts include allylpalladium chloride dimer, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), and dichlorobis(triphenylphosphine)nickel(II).
  • bases include N,N,N,N-tetramethyl-l,8-naphthalenediamine (Proton-Sponge ® ), triethylamine and N,N-diisopropylethylamine.
  • additives include triphenylphosphine, triphenylarsine, and copper(I) iodide.
  • Solvents useful for the reaction include acetonitrile, THF, 1,4-dioxane, DME, triethylamine, and mixtures thereof.
  • the temperatures at which the reactions are conducted typically range from about 25 °C to about 100 °C; and reaction times are typically from about 6 hours to about 24 hours.
  • compounds of formula (x) can be converted to compounds of formula (xii) by treatment ofthe former with compounds of formula W -A 1 , wherein W is halogen, - OSO 2 CF 3 , or -S11R 3 (R is C C 4 alkyl), carbon monoxide, a coupling catalyst, and, optionally, a base and an additive.
  • coupling catalysts include allylpalladium chloride dimer, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), and dichlorobis(triphenylphosphine)nickel(II).
  • bases include N,N,N,N-tetramethyl-l,8-naphthalenediamine (Proton-Sponge®), triethylamine and N,N-diisopropylethylamine.
  • additives include triphenylphosphine, triphenylarsine, and copper(I) iodide.
  • Solvents useful for the reaction include acetonitrile, THF, 1,4-dioxane, DME, triethylamine, and mixtures thereof.
  • the temperatures at which the reactions are conducted typically range from about 25 °C to about 100 °C; and reaction times are typically from about 6 hours to about 24 hours.
  • Conversion of compounds of formula (xii) to compounds of formula (If) can be achieved by treatment ofthe former with N-hydroxylamine-O-sulfonic acid, sodium hydrosulfide, and a base.
  • bases include sodium bicarbonate, sodium carbonate, and potassium carbonate.
  • Solvents useful for the reaction include 0 ⁇ 4 alcohols, water, acetonitrile, THF, 1,4-dioxane, DME, and mixtures thereof.
  • the temperatures at which the reactions are conducted typically range from about 0 °C to about 50 °C; and reaction times are typically from about 6 hours to about 24 hours.
  • compounds of formula (xi) can be converted to compounds of formula (xiii) by treatment ofthe former with an oxidizing agent, and, optionally, an additive.
  • oxidizing agents include potassium permanganate, sodium periodate, and ozone.
  • additives include osmium tetroxide, N-methylmorpholine N-oxide, and hydrogen peroxide.
  • Solvents useful for the reaction include acetonitrile, acetone, water, THF, and mixtures thereof.
  • the temperatures at which the reactions are conducted typically range from about 0 °C to about 50 °C; and reaction times are typically from about 1 hour to about 4 hours.
  • Conversion of compounds of formula (xiii) to compounds of formula (Ig) can be achieved by treatment ofthe former with compounds of formula (xiv), triphenylphosphine, and an additive.
  • additives include carbon tetrachloride, carbon tetrabromide, and diethyl azodicarboxylate.
  • Solvents useful for the reaction include acetonitrile, THF, 1,4- dioxane, and mixtures thereof.
  • the temperatures at which the reactions are conducted typically range from about 0 °C to about 50 °C; and reaction times are typically from about 1 hour to about 24 hours.
  • Conversion of compounds of formula (Ig) to compounds of formula (Ih) can be achieved by treatment ofthe former with oxidizing agents.
  • oxidizing agents include manganese dioxide, barium manganate, and DDQ.
  • Solvents useful for the reaction include THF, 1,4-dioxane, and mixtures thereof.
  • the temperatures at which the reactions are conducted typically range from about 50 °C to about 100 °C; and reaction times are typically from about 12 hours to about 96 hours.
  • Patent 5,866,549 in dichloromethane can be treated with 90% technical grade benzoic anhydride and triethylamine over 10 minutes, stirred for 48 hours, treated with saturated NaHCO 3 , and stirred for 30 minutes.
  • the layers can be separated, and the organic layer can be washed with water and brine, dried (Na 2 SO 4 ), filtered, and concentrated.
  • the concentrate can be triturated with a warm mixture of hexane and ethyl acetate and dried in a vacuum oven at ambient temperature to provide the desired product.
  • Example IB compound of formula (ix) in Scheme 6 X is hydrogen; R 1 is C 6 H ⁇ C(O)
  • X is hydrogen; R 1 is C 6 H ⁇ C(O)
  • a solution of Example 1 A (15 g, 0.02 mol) in acetonitrile (150 mL) and triethylamine (75 mL) at room temperature was treated with dichlorobis(triphenylphosphine)palladium(II) (0.994 g, 1.4 mmol), copper(I) iodide (0J 15 g, 0.6 rnmol), and l-iodo-2-
  • Example 1C compound of formula (x) in Scheme 6 X is hydrogen; R 1 is C 6 H 5 C(O)
  • a solution of Example IB (7.07g, 8.44 mmol) in methanol (80 mL) at room temperature was treated with potassium carbonate (0.514 g, 4.22 mmol), stirred for 10 minutes, treated with ethyl acetate, washed with water and brine, dried (Na 2 SO 4 ), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 80:20 hexanes/acetone to provide the desired product. MS (ESI(+)) m/z 765 (M+H) + .
  • Example ID compound of formula (x) in Scheme 6 X is hydrogen; R 1 is hydrogen A solution of Example 1C (3.5 g, 4.57 mmol) in methanol (40 mL) at room temperature was stirred for 60 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 98:1.5:1 dichloromethane/methanol/concentrated ammonium hydroxide to provide the desired product.
  • Patent 5,866,549 in dichloromethane can be treated with 90% technical grade benzoic anhydride and triethylamine over 10 minutes, stirred for 48 hours, treated with saturated NaHCO 3 , and stirred for 30 minutes.
  • the layers can be separated, and the organic layer can be washed with water and brine, dried (Na 2 SO 4 ), filtered, and concentrated.
  • the concentrate can be triturated with a warm mixture of hexane and ethyl acetate and dried in a vacuum oven at ambient temperature to provide the desired product.
  • Example IB compound of formula (ix) in Scheme 6 X is hydrogen; R is C fi H-;C(O)
  • X is hydrogen; R is C fi H-;C(O)
  • a solution of Example 1 A (15 g, 0.02 mol) in acetonitrile (150 mL) and triethylamine (75 mL) at room temperature was treated with dichlorobis(triphenylphosphine)palladium(II) (0.994 g, 1.4 mmol), copper(I) iodide (0J 15 g, 0.6 mmol), and l-iodo-2-
  • Example 1C compound of formula (x) in Scheme 6 X is hydrogen; R is C H s C(O)
  • X is hydrogen; R is C H s C(O)
  • methanol 80 mL
  • potassium carbonate 0.514 g, 4.22 mmol
  • the concentrate was purified by flash column chromatography on silica gel with 80:20 hexanes/acetone to provide the desired product.
  • MS (ESI(+)) m/z 765 (M+H) + .
  • Example ID compound of formula (x) in Scheme 6 X is hydrogen; R 1 is hydrogen
  • a solution of Example 1C (3.5 g, 4.57 mmol) in methanol (40 mL) at room temperature was stirred for 60 hours and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with 98:1.5:1 dichloromethane/methanol/concentrated ammonium hydroxide to provide the desired product.
  • the desired compound was prepared as described in Example 1 of WO 99/21871, and substituting the instant Example 1A for the compound of formula (I) wherein R p is benzoyl, R 1 is methyl, and X is F.
  • Example 2C compound of formula (x) in Scheme 6 X is fluoride; R 1 is CJJ s C(O)
  • the desired product was prepared by substituting Example 2B for Example IB in Example 1C.
  • X is fluoride
  • R is hydrogen
  • Example 3B 2-(5-iodo-3 -isoxazoryDpyridine or compound of formula (v) in Scheme 1:
  • a 1 is pyrid-2-yl
  • the concentrate was purified by flash column chromatography on silica gel with 10:1 to 5:1 hexanes/ethyl acetate to provide the desired product. MS m/z 272 (M+H) + .
  • a solution of Example 2A (1.715 g, 2.26 mmol) and Example 3B (737 mg, 2.71 mmol) in acetonitrile (10 mL) and triethylamine (2 mL) at room temperature was degassed, treated with dichlorobis(triphenylphosphine)palladium(II) (5 mole %), degassed again, stirred for 30 minutes, heated at 65 °C for 18 hours, concentrated to remove most ofthe solvent, treated with isopropyl acetate (500 mL), washed with saturated NaHCO 3 , water, and brine, dried (Na 2 SO 4 ), filtered, and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with 2: 1 hexanes/acetone to provide the desired product. MS m
  • X is fluoride, R is hydrogen;
  • X is hydrogen, R 1 is hydrogen;
  • Example 4B 3-(5-(tributylstannyl)-3-isoxazolyl)quinoline or compound of formula (iv) in Scheme 1 :
  • a 1 is quinol-3-yl;
  • R is n-butyl
  • Example 4 A for Example 11 A in Example 1 IB and purified by flash column cliromatography on silica gel with 95:5 hexanes/acetone.
  • Example 1 ID and purified by flash column chromatography on silica gel with 90:10 hexanes/acetone .
  • X is hydrogen
  • R is hydrogen
  • Example 4D 198 mg, 0.212 mmol
  • methanol (10 mL) methanol (10 mL) was heated at 55 °C for 16 hours and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with 98:1:1 dichloromethane/methanol/concentrated ammonium hydroxide to provide the desired product.
  • Example 5A 2-quinolinecarbaldehyde oxime or compound of formula (i) in Scheme 1 : A 1 is quinol-2-yl The desired product was prepared by substituting 2-quinolinecarbaldehyde for 4- formylbenzonitrile in Example 9A.
  • Example 5B 2-(5-(tributylstannyl)-3-isoxazolyl)quinoline or compound of formula (iv) in Scheme 1 : A is quinol-2-yl; R is n-butyl The desired product was prepared by substituting Example 5 A for Example 11 A in
  • Example 5C 2-(5-iodo-3-isoxazolyl)quinoline or compound of formula (v) in Scheme 1: A is quinol-2-yl
  • the desired product was prepared by substituting Example 5B for Example 1 IB in Example 11C and purified by flash column chromatography on silica gel with 95:5 hexanes/acetone.
  • the desired product was prepared by substituting Example 5C for Example 11 C in Example 1 ID and purified by flash column chromatography on silica gel with 75:25 hexanes/acetone.
  • Example 5D was prepared by substituting Example 5D for Example 4D in Example 4E.
  • the desired product was prepared by substituting 4-quinolinecarbaldehyde for 4- formylbenzonitrile in Example 9A.
  • Example 6B 4-(5-(tributylstannyl)-3-isoxazolyl)quinoline or compound of formula (iv) in Scheme 1: A 1 is quinol-4-yl; R is n-butyl The desired product was prepared by substituting Example 6 A for Example 11 A in Example 1 IB and purified by flash column chromatography on silica gel with 95:5 hexanes/acetone.
  • Example 6B for Example 1 IB in Example l lC.
  • the desired product was prepared by substituting Example 6C for Example 11C in Example 1 ID and purified by flash column chromatography on silica gel with 70:30 hexanes/acetone.
  • Example 6E compound of formula (I): D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl, A 1 is quinol-4-yl;
  • Example 7 compound of formula (I): D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl, A 1 is 4-fluorophenyl;
  • X is hydrogen;
  • R 1 is H ⁇ C(O)
  • Example 1C (0J2 g, 0J57 mmol) in ethyl acetate (1 mL) and water (one drop) was treated with Example 7A (37 mg, 0.212 mmol) and sodium bicarbonate (26.3 mg, 0.314 mmol), stirred at room temperature for 16 hours, and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with 80:20 hexanes/acetone to provide the desired product.
  • Example 7B Example 1 ID in Example 1 IE and purified by flash column chromatography on silica gel with 50:50 hexanes/acetone. MS (ESI(+)) m/z 798 (M+H) + .
  • D is C ⁇ C
  • Y is isoxazol-3,5-diyl
  • A is pyrid-4-yl
  • Example 8A 4-(5-(tributylstannyl)-3-isoxazolyl)pyridine or compound of formula (iv) in Scheme 1: A 1 is pyrid-4-yl; R is n-butyl The desired product was prepared by substituting 4-pyridinecarbaldehyde oxime for Example 11 A in Example 1 IB and purified by flash column chromatography on silica gel with 95:5 hexanes/acetone.
  • Example 8B 4-(5 -iodo-3 -isoxazoly Dpyridine or compound of formula (v) in Scheme 1: A 1 is pyrid-4-yl
  • Example 8 A was prepared by substituting Example 8 A for Example 1 IB in Example l lC.
  • Example 8C was prepared by substituting Example 8C for Example 4D in Example 4E.
  • Example 9 compound of formula (I): D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl, A 1 is 4-cyanophenyl;
  • Example 9A 4-((hydroxyimino)methyl)benzonitrile or compound of formula (i) in Scheme 1 :
  • A is 4-cyanophenyl
  • a solution of 4-formylbenzonitrile (2 g, 15.27 mmol) in methanol (6 mL) was treated with hydroxylamine hydrochloride (1.09g, 15.72 mmol), stirred at room temperature for 24 hours, and concentrated.
  • the concentrate was treated with 5% Na 2 CO 3 and extracted with ethyl acetate. The extract was washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated to provide the desired oxime.
  • Example 9B 4-cyano-N-hydroxybenzenecarboximidoyl chloride or compound of formula (ii) in Scheme 1 :
  • A is 4-cyanophenyl
  • Example ID OJg, 0J31 mmol
  • benzene 1.5 mL
  • Example 9B 23.5 mg, 0J31 mmol
  • triethylamine (19.8 mg, 0J96 mmol)
  • Example 9B additional Example 9B (19 mg, 0J05 mmol) and triethylamine (13.2 mg, 0J31 mmol)
  • ethyl acetate washed with water and brine, dried (Na 2 SO 4 ), filtered, and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with 98:1:1 dichloromethane/methanol/concentrated ammonium hydroxide to provide the desired product.
  • Example 10A was prepared by substituting Example 10A for Example 9B in Example 9C.
  • the desired product was prepared by substituting 2-thiophenecarbaldehyde for 4- formylbenzonitrile in Example 9A.
  • Example 11B 3-(2-thienyl)-5-(tributylstannyl)isoxazole or compound of formula (iv) in Scheme 1 :
  • a 1 is thien-2-yl;
  • R is n-butyl
  • a solution of Example 11A (3 g, 23.6 mmol) in ethyl acetate (70 mL) and water (100 ⁇ L) was treated with tributyl(ethynyl)stannane (6.82 mL, 23.6 mmol), N-chlorosuccinimide (3J3g, 23.6 mmol) and sodium bicarbonate (4.75 g, 56.6 mmol), stirred at room temperature for 48 hours, treated with more ethyl acetate (100 mL), washed with water and brine, dried (Na 2 SO 4 ), filtered, and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with 98:2 hexanes
  • A is thien-2-yl
  • a solution of Example 1 IB (1.05 g, 2.38 mmol) in THF (25 mL) at room temperature was treated with iodine (0.54 g, 2J4 mmol) in THF (15 mL) over 10 minutes, stirred for 3 hours, treated with ether (75 mL), washed with 5% NaHCO 3 , 5% Na 2 S 2 O 3 , and brine, dried (Na 2 SO 4 ), filtered, and concentrated. The concentrate was treated with hexanes and filtered to provide the desired product.
  • Example 1A is hydrogen; R 1 is H C(O)
  • Example 1A is hydrogen; R 1 is H C(O)
  • Example 11C 216 mg, 0.782 mmol
  • dichlorobis(triphenylphosphine)palladium(II) 47.6 mg, 0.068 mmol
  • Example 1 ID is hydrogen; R 1 is hydrogen
  • a solution of Example 1 ID (370 mg, 0.416 mmol) in methanol (15 mL) was stirred at room temperature for 60 hours and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with 98:1:1 dichloromethane/methanol/concentrated ammonium hydroxide to provide the desired product.
  • Example 12 compound of formula (I): D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl, A 1 is thiazol-2-yl;
  • the desired product was prepared by substituting thiazole-2-carbaldehyde for 4- formylbenzonitrile in Example 9A.
  • Example 12B 3-(thiazol-2-yl)-5-(tributylstannyl)isoxazole or compound of formula (iv) in Scheme 1 : A 1 is thiazol-2-yl; R is n-butyl The desired product was prepared by substituting Example 12A for Example 11 A in
  • Example 1 IB and purified by flash column chromatography on silica gel with 98:2 hexanes/ethyl acetate.
  • the desired product was prepared by substituting Example 12C for Example 11C in Example 1 ID and purified by flash column chromatography on silica gel with 80:20 hexanes/acetone.
  • Example 12E compound of formula (I): D is C ⁇ C, Y is isoxazol-3,5-diyl, A is thiazol-2-yl;
  • the desired product was prepared by substituting Examples 1C and 13B for Examples ID and 9B, respectively, in Example 9C and purified by flash column chromatography on silica gel with 85:15 hexanes/acetone.
  • Example 4E 13 C NMR (CDC1 3 ) ⁇ 217.0 (C-9), 205J (C-3), 169.5 (C-1), 160.8, 157.8, 154.0, 152.7, 150.0 125.7, d (123.3 and 123.5), d (118.0 and 117.8), d (116.2 and 116.0), 106.2, 103.2, 95.9, 83.6, 80J, 77.3, 77.3, 72.3, 70.2, 69.6, 66.0, 58.0, 51.3, 51J, 47.0, 44.7, 40.2, 38.5, 37.4, 28.4, 22.4, 21.2, 19.9, 18.0, 15J, 14.5, 13.6, 13.6, 10.6; HRMS m/z (M+H) + calcd for C ⁇ H j ⁇ O j j : 816.3877. Found 816.3886.
  • A is 3-(trifluoromethyl)phenyl; X is hydrogen; R is hydrogen
  • the desired product was prepared by substituting Examples 1C and 14A for Examples ID and 9B, respectively, in Example 9C and purified by flash column chromatography on silica gel with 85:15 hexanes/acetone.
  • D 1 is C ⁇ C
  • Y 1 is isoxazol-3,5-diyl
  • a 1 is 3-(trifluoromethyl)phenyl
  • X is hydrogen
  • R 1 is hydrogen
  • Example 9B The desired product was prepared by substituting 3,4-dichlorobenzaldehyde oxime for Example 9 A in Example 9B.
  • the desired product was prepared by substituting Examples 1C and 15A for Examples ID and 9B, respectively, in Example 9C and purified by flash column chromatography on silica gel with 85:15 hexanes/acetone.
  • Example 16A 3-((hydroxyimino)methyl)benzonitrile or compound of formula (i) in Scheme 1: A 1 is 3-cyanophenyl The desired product was prepared by substituting 3-formylbenzonitrile for 4- formylbenzonitrile in Example 9A.
  • Example 16B 3 -cyano-N-hydroxybenzenecarboximidoyl chloride or compound of formula (ii) in Scheme 1 : A is 3-cyanophenyl
  • the desired product was prepared by substituting Example 16A for Example 9 A in Example 9B.
  • the desired product was prepared by substituting Examples 1C and 16B for Examples ID and 9B, respectively, in Example 9C and purified by flash column cliromatography on silica gel with 85:15 hexanes/acetone.
  • Example 17B 5-cyano-N-hydroxy-6-(methylsulfanyl)-2-pyridinecarboximidoyl chloride or compound of formula (ii) in Scheme 1: A is 4-cyano-3-(methylsulfanyl)pyrid-2-yl
  • the desired product was prepared by substituting Example 17A for Example 9A in Example 9B.
  • Example IE 125 mg, 0J79 mmol
  • Example 17B 61mg, 0.267mmol
  • sodium bicarbonate 44.8 mg, 0.534 mmol
  • stirred for 2 hours treated with additional Example 17B (202 mg, 0.89 mmol) and sodium bicarbonate (30.0 mg, 0.3576 mmol) added simultaneously in 4 portions over 7 hours, treated with ethyl acetate, washed with water and brine, dried (Na 2 SO 4 ), filtered, and concentrated.
  • the concentrate was purified by flash column chromatography on silica gel with 60:40 hexanes/acetone to provide the desired product.
  • Example 18B thiazole-5-carbaldehyde
  • the desired product was prepared from Example 18A as described in Syn. Comm., 25(24), 4081-4086 (1995).
  • Example 18C thiazole-5-carbaldehyde oxime or compound of formula (i) in Scheme 1: A 1 is thiazol-5-yl The desired product was prepared by substituting Example 18B for 4- formylbenzonitrile in Example 9A.
  • Example 18D 3-(thiazol-5-yl)-5-(tributylstannyl)isoxazole or compound of formula (iv) in Scheme 1 :
  • a 1 is thiazol-5-yl;
  • R is n-butyl
  • the desired product was prepared by substituting Example 18C for Example 11A in Example 11B.
  • Example 18F compound of formula (I): D 1 is C ⁇ C, Y is isoxazol-3,5-diyl, A is thiazol-5-yl;
  • the desired product was prepared by substituting Example 18E for Example 11C in Example 1 ID and purified by flash column chromatography on silica gel with 80:20 hexanes/acetone.
  • Example 4E 13 C NMR (CDC1 3 ) ⁇ 217J (C-9), 205J (C-3), 169.6 (C-1), 157.8, 155.4, 154.6, 154J, 143.4 106.3, 103.2, 96.4, 83.6, 80J, 77.3, 72.1, 70.2, 69.7, 65.9, 58.0, 53.4, 51.2, 51J, 47.0, 44.7, 40.2, 38.6, 37.4, 28.2, 22.4, 21J, 19.8, 18.0, 15J, 14.5, 13.6, 13.6, 10.6; HRMS m/z (M+H) + calcd for C 39 H 55 N 4 O ⁇ S: 787.3588. Found 787.3583.
  • Example 19 compound of formula (I): D is C ⁇ C, Y is isoxazol-3,5-diyl,
  • a 1 is 6-chloroimidazo(2J-b)thiazol-5-yl; X is fluoride; R 1 is hydrogen
  • 6-chloroimidazo(2, 1 -b)thiazole-5-carbaldehyde oxime or compound of formula (i) in Scheme 1 A is 6-chloroimidazo(2J-b)thiazol-5-yl
  • the desired product was prepared by substituting 6-chloroimidazo(2,l-b)thiazole-5- carbaldehyde for 4-formylbenzonitrile in Example 9A.
  • a 1 is 6-chloroimidazo(2J-b)thiazol-5-yl; R is n- butyl
  • the desired product was prepared by substituting Example 19A for Example 11 A in Example 11B.
  • Example 19C 6-chloro-5-(5-iodo-3-isoxazolyl)imidazo(2J-b)thiazole or compound of formula (v) in Scheme 1: A 1 is 6-chloroimidazo(2J-b)thiazol-5-yl
  • the desired product was prepared by substituting Example 19B for Example 1 IB in
  • the desired product was prepared by substituting Examples 2A and 19C for Examples 1 A and 1 IC, respectively, in Example 1 ID and purified by flash column chromatography on silica gel with 80:20 hexanes/acetone.
  • D 1 is C ⁇ C
  • Y 1 is isoxazol-3,5-diyl
  • A is 6-chloroimidazo(2J-b)thiazol-5-yl
  • X is fluoride
  • R is hydrogen
  • the desired product was prepared by substituting Example 19D for Example 4D in Example 4E and purified by flash column chromatography on silica gel with 98:2 dichloromethane/methanol.
  • Example 20 compound of formula (I): D is C ⁇ C, Y 1 is isoxazol-3,5-diyl, A 1 is thiazol-5-yl;
  • X is fluoride
  • Example 20B compound of formula (I): D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl, A 1 is thiazol-5-yl;
  • Example 21 compound of formula (I): D 1 is C ⁇ C, Y is isoxazol-3,5-diyl, A is thiazol-2-yl;
  • Example 21 A compound of formula (I): D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl, A 1 is thiazol-2-yl;
  • X is fluoride
  • R 1 is C JLC(O)
  • the desired product was prepared by substituting Examples 2 A and 12C for Examples 1 A and 1 IC, respectively, in Example 1 ID and purified by flash column chromatography on silica gel with 80:20 hexanes/acetone.
  • Example 21B compound of formula (I): D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl, A 1 is thiazol-2-yl; X is fluoride; R is hydrogen
  • Example 21 A was prepared by substituting Example 21 A for Example 14B in Example 14C.
  • X is fluoride
  • R 1 is CjH C(O)
  • the desired product was prepared by substituting Examples 2C and 15 A for Examples ID and 9B, respectively, in Example 9C and purified by flash column chromatography on silica gel with 85:15 hexanes/acetone.
  • Example 22B compound of formula (I): D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl, A is 3,4-dichlorophenyl;
  • Example 4E 13 C NMR (CDC1 3 ) ⁇ 216.8 (C-9), d (204.3 and 203.9) (C-3), d (166.0 and 166.8) (C-1), 160.7, 157.4, 154J, 134.3, 133.3, 131.0, 128.7, 128.5, 126J, 106.2, 104.2, d (98.8 and 96.3), 96.5, 83.5, 80.7, 80.0, 78.8, 72.2, 70.3, 69.8, 65.9, 58J, 50.7, 44J, 40.5, 40.2, 38.3, 37.4, 28.2, d (25.4 and 25J), 22.3, 21.2, 20.4, 17.6, 15.4, 13.7, 13.2, 10.6; HRMS m/z (M+H) + calcd for C ⁇ H ⁇ C ⁇ FNgO j , : 866.3192. Found 866.3196.
  • Example 23 compound of formula (I): D is C ⁇ C, Y is isoxazol-3,5-diyl, A is pyrimidin-5-yl;
  • Example 23A 5-pyrimidinecarbaldehyde A solution of 5-bromopyrimidine (12 g, 0.075 mol) in THF (500 mL) at -100 °C was treated with 2.5M n-butyllithium in hexanes (30.2 mL, 79 mmol) over 35 minutes, stirred for 15 minutes at -100 °C, treated with ethyl formate (6.7 mL, 0.0825 mol) over 15 minutes, stirred for 15 minutes at -95 °C, treated with 1M HCl in ether (79 mL, 0.0787 mol) over 10 minutes, warmed to room temperature over 1 hour, and concentrated. The concentrate was treated with dichloromethane, and the resulting solution was washed with water and brine, dried (MgSO 4 ), filtered, and concentrated to provide the desired product.
  • the desired product was prepared by substituting Example 23 B for Example 9 A in
  • Example 23 D compound of formula (I): D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl, A 1 is pyrimidin-5-yl;
  • X is fluoride
  • R 1 is C H C(O)
  • the desired product was prepared by substituting Examples 2C and 23 C for Examples ID and 9B, respectively, in Example 9C and purified by flash column chromatography on silica gel with 80:20 hexanes/acetone.
  • Example 23 E compound of formula (I): D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl, A 1 is pyrimidin-5-yl;
  • a 1 is 2-methyl-2H-tetrazol-5-yl; X is hydrogen; R 1 is hydrogen
  • the desired product was prepared by substituting Examples IC and 24C for Examples ID and 9B, respectively, in Example 9C and purified by flash column cliromatography on silica gel with 80:20 hexanes/acetone.
  • A is 2-methyl-2H-tetrazol-5-yl; X is hydrogen; R 1 is hydrogen
  • the desired product was prepared by substituting the product from Example 24D for Example 14B in Example 14C. 13 C NMR (CDC1 3 ) ⁇ 217J (C-9), 205.0 (C-3), 169.7 (C-1),
  • Example 25 compound of formula (I): D is C ⁇ C, Y 1 is isoxazol-3,5-diyl, A 1 is 2-methyl-2H-tetrazol-5-yl; X is fluoride; R 1 is hydrogen
  • a 1 is 2-methyl-2H-tetrazol-5-yl; X is fluoride; R 1 is H,C(O)
  • the desired product was prepared by substituting Example 2C for Example IC in Example 24D.
  • D is C ⁇ C
  • Y 1 is isoxazol-3,5-diyl
  • a 1 is 2-methyl-2H-tetrazol-5-yl
  • X is fluoride
  • R 1 is hydrogen
  • the desired product was prepared by substituting Example 25A for Example 4D in Example 4E.
  • Example 26 compound of formula (I): D 1 is C ⁇ C, Y is isoxazol-3,5-diyl, A 1 is 2-chloroquinol-3-yl;
  • Example 26A 2-chloro-3-quinolinecarbaldehyde oxime or compound of formula (i) in Scheme 1 :
  • a 1 is 2-chloroquinol-3-yl
  • the desired product was prepared by substituting 2-chloro-3-quinolinecarbaldehyde for 4-formylbenzonitrile in Example 9A.
  • Example IE 125 mg, 0J788 mmol
  • benzene 1.5 ml
  • Example 26B 51mg, 0.213mmol
  • triethylamine 30.5, 0.302 mmol
  • the concentrate was purified by flash column chromatography on silica gel with 99:1 dichloromethane/methanol to provide the desired product.
  • Example 27 compound of formula (I): D is C ⁇ C, Y is isoxazol-3,5-diyl,
  • A is 3-methylbenzo(b)thien-2-yl; X is hydrogen; R is hydrogen
  • Example 27A 3 -methylbenzo(b)thiophene-2-carbaldehyde oxime or compound of formula (i) in Scheme 1: A is 3-methylbenzo(b)thien-2-yl
  • the desired product was prepared by substituting 3-methylbenzo(b)thiophene-2- carbaldehyde for 4-formylbenzonitrile in Example 9A.
  • a 1 is 3-methylbenzo(b)thien-2-yl
  • the desired product was prepared by substituting Example 27A for Example 9A in Example 9B.
  • Example 28 compound of formula (I): D 1 is C ⁇ C, Y 1 is isoxazol-3,5-diyl, A is pyrid-2-yl;
  • Example 28 A compound of formula (I): D is C ⁇ C, Y is isoxazol-3,5-diyl, A is pyrid-2-yl;
  • X is hydrogen;
  • R 1 is C H,C(O)
  • Example 28A (1.24 g, 1.4 mmol) in methanol (20 mL) was heated at reflux for 6 hours and concentrated. The concentrate was purified by flash column cliromatography on silica gel with 100:1:0.5 dichloromethane/methanol/concentrated ammonium hydroxide to provide the desired product.
  • the desired product was prepared by substituting Example 29A for Example 3 A in Example 3B.
  • X is fluoride
  • R 1 is H,C(O)
  • the desired product was prepared by substituting Examples 2A and 29B for Examples 1 A and 3B, respectively, in Example 28A.
  • Example 29C The desired product was prepared by substituting Example 29C for Example 28A in Example 28B.
  • MS m/z 849 (M+H) + ; 13 C NMR (75 MHz, CDC1 3 ) ⁇ 216.8, d (204.3 and 203.9), d (166.1 and 165.8), 106.4, 157.5, 154.0, 148.6, 148.4, 134.3, 130.5, 129.4, 128.4, 127.5, 127.3, 121.8, 106.3, 104.2, d (99.0 and 96.2), 96.6, 83.5, 80.7, 80.0, 78.7, 72.3, 70.3, 69.8, 65.8, 58.1, 50.7, 44J, 40.5, 40.2, 38.3, 37.4, 28J, d (25.4 and 25J), 22.2, 21.2, 20.3, 17.6, 15.4, 13.7, 13.2, 10.6; HRMS m/z calcd (M+H) + for C 45 H 57 FN 4 O ⁇ : 849.4081. Found

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