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WO2008120003A1 - Pipéridines substituées destinées à être utilisées dans le traitement d'infections bactériennes - Google Patents

Pipéridines substituées destinées à être utilisées dans le traitement d'infections bactériennes Download PDF

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Publication number
WO2008120003A1
WO2008120003A1 PCT/GB2008/001182 GB2008001182W WO2008120003A1 WO 2008120003 A1 WO2008120003 A1 WO 2008120003A1 GB 2008001182 W GB2008001182 W GB 2008001182W WO 2008120003 A1 WO2008120003 A1 WO 2008120003A1
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Prior art keywords
carbocyclyl
heterocyclyl
alkenyl
alkyl
formula
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PCT/GB2008/001182
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English (en)
Inventor
Mark Cornebise
Folkert Reck
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AstraZeneca UK Ltd
AstraZeneca AB
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AstraZeneca UK Ltd
AstraZeneca AB
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Publication of WO2008120003A1 publication Critical patent/WO2008120003A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-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

Definitions

  • the present invention relates to novel piperidines, pharmaceutical compositions thereof, and methods of use.
  • the present invention relates to therapeutic methods for the treatment of bacterial infections.
  • the compounds of Formula (I) are believed to possess antibacterial activity, and are therefore useful for the treatment of bacterial infections.
  • the present invention also provides processes for the preparation of compounds of Formula (I), pharmaceutical compositions containing them as the active ingredient, their use as medicaments, methods of using such compounds, and their use in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as man.
  • the present invention provides a compound of Formula (I):
  • R 1 is selected from H, halo, -CN, Ci- ⁇ alkyl, C 2 - 6 alkenyl, C 2- 6alkynyl, carbocyclyl, heterocyclyl, -OR la , -SR la , -N(R la ) 2 , -N(R la )C(O)R lb , -N(R la )N(R la ) 2; -C(O)H, -C(O)R lb , -C(O) 2 R la , -C(O)N(R la ) 2 , -OC(O)N(R la ) 2 , -N(R la )C(O) 2 R la , -N(R la )C(O)N(R la ) 2 , -OC(O)R lb , -S(O)R lb , -S(O) 2 R lb , -S(O) 2 R
  • R la in each occurrence is independently selected from H, C ⁇ aUcyl, carbocyclyl, and heterocyclyl, wherein said Ci- ⁇ alkyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R 10 ;
  • R lb in each occurrence is independently selected from C 2- 6alkenyl, C 2- 6alkynyl, carbocyclyl, and heterocyclyl, wherein said Q ⁇ alkyl, C 2-6 alkenyl, C 2-6 aU ⁇ ynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R 10 ;
  • R 2 is selected from H, halo, -CN, C h alky., C 2-6 alkenyl, C 2- 6alkynyl, carbocyclyl, heterocyclyl, -OR 2a , -SR 2a , -N(R 2a ) 2 , -N(R 2a )C(O)R 2b , -N(R 2a )N(R 2a ) 2 , -C(O)H, -C(O)R 2b , -C(O) 2 R 2a , -C(O)N(R
  • R 2a in each occurrence is independently selected from H, C ⁇ aUcyl, carbocyclyl, and heterocyclyl, wherein said C ⁇ aUcyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R 20 ;
  • R 2b in each occurrence is independently selected from Q- ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci -6 alkyl, C 2-6 alkenyl, C 2- 6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R 20 ;
  • R 3 is selected from H, halo, -CN, C 2-6 alkenyl, C 2 .6alkynyl, carbocyclyl, heterocyclyl, -OR 3a , -SR 3a , -N(R 3a ) 2 , - -N(R 3a )N(R 3a ) 2 , -C(O)R 3b , , -C(O)N(R 3a ) 2 , -OC(O)N(R 3a ) 2 , -N(R 3a )C(
  • R 3b in each occurrence is independently selected from C 1-6 alkyl, C 2- 6alkenyl, C 2- 6alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2- 6alkenyl, C 2- 6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R 30 ;
  • R 4 in each occurrence is independently selected from halo, -CN, Q- ⁇ alkyl, C 2- 6alkenyl,
  • Ci -6 alkyl, C 2-6 alkenyl, C 2 . 6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 40 , or two R substituents on the 2 and 6 carbon atoms optionally may together form an ethylene bridge;
  • R 4a in each occurrence is independently selected from H, Q ⁇ alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R 40 ;
  • R 4b in each occurrence is independently selected from C ⁇ aHcyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C ⁇ alkyl, C 2- 6alkenyl, C 2- 6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R 40 ;
  • R 5 is selected from H, halo, -CN, Ci- ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 5a , -SR 5a , -N(R 5a ) 2 , -N(R 5a )C(O)R 5b , -N(R 5a )N(R 5a ) 2 , -C(O)H, -C(O)R 5b ,
  • Ci- ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R 50 ;
  • R Sa in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said C ⁇ aUcyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R 50 ;
  • R 5b in each occurrence is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2- 6alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R 50 ;
  • R 10 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 10a , -SR 1Oa , -N(R 1Oa ) 2 , -N(R 10a )C(O)R 10b , -N(R 10a )N(R 10a ) 2 , -C(O)H, -C(O)R 10b , -C(O) 2 R 10a , -C(O)N(R 1 Oa ) 2 , -OC(O)N(R 10a ) 2 , -N(R 10a )C(O) 2 R 10a , -N(R 10a )C(O) 2 R 10a , -N(R 10a )C(O)N(R 10a ) 2 , -OC(O)R 10b ,
  • R 1Oa in each occurrence is independently selected from H, C ⁇ aHcyl, carbocyclyl, and heterocyclyl, wherein said Ci ⁇ alkyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R a ;
  • R 1Ob in each occurrence is independently selected from Ci -6 alkyl, C 2- 6alkenyl, C 2- 6alkynyl, carbocyclyl, and heterocyclyl, wherein said C ⁇ alkyl, C 2-6 alkenyl, C 2- galkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R a ;
  • R 20 in each occurrence is independently selected from halo, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 20a , -SR 20a , -N(R 2Oa ) 2 , -N(R 20a )C(O)R 20b , -N(R 20a )N(R 20a ) 2 , -C(O)H, -C(O)R 20b , -C(O) 2 R 20a ,
  • R 20a in each occurrence is independently selected from H, C ⁇ aUcyl, carbocyclyl, and heterocyclyl, wherein said Ci- ⁇ alkyl, carbocyclyl, and heterocyclyl are each, independently and optionally substituted with one or more R b ;
  • R 20b in each occurrence is independently selected from C ⁇ aUcyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C ⁇ aHcyl, C 2- 6alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R b ;
  • R 30 in each occurrence is independently selected from halo, -CN, C ⁇ aUcyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 30a , -SR 30a , -N(R 30a ) 2s -N(R 30a )C(O)R 30b , -N(R 30a )N(R 30a ) 2 , -C(O)H, -C(O)R 30b , -C(O) 2 R 30a
  • R 3Ob in each occurrence is independently selected from C ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C ⁇ alkyl, C 2- 6alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R c ;
  • R 40 in each occurrence is independently selected from halo, -CN, C ⁇ alkyl, C 2- 6alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 40a , -SR 40a , -N(R 4Oa ) 2 , -N(R 40a )C(O)R 40b , -N(R 40a )N(R 40a ) 2 , -C(O)H, -C(O)R 40b , -C(O) 2 R 403 , -
  • R 40a in each occurrence is independently selected from H, C ⁇ alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_ 6 alkyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R d ;
  • R 40b in each occurrence is independently selected from C ⁇ ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci ⁇ alkyL C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally substituted with one or more R d ;
  • R 50 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 50a , -SR 50a , -N(R 50a ) 2 , -N(R 50a )C(O)R 50b , -N(R 50a )N(R 50a ) 2 , -C(O)H, -C(O)R 50b , -C(O) 2 R 50a , -C
  • R 50a in each occurrence is independently selected from H, C ⁇ aUcyl, carbocyclyl, and heterocyclyl, wherein said C ⁇ aUcyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R e ;
  • R 5Ob in each occurrence is independently selected from C 1-6 alkyl, C 2- 6alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R e ; R a , R b , R c , R d , and R e in each occurrence are independently selected from halo, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR m , -SR m , -N(R ra ) 2 , -N(R ra )C(O)R n , -N(R m )N(R m ) 2 , -C(O)H,
  • R m in each occurrence is independently selected from H and C ⁇ alkyl
  • R" in each occurrence is and n is selected from O, 1, 2, and 3.
  • Ci ⁇ alkyl includes Qalkyl (methyl), C 2 alkyl (ethyl), Caalkyl (propyl and isopropyl) and C 4 alkyl (butyl, 1-methylpropyl, 2-methylpropyl, and /-butyl).
  • alkyl refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only.
  • “Ci,6alkyl” includes, but is not limited to, groups such as methyl, ethyl, propyl, isopropyl, 1-methylpropyl, butyl, ⁇ -butyl, pentyl, and hexyl. In one aspect, the term “alkyl” refers to methyl.
  • alkenyl refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon double bond.
  • C 2-6 alkenyl includes, but is not limited to, groups such as C 2-6 alkenyl, C2 -4 alkenyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.
  • alkynyl refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon triple bond.
  • C 2-6 alkynyl includes, but is not limited to, groups such as C 2- 6alkynyl, C 2-4 alkynyl, ethynyl, 2-propynyl, 2-methyl-2-propynyl, 3-butynyl, 4-pentynyl, and 5-hexynyl.
  • halo refers to fluoro, chloro, and bromo. In one aspect, the term “halo” refers to fluoro and chloro. In another aspect, the term “halo” refers to fluoro.
  • carbocyclyl refers to a saturated, partially saturated, or unsaturated, mono or bicyclic carbon ring that contains 3-12 ring atoms, wherein one or more -CH 2 - groups can optionally be replaced by a corresponding number of -C(O)- groups. In one aspect, the term “carbocyclyl” may refer to a monocyclic ring containing 3 to 6 ring atoms or a bicyclic ring containing 9 or 10 atoms.
  • the term “carbocyclyl” may refer to a monocyclic ring containing 5 or 6 atoms.
  • Illustrative examples of “carbocyclyl” include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1-oxocyclopentyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.
  • a particular example of a "carbocyclyl” group is phenyl.
  • heterocyclyl refers to a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 ring atoms of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group can optionally be replaced by a -C(O)-.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms may be optionally oxidized to form N-oxides.
  • heterocyclyl include, but are not limited to, 1,3-benzodioxolyl, 3,5-dioxopiperidinyl, imidazolyl, indolyl, isoquinolone, isothiazolyl, isoxazolyl, morpholino, 2-oxopyrrolidinyl, 2-oxo-l,3-thiazolidinyl, piperazinyl, piperidyl, pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, pyrimidyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridone, quinolyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thienyl, thiomorpholino, thiophenyl,
  • heterocyclyl may refer to a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 atoms of which at least one atom is selected from nitrogen, sulfur, and oxygen, and may, unless otherwise specified, be carbon or nitrogen linked, and a ring nitrogen atom may be optionally oxidized to form an ⁇ -oxide.
  • the -N(R) 2 group is intended to encompass: 1) those -N(R) 2 groups in which both R substituents are the same, such as those in which both R substituents are, for example, C ⁇ aUcyl; and 2) those -N(R) 2 groups in which each R substituent is different, such as those in which one R substituent is, for example, H, and the other R substituent is, for example, carbocyclyl.
  • the bonding atom of a group may be any suitable atom of that group; for example, propyl includes prop-1-yl and prop-2-yl.
  • the phrase "effective amount” means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response).
  • the effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.
  • leaving group is intended to refer to groups readily displaceable by a nucleophile such as an amine nucleophile, and alcohol nucleophile, or a thiol nucleophile.
  • suitable leaving groups include halo, such as chloro and bromo, and sulfonyloxy group, such as methanesulfonyloxy and toluene-4-sulfonyloxy.
  • substitution is optional and therefore it is possible for the designated group to be either substituted or unsubstituted.
  • any number of hydrogens on the designated group may be replaced with a selection from the indicated substituents, provided that the normal valency of the atoms on a particular substituent is not exceeded, and that the substitution results in a stable compound.
  • a particular group when a particular group is designated as being optionally substituted with "one or more" substituents, the particular may be unsubstituted.
  • the particular group may bear one substituent.
  • the particular substituent may bear two substituents.
  • the particular group may bear three substituents.
  • the particular group may bear four substituents.
  • the particular group may bear one or two substituents.
  • the particular group may be unsubstituted, or may bear one or two substituents.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • protecting group is intended to refer to those groups used to prevent selected reactive groups (such as carboxy, amino, hydroxy, and mercapto groups) from undergoing undesired reactions.
  • suitable protecting groups for a hydroxy group include, but are not limited to, an acyl group; alkanoyl groups such as acetyl; aroyl groups, such as benzoyl; silyl groups, such as trimethylsilyl; and arylmethyl groups, such as benzyl.
  • the deprotection conditions for the above hydroxy protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon.
  • suitable protecting groups for an amino group include, but are not limited to, acyl groups; alkanoyl groups such as acetyl; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, and ⁇ -butoxycarbonyl; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; and aroyl groups, such benzoyl.
  • alkanoyl groups such as acetyl
  • alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, and ⁇ -butoxycarbonyl
  • arylmethoxycarbonyl groups such as benzyloxycarbonyl
  • aroyl groups such benzoyl.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric, phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid, for example boron trichloride).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine.
  • Another suitable protecting group for an amine is, for example, a cyclic ether such as tetrahydrofuran, which may be removed by treatment with a suitable acid such as trifluoroacetic acid.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.
  • R 1a R 13 -N(R 1a )N(R 1a ) 2 j— N-N-R 13
  • Acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate,
  • base salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as aluminum, calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, ornithine, and so forth.
  • basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates such as dimethyl, diethyl, and dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; arylalkyl halides such as benzyl bromide, and others.
  • Non-toxic physiologically-acceptable salts are preferred, although other salts are also useful, such as in isolating or purifying the product.
  • the salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.
  • Compounds of Formula (I) have a chiral centre and may have multiple chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess antibacterial activity.
  • the invention further relates to any and all tautomeric forms of the compounds of Formula (I) that possess antibacterial activity.
  • Additional embodiments of the invention are as follows. These additional embodiments relate to compounds of Formula (I) and pharmaceutical salts thereof. Such specific substituents may be used, where appropriate, with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
  • A may be N.
  • D may be CH.
  • E may be O.
  • G may be O.
  • X may be O.
  • R 1 may be selected from H and C ⁇ aUcyl.
  • R 1 may be C ⁇ alkyL
  • R 1 may be Ci -3 alkyl.
  • R 1 may be methyl
  • R 1 may be H.
  • R may be H.
  • R 3 may be selected from halo, -CN, and -OR 3a ; and R 3a may be Ci -6 alkyl.
  • R 3 may be halo
  • R 3 may be -CN.
  • R 3 may be -OR 3a ; and R 3a may be Ci -6 alkyl.
  • R 3 may be fluoro
  • R 3 may be methoxy
  • R 3 may be selected from fluoro, -CN, and methoxy.
  • R 4 may be selected from halo, C h alky!, and -OR 4a ; and R 4a may be selected from H and C ⁇ alkyl.
  • R may be halo
  • R 4 may be Ci ⁇ alkyL
  • R 4 may be C ⁇ aUcyl.
  • R 4 may be -OR 4a ; and R 4a may be selected from H and Ci- ⁇ alkyl.
  • R 4 may be selected from halo, C 1-3 alkyl, and -OR 4a ; and R 4a may be selected from H and C h alky!. In yet a further aspect, R 4 may be selected from fluoro, methyl, and -OR 4a ; and R 4a may be selected from H and methyl.
  • R 4 may be fluoro
  • R may be methyl
  • R 4 may be hydroxy
  • R may be methoxy
  • the R 4 substituent may be a substituent on the 3 -carbon or the 5-carbon.
  • two R 4 substituents on the 2 and 6 carbon atoms optionally may together form an ethylene bridge.
  • R 6 and R 7 are each hydrogen.
  • n may be 0, 1, or 2.
  • n may be 0 or 1, and wherein if n is 1,
  • R 4 may be selected from halo, C h alky., and -OR 4a ;
  • R 4a may be selected from H and C ⁇ aUcyl.
  • n may be 0.
  • n may be 1;
  • R 4 may be selected from halo, C ⁇ aUcyl, and -OR 4a ;
  • R 4a may be selected from H and Ci -6 alkyl.
  • the compound of Formula (I) may be a compound of Formula (Ia):
  • the compound of Formula (I) may be a compound of Formula (Ib):
  • the compound of Formula (I) may be a compound of Formula (Ia):
  • R 1 may be selected from H and Ci ⁇ alkyl
  • R 2 may be H
  • R 3 may be selected from halo, -CN, and -OR 3a ; R 3a may be C 1-6 alkyl;
  • R 4 may be selected from halo, Ci -6 alkyl, and -OR 4a ; R 4a may be selected from H and Ci -6 alkyl; and n may be 0 or 1.
  • X may be O
  • R 1 may be selected from H and Ci -6 alkyl
  • R 2 may be H
  • R 3 may be selected from halo, -CN, and -OR 3a ;
  • R 3a may be Ci ⁇ alkyl; and n may be 0.
  • R 3a may be Ci ⁇ alkyl; and n may be 0.
  • X may be O
  • R 1 may be selected from H and C ⁇ aUcyl
  • R 2 may be H
  • R 3 may be selected from halo, -CN, and -OR 3a ;
  • R 3a may be Ci -6 alkyl
  • R 4 may be selected from halo, C ⁇ aHcyl, and -OR 4a ;
  • R 4a may be selected from H and C ⁇ alkyl; and n may be 1.
  • X may be O
  • R 1 may be selected from H and methyl
  • R 2 may be H
  • R 3 may be selected from fluoro, -CN, and methoxy
  • R 4 may be selected from fluoro, methyl, and methoxy; and n may be 0 or 1.
  • X may be O
  • R 1 may be selected from H and methyl
  • R 2 may be H
  • R 3 may be selected from fluoro, -CN, and methoxy
  • R 4 may be selected from fluoro, methyl, and methoxy; and n may be 1.
  • X may be O
  • R 1 may be selected from H and methyl;
  • R 2 may be H;
  • R 3 may be selected from halo, -CN, and methoxy; and n may be 0.
  • the compound of Formula (I) may be a compound of Formula (Ib):
  • X may be O
  • R 1 may be H
  • R 2 may be H
  • R 3 may be selected from halo, -CN, and -OR 3a ;
  • R 3a may be Q- ⁇ alkyl; and n may be 0.
  • X may be O
  • R 1 may be H
  • R 2 may be H
  • R 3 may be selected from -CN and -OR 3a ; R 3a may be Ci -6 alkyl; and n may be 0.
  • X may be O
  • R 1 may be H
  • R 2 may be H
  • R 3 may be selected from -CN and methoxy; and n may be 0.
  • the present invention provides compounds of Formulas (I), and pharmaceutically acceptable salts thereof, as illustrated by the Examples, each of which provides a further independent aspect of the invention.
  • the present invention provides a compound of Formula (I) selected from:
  • the compounds of Formula (I) are of interest due to their antibacterial effects.
  • the ability of the invention compounds disclosed herein to achieve an antibacterial effect may be demonstrated by the following tests.
  • the assay utilizes the ATPase activity of the ParE subunit of reconstituted Escherichia coli ParC/ParE tetramer protein. Inhibition of ATPase activity was monitored by reduced production of inorganic phosphate, a product of the ATPase reaction. Inorganic phosphate was quantified using the ammonium molybdate/malachite green-based detection systenxFor determination of IC50 values, assays were performed 384-well microtiter plates. Each well contained a dilution range of the compound dissolved in DMSO.
  • each well contained: 20 mM Tris pH 8.0, 50 mM ammonium acetate, 0.16 mM ATP, 0.005% Brij-35, 8.0 mM magnesium chloride, 0.5 mM EDTA, 2.5% v/v glycerol, 5 mM dithiothreitol, 0.005 mg/mL sheared salmon sperm DNA, 0.5 nM E. coli ParC protein, 0.5 nM E, coli ParE protein.
  • Final volume of assays was 30 ⁇ L. Reactions were incubated 24 hours at room temperature and then quenched with the addition of 45 ⁇ L malachite green reagent (Lanzetta, P. A., L. J.
  • Compounds may be tested for antimicrobial activity by susceptibility testing in liquid media in a 96 well format.
  • Compounds may be dissolved in dimethylsulfoxide and tested in 10 doubling dilutions in the susceptibility assays.
  • the organisms used in the assay may be grown overnight on suitable agar media and then suspended in a liquid medium appropriate for the growth of the organism.
  • the suspension may be a 0.5 McFarland and a further 1 in 10 dilution may be advantageously made into the same liquid medium to prepare the final organism suspension in 100 ⁇ L. Plates may be incubated under appropriate conditions at 37 0 C for 24 hours prior to reading.
  • the Minimum Inhibitory Concentration (MIC) is intended to refer to the lowest drug concentration able to reduce growth by 80% or more.
  • Compounds may be evaluated against organisms such as Gram-positive species, including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Enterococcus faecium; and Gram-negative species including Haemophilus influenzae, Escherichia coli, Moraxella catarrhalis and Pseudomonas aeruginosa.
  • Gram-positive species including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Enterococcus faecium
  • Gram-negative species including Haemophilus influenzae, Escherichia coli, Moraxella catarrhalis and Pseudomonas aeruginosa.
  • Compounds of the present invention are believed to have MICs less than or equal to 8 ⁇ g/ml versus one or more of the organisms named above.
  • the compound of Example 1 had an MIC of 0.13 (mg/L) against Staphylococcus aureus and an MIC of 2.0 (mg/L) against Escherichia coli.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a bacterial infection in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a bacterial infection in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a bacterial infection caused by one or more pathogenic organisms such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of an infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man.
  • an infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a bacterial infection
  • the bacteria is of a genus selected from Aeromonas, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, in a warm-blooded animal such as man
  • a method for treating a bacterial infection in a warmblooded animal such as man including administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for treating a bacterial infection caused by one or more pathogenic organisms such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorr
  • a method for treating a bacterial infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man, said method including administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a bacterial infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft
  • a method for treating a bacterial infection wherein the bacteria is of a genus selected from Aeromonas, Acinetohacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, in a warm-blooded animal such as man, said method including administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in treating a bacterial infection in a warm-blooded animal, such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in treating a bacterial infection caused by one or more pathogenic organisms such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii,
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for use in treating infections such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man.
  • infections such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a bacterial infection wherein the bacteria is of a genus selected from Aeromonas, Acmetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, and Munnheimia, in a warm-blooded animal such as man.
  • the bacteria is of a genus selected from Aero
  • a pharmaceutical composition including a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixir
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl /?-hydroxybenzoate; and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate
  • granulating and disintegrating agents such as corn starch or algenic acid
  • binding agents such as starch
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form or in the form of nano or micronized particles together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexito
  • the aqueous suspensions may also contain one or more preservatives such as ethyl or propyl ]> hydroxybenzoate; anti-oxidants such as ascorbic acid); coloring agents; flavoring agents; and/or sweetening agents such as sucrose, saccharine or aspartame.
  • preservatives such as ethyl or propyl ]> hydroxybenzoate
  • anti-oxidants such as ascorbic acid
  • coloring agents such as ascorbic acid
  • flavoring agents such as saccharine or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin.
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.
  • compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 4 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
  • a daily dose in the range of 1-50 mg/kg is employed. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • the necessary starting materials for the procedures such as those described herein may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the described procedure or the procedures described in the Examples.
  • the present invention provides a process for preparing compounds of Formula (I), the process including reacting a compound of Formula (ID):
  • boron reducing agents such as NaB(OAc) 3 H.
  • Scheme 1 depicts a process for preparing compound (ID).
  • Compound (IA) may be coupled with protected 4-aminopiperidme (IB). Reduction of the resulting compound with a suitable reducing agent provides compound (1C). Protecting groups suitable for such a reaction include if-butoxycarbonyl. Deprotection of the amino group of compound (1C) provides a compound of Formula (ID).
  • Scheme 1 Another type of protected 4-aminopiperidines suitable for use in the process shown in Scheme 1 may be prepared following procedures published in the patent literature, such as those described in PCT Pub. Nos. WO 2006106326, WO 2006087543, WO 2005/068461 and WO 2005066176.
  • Scheme 2 depicts the synthesis of a typical protected 4-aminopiperidine, which bears a silyl-protected hydroxy substituent, and of which the amino group is protected as an azide.
  • the ring nitrogen of piperidine (2A) may be protected in the form of a carbamate, providing piperidine (2B).
  • a hydroxy group may be introduced into the 3- position of the piperidine ring by reaction of epoxypiperidine (3A) with HBr to give trans 3-hydroxy-4- bromo piperidine (3C), which may be converted to the cis configuration (represented by compound (3D)) by reaction with sodium azide.
  • the epoxide may be opened directly with sodium azide to provide the trans configuration, represented by compound (3B).
  • the hydroxy group may be converted into an alkoxy group using standard alkylation procedures. For example, a hydroxy group may be converted into a methoxy group by alkylation with methyl iodide in the presence of a base, such as sodium hydride.
  • Scheme 4 depicts a typical process for introducing a fluoro substituent to the piperidine ring.
  • Protected 4-Piperidone (4A) (for which suitable protecting groups include ⁇ -butoxycarbonyl) may be converted to a silyl enolate by reaction with trimethylsilyl chloride (TMSCl) in the presence of a suitable base.
  • TMSCl trimethylsilyl chloride
  • the resulting silyl enolate (4B) may be reacted with a suitable fiuorinating agent, such as Selectfiuor® (sold by Air Products, Inc.), providing fluorinated compound (4C).
  • a suitable fiuorinating agent such as Selectfiuor® (sold by Air Products, Inc.
  • the carbonyl group of compound (4C) may be converted to a protected nitrogen via reductive amination. If desired, the amino group may be further protected in a subsequent step, providing compound (4D).
  • 3-hydroxy piperidine (5A) may be fluorinated with an appropriate fiuorinating agent such as diethylaminosulfur trifluoride (DAST), as depicted in Scheme 5, to provide fluorinated compound (5B).
  • DAST diethylaminosulfur trifluoride
  • suitable aldehyde for the first reductive animation step in Scheme 1 may be obtained by oxidation of the corresponding alcohol (6A) with a suitable oxidizing agent, such as activated DMSO ("Swern oxidation"), or o-iodoxybenzoic acid (IBX).
  • a suitable oxidizing agent such as activated DMSO ("Swern oxidation"), or o-iodoxybenzoic acid (IBX).
  • Scheme 7 depicts a typical process for preparing alcohol (6A), in which quinolin-2(lH)-one (7A) may be alkylated with epichlorohydrin and treated with an appropriate base to provide compound (6A). Alternatively, the alkylation may be performed with cesium fluoride on celite instead of using a base.
  • Quinolin-2(lH)-one 7(A) may be prepared by a number of procedures well known to the skilled chemist (see for example, The Chemistry of ⁇ eterocycles, Eicher and ⁇ auptmann, Wiley- VCH, ISBN 3-527-30720-6).
  • Scheme 8 depicts the preparation of quinolin-2(lH)-one (8C), which is a quinolin-2(lH)-one (7A) wherein R 1 is ⁇ .
  • Reaction of aniline (8A) with cinnamoylchloride in the presence of a suitable base, such as 2,6-lutidine provides compound (8B).
  • Compound (8B) may cyclized by treatment with aluminum trichloride, which can also cleave the methyl ether.
  • cinnamoyl chloride may be substituted with E-ethoxyacryloyl chloride and cyclization of the intermediate E-ethoxyacryloylamide may be effected with a suitable acid, such as sulfuric, acid instead of aluminium trichloride (E. Baston et al, European Journal of Medicinal Chemistry 35 (2000) 931).
  • a suitable acid such as sulfuric, acid instead of aluminium trichloride
  • Unsymmetrical substituted anilines generally lead to regioisomeric quinolin-2(lH)-one derivatives, which may be separated either by crystallization or may be converted to the corresponding 2-chloroquinoline (with, for example, phosphorusIII oxychloride), which may be separated by chromatography or by crystallization and may then be hydrolyzed back with refluxing hydrochloride acid to the single regioisomers of the quinolin-2(lH)-ones.
  • 2-chloroquinoline with, for example, phosphorusIII oxychloride
  • the carbon-carbon bond formation may be performed via Sonogashira Coupling, providing alkyne intermediate (9D), which may be partially hydrogenated to a cis double bond under Lindlar conditions, providing compound (9E).
  • 4-Substituted quinolin-2(lH)-one (7A), suitable for alkylation as depicted in Scheme 7, may be prepared by acylation of aniline (10A), or aza analogs thereof, with ethylaceto acetate or derivatives thereof, in the presence of base, followed by cyclization of the resulting compound (10B) under acidic conditions. Such a process is depicted in Scheme 10.
  • Substituents at R » 1 , R ⁇ >2 or R may advantageously be introduced by conversion of a more stable substituent.
  • quinolin-2(lH)-one (HB) substituted in the R3 position with a cyano group
  • HB quinolin-2(lH)-one
  • a cyanide such as zinc cyanide or copper cyanide
  • a palladium catalyst may be advantageously used for this reaction.
  • An example of an amino protecting group suitable for use in such a reaction is t-butoxycarbonyl.
  • an optically active form of a compound of the invention When an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure enantiomer as a starting material, or by resolution of a mixture of the enantiomers or diastereomers of the final products or chiral intermediates using a standard procedure.
  • the resolution of enantiomers may be achieved by chromatography on a chiral stationary phase, such as a Chiralpak AD column. Consideration should to be given to solubility as well as resolution.
  • resolution may be obtained by the preparation and selective crystallization of a diastereomeric salt of a chiral intermediate or chiral product with a chiral acid, such as camphersulfonic acid.
  • a method of stereoselective synthesis may be employed, for example by using a chiral variant of a protection group, a chiral catalyst or a chiral reagent where appropriate in the reaction sequence.
  • Enzymatic techniques may also be useful for the preparation of optically active compounds and/or intermediates.
  • FAB mass spectral data were generally obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were collected or using Agilent 1100 series LC/MSD equipped with Sedex 75ELSD, and where appropriate, either positive ion data or negative ion data were collected. The lowest mass major ion is reported for molecules where isotope splitting results in multiple mass spectral peaks (for example when chlorine is present).
  • Reverse Phase HPLC was carried out using YMC Pack ODS-AQ (100x20 mmID, S-5 ⁇ particle size, 12 nm pore size) on Agilent instruments;
  • each intermediate was purified to the standard required for the subsequent stage and was characterized in sufficient detail to confirm that the assigned structure was correct; purity was assessed by HPLC, TLC, or NMR and identity was determined by infra-red spectroscopy (IR), mass spectroscopy or NMR spectroscopy as appropriate; and
  • TLC thin layer chromatography
  • HPLC high pressure liquid chromatography
  • MPLC medium pressure liquid chromatography
  • NMR nuclear magnetic resonance spectroscopy
  • DMSO dimethylsulfoxide
  • CDCl 3 deuterated chloroform
  • MeOD deuterated methanol, i.e.
  • the resulting reaction mixture was stirred at room temperature for 30 minutes and then was filtered through a 0.45 ⁇ m membrane and concentrated to dryness under reduced pressure.
  • the mixture was purified by chromatography on silica gel with dichloromethane/ methanol (6:1). Fractions containing product were combined and concentrated to dryness. The residue was taken up in dichloromethane/ diethyl ether (1:2, 10 mL), and HCl in diethyl ether (2M, -0.10 mL) was added.
  • the resulting mixture of enantiomers was separated by chiral HPLC on a Chiralpak AD column (250 x 20 mm, 10 micron) eluting with 70:15:15:0.1 hexanes:ethanol:methanol:diethylamine at a flow rate of 20 mL/min.
  • trans-N- (3-bromo-2-methoxyphenyl)-3- ethoxy-2-propenamide (Intermediate 15, 1.96 g, 6.5 mmol) in portions over 15 minutes to give a pale yellow solution which was stirred overnight at ambient temperature.
  • the yellow solution was poured into ca. 300 mL ice-water to give a pale yellow precipitate, which was collected by filtration, washed with water and crystallized from 2-propanol to give 1.2 g
  • the R and S enantiomers of the title compound of Example 4 may be separated by chiral chromatography, using a procedure similar to the one described for the separation of Interemediates 7 and 8.
  • the colorless solution of sodium methoxide was cannulated into a stirring mixture of 10-bromo-3- (hydroxymethyl)-2 ⁇ -[l,4]oxazino[2,3,4-ij]quinolin-5(3 ⁇ )-one (Intermediate 12, 0.5 g, 1.7 mmol) and copper (I) iodide (0.16 g, 0.84 mmol) in 6 mL dry N,N-dimethylformamide under dry N 2 to give a yellow solution.
  • This mixture was heated to 140 0 C for two hours, filtered through Celite, and the filter cake washed with dichloromethane.

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Abstract

La présente invention porte sur des composés de Formule (I) : ou sur des sels pharmaceutiquement acceptables de ces composés, qui sont estimés posséder une activité antibactérienne.
PCT/GB2008/001182 2007-04-03 2008-04-03 Pipéridines substituées destinées à être utilisées dans le traitement d'infections bactériennes Ceased WO2008120003A1 (fr)

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US8349828B2 (en) 2008-02-20 2013-01-08 Actelion Pharmaceuticals Ltd. Azatricyclic antibiotic compounds
US8618092B2 (en) 2008-10-07 2013-12-31 Actelion Pharmaceuticals Ltd. Tricyclic oxazolidinone antibiotic compounds
CN107629000A (zh) * 2017-09-19 2018-01-26 南京法恩化学有限公司 茚达特罗中间体5‑氯乙酰基‑8‑苄氧基‑2(1h)‑喹啉酮的制备方法
US10208052B1 (en) 2017-03-20 2019-02-19 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
US10675274B2 (en) 2018-09-19 2020-06-09 Forma Therapeutics, Inc. Activating pyruvate kinase R
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US12128035B2 (en) 2021-03-19 2024-10-29 Novo Nordisk Health Care Ag Activating pyruvate kinase R
US12161634B2 (en) 2019-09-19 2024-12-10 Novo Nordisk Health Care Ag Pyruvate kinase R (PKR) activating compositions

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Cited By (21)

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US8349828B2 (en) 2008-02-20 2013-01-08 Actelion Pharmaceuticals Ltd. Azatricyclic antibiotic compounds
US8618092B2 (en) 2008-10-07 2013-12-31 Actelion Pharmaceuticals Ltd. Tricyclic oxazolidinone antibiotic compounds
US9346804B2 (en) 2008-10-07 2016-05-24 Actelion Pharmaceuticals Ltd. Tricyclic oxazolidinone antibiotic compounds
US9822114B2 (en) 2008-10-07 2017-11-21 Idorsia Pharmaceuticals Ltd Tricyclic oxazolidinone antibiotic compounds
US11014927B2 (en) 2017-03-20 2021-05-25 Forma Therapeutics, Inc. Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators
US12071440B2 (en) 2017-03-20 2024-08-27 Novo Nordisk Health Care Ag Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators
US10472371B2 (en) 2017-03-20 2019-11-12 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
US10208052B1 (en) 2017-03-20 2019-02-19 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
US10836771B2 (en) 2017-03-20 2020-11-17 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
US11649242B2 (en) 2017-03-20 2023-05-16 Forma Therapeutics, Inc. Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators
US11396513B2 (en) 2017-03-20 2022-07-26 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
CN107629000A (zh) * 2017-09-19 2018-01-26 南京法恩化学有限公司 茚达特罗中间体5‑氯乙酰基‑8‑苄氧基‑2(1h)‑喹啉酮的制备方法
US11071725B2 (en) 2018-09-19 2021-07-27 Forma Therapeutics, Inc. Activating pyruvate kinase R
US11001588B2 (en) 2018-09-19 2021-05-11 Forma Therapeutics, Inc. Activating pyruvate kinase R and mutants thereof
US11844787B2 (en) 2018-09-19 2023-12-19 Novo Nordisk Health Care Ag Activating pyruvate kinase R
US11980611B2 (en) 2018-09-19 2024-05-14 Novo Nordisk Health Care Ag Treating sickle cell disease with a pyruvate kinase R activating compound
US12053458B2 (en) 2018-09-19 2024-08-06 Novo Nordisk Health Care Ag Treating sickle cell disease with a pyruvate kinase R activating compound
US10675274B2 (en) 2018-09-19 2020-06-09 Forma Therapeutics, Inc. Activating pyruvate kinase R
US12122778B2 (en) 2018-09-19 2024-10-22 Novo Nordisk Health Care Ag Activating pyruvate kinase R
US12161634B2 (en) 2019-09-19 2024-12-10 Novo Nordisk Health Care Ag Pyruvate kinase R (PKR) activating compositions
US12128035B2 (en) 2021-03-19 2024-10-29 Novo Nordisk Health Care Ag Activating pyruvate kinase R

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