WO2009001126A1 - Dérivés de pipéridine substitués et leur utilisation comme agents antibactériens - Google Patents

Dérivés de pipéridine substitués et leur utilisation comme agents antibactériens Download PDF

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Publication number
WO2009001126A1
WO2009001126A1 PCT/GB2008/050482 GB2008050482W WO2009001126A1 WO 2009001126 A1 WO2009001126 A1 WO 2009001126A1 GB 2008050482 W GB2008050482 W GB 2008050482W WO 2009001126 A1 WO2009001126 A1 WO 2009001126A1
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Prior art keywords
heterocyclyl
carbocyclyl
occurrence
alkyl
optionally
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PCT/GB2008/050482
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English (en)
Inventor
Mark Cronin
Bolin Geng
Folkert Reck
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2009001126A1 publication Critical patent/WO2009001126A1/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
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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 present invention provides compounds of Formula (I):
  • Typical compounds of Formula (I) are believed to possess antibacterial activity, and are therefore believed to be 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 the treatment of bacterial infections in warm-blooded animals such as man.
  • the present invention provides compounds of Formula (I):
  • R 1 is selected from H, halo, -CN, C ⁇ aHcyl, C 2 -6alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR la , -SR la , -N(R la ) 2 , -N(R la )C(O)R lb , -N(R la )N(R la ) 2 , -NO 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 1 ⁇ C(O) 2 R 1 a , -N(R 1 ⁇ C(O)N(R 1 a ) 2 , -OC(O)R lb , -S(O)R lb , -S(O) 2 R
  • R 2 is selected from H, halo, -CN, Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -0R 2a , -SR 2a , -N(R 2a ) 2 , -N(R 2a )N(R 2a ) 2 , -NO 2 , -C(O)H, -C(O)R 2b , -C(O)N(R 2a ) 2 , -OC(O)N(R 2a ) 2 , -N(R 2a )C(O) 2 R 2a , -N(R 2a )C(O)N(R 2a ) 2 , -OC(O)N(R 2a ) 2 , -N(R 2a )C(O) 2 R 2a , -N(R 2a )C(O)N(R 2a ) 2 ,
  • R 2a in each occurrence is independently selected from H, Ci -6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_ 6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 20* ;
  • R 2b in each occurrence is selected from C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 20* ;
  • R 3 is selected from H, halo, -CN
  • R 4 is selected from H, halo, -CN, Ci-6alkyl, C 2- 6alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 4a , -SR 4a , -N(R 4a ) 2 , -N(R 4a )C(O)R 4b , -N(R 4a )N(R 4a ) 2 , -NO 2 , -C(O)H, -C(O)R 4b , -C(O) 2 R 4a , -C(O)N(R 4a ) 2 , -OC(O)N(R 4a ) 2 , -N(R 4a )C(O) 2 R 4a , -N(R 4a )C(O) 2 R 4a , -N(R 4a )C(O)N(R 4a ) 2 , -OC(O)R 4b ,
  • R 5a in each occurrence is independently selected from H, carbocyclyl, and heterocyclyl, wherein said Ci_ 6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 50 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 50* ;
  • R 5b in each occurrence is selected from C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 50 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 50* ;
  • R 6 is Ci -6 alkyl, wherein said is optionally substituted with one or more R 60 ;
  • R 7 is selected from H, halo, -CN, Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 7a , -SR 7a , -N(R 7a ) 2 , -N(R 7a )C(O)R 7b , -N(R 7a )N(R 7a ) 2 , -NO 2 , -C(O)H, -C(O)R 7b , -C(O) 2 R 7a , -C(O)N(R 7a ) 2 , -OC(O)N(R 7a ) 2 , -N(R 7a )C(O) 2 R 7a , -N(R 7a )C(O)N(R 7a ) 2 , -
  • R 10 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl,
  • Ci_ 6 alkyl, C 2-6 alkenyl, C 2- 6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R a , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R a *;
  • R 10* in each occurrence is independently selected from Ci_ 6 alkyl, carbocyclyl, heterocyclyl,
  • Ci -6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R a , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R a* ;
  • R 1Oa in each occurrence is independently selected from H, Ci -6 alkyl, carbocyclyl, and heterocyclyl, wherein said carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R a , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R a ;
  • R 10b in each occurrence is independently selected from Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R a , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R a* ;
  • R 1Oc in each occurrence is independently selected from Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_ 6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R a , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R a ;
  • R 20 in each occurrence is independently selected from halo, -CN, Ci -6 alkyl, C 2-6 alkenyl,
  • R 20a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R b , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R b* ;
  • R 20b in each occurrence is independently selected from C 1-6 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 in each occurrence are optionally and independently substituted on carbon with one or more R b , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R b* ;
  • R 20c in each occurrence is independently selected from H, Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R b , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R b* ;
  • R 30 in each occurrence is independently selected from halo, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 30a , -SR 30a , -N(R 30a ) 2 , -N(R 30a )C(O)R 30b , -N(R 30a )N(R 30a ) 2 , -NO 2 , -C(O)H, -C(O)R 30b , -C
  • R 30a in each occurrence is independently selected from H, Ci_6alkyl, carbocyclyl, and heterocyclyl, wherein said carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R c , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 0* ;
  • R 30b in each occurrence is independently selected from d -6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R c , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R c ;
  • R 30c in each occurrence is independently selected from Ci-6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R c , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R c ;
  • R 40 in each occurrence is independently selected from halo, -CN, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 40a , -SR 40a , -N(R 40a ) 2 , -N(R 40a )C(O)R 40b , -N(R 40a )N(R 40a ) 2 , -NO 2 , -C(O)H, -C(O)R 40b , -C(O) 2 R 40a , -
  • R 40c in each occurrence is independently selected from Ci- ⁇ alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R d , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with 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 5Oa , -N(R 50a ) 2 , -N(R 50a )C(O)R 50b , -N(R 5Oa )N(R 5Oa ) 2 , -NO 2 , -C(O)H, -C(O)R 50b , -
  • R 50a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R e , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R e ;
  • R 50b in each occurrence is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2- 6alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R e , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R e ;
  • R 50a in each occurrence is independently selected from carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R e , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R e* ;
  • R 60 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl,
  • Ci_6alkyl, C 2- 6alkenyl, C 2- 6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R f , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R r* ;
  • R 60a in each occurrence is independently selected from H, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R f , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R r* ;
  • R 60b in each occurrence is independently selected from Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_6alkyl, C 2- 6alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R f , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R r* ;
  • R 60c in each occurrence is independently selected from Ci_ 6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci -6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R f , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R r* ;
  • R 70 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2-6 alkenyl,
  • Ci- ⁇ alkyl, C 2- 6alkenyl, C 2- 6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R g , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R g ;
  • R 70* in each occurrence is independently selected from carbocyclyl, heterocyclyl,
  • R 70a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_ 6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R g , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R g ;
  • R 70b in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R g , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R g* ;
  • R 70c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R g , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R g ;
  • R a , R b , R c , R d , R e , R f , and R 8 in each occurrence are independently selected from halo, -CN,
  • Ci- ⁇ alkyl C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR m , -SR m , -N(R m ) 2 ,
  • R a *, R b *, R c *, R d *, R e *, R f *, and R g * in each occurrence are independently selected from
  • R m in each occurrence is independently selected from H, C] -6 alkyl, carbocyclyl, and heterocyclyl;
  • R" in each occurrence is independently selected from Ci- ⁇ alkyi, C 2 -6alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl; and n is selected from O, 1, 2, and 3.
  • C x-y indicates the numerical range of carbon atoms that are present in the group; for example, C ⁇ alkyl includes Qalkyl (methyl), C 2 alkyl (ethyl), C ⁇ alkyl (propyl and isopropyl) and C4alkyl (butyl, 1-methylpropyl, 2-methylpropyl, and t-butyl).
  • 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, Ci_6alkyl; 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.
  • 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.
  • 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- 6alkenyl includes, but is not limited to, groups such as C 2- 6alkenyl, C 2- 4alkenyl, 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 -6alkynyl includes, but is not limited to, groups such as C2-6alkynyl, C2-4alkynyl, ethynyl, 2-propynyl, 2-methyl-2-propynyl, 3-butynyl, 4-pentynyl, and 5-hexynyl.
  • Carbocyclyl - refers to a saturated, partially saturated, or unsaturated, mono or bicyclic carbon ring that contains 3 to 12 ring atoms, of which one or more -CH 2 - groups may be optionally replaced with a corresponding number of -C(O)- groups.
  • Carbocyclyl include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, indanyl, naphthyl, oxocyclopentyl, 1-oxoindanyl, phenyl, and tetralinyl.
  • Halo includes fiuoro, chloro, bromo and iodo. In one aspect, the term “halo” may refer to fiuoro, chloro, and bromo. In another aspect, the term “halo” may refer to fiuoro and chloro. In still another aspect, the term “halo” may refer to fiuoro.
  • Heterocvclyl refers to a saturated, partially saturated, or unsaturated, mono or bicyclic ring containing 4 to 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, and of which 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, furanyl, imidazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholino, 2-oxa-5- azabicyclo[2.2.1]hept-5-yl, oxazolyl, 2-oxopyrrolidinyl, 2-oxo-l,3-thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, quinolyl, tetrahydrofuranyl, te
  • heterocyclyl may be “5- or 6-membered heterocyclyl,” which refers to a saturated, partially saturated, or unsaturated, monocyclic ring containing 5 or 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH 2 - group may be optionally replaced by a -C(O)- group.
  • “5- or 6-membered heterocyclyl” groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide. Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • 5- or 6- membered heterocyclyl include, but are not limited to, 3,5-dioxopiperidinyl, furanyl, imidazolyl, isothiazolyl, isoxazolyl, morpholino, oxazolyl, 2-oxopyrrolidinyl, 2-oxo-l,3- thiazolidinyl, piperazinyl, piperidyl, 2H-pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolidinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridonyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thiomorpholino, thioenyl, pyridine- ⁇ /-oxid
  • heterocyclyl and “5- or 6-membered heterocyclyl” may be “6-membered heterocyclyl,” which refers to a saturated, partially saturated, or unsaturated, monocyclic ring containing 6 ring atoms, of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and of which a -CH 2 - group may be optionally replaced by a -C(O)- group.
  • 6-membered heterocyclyl groups may be carbon or nitrogen linked. Ring nitrogen atoms may be optionally oxidized to form an N-oxide.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Illustrative examples of "6-membered heterocyclyl” include, but are not limited to, 3,5-dioxopiperidinyl, morpholino, piperazinyl, piperidinyl, 2H-pyranyl, pyrazinyl, pyridazinyl, pyridinyl, and pyrimidinyl.
  • 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.
  • an effective amount of a compound of Formula (I) for use in the treatment of cancer is an amount sufficient to symptomatically relieve in a warm-blooded animal such as man, the symptoms of cancer and myeloproliferative diseases, to slow the progression of cancer and myeloproliferative diseases, or to reduce in patients with symptoms of cancer and myeloproliferative diseases the risk of getting worse.
  • 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.
  • Optionally substituted indicates that 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.
  • Heterocyclyl groups containing nitrogen atoms may be substituted on ring carbon atoms and/or ring nitrogen atoms.
  • a particular group when a particular group is designated as being optionally substituted with one or more substituents, that particular group may be unsubstituted.
  • the particular group may bear one substituent.
  • the particular group 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.
  • 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.
  • a 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 t-butoxycarbonyl; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; and aroyl groups, such benzoyl.
  • alkanoyl groups such as acetyl
  • alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, and t-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 during work-up.
  • substituent R 1 for illustrative purposes, the following substituent definitions have the indicated meanings:
  • Compounds of Formula (I) may form stable pharmaceutically acceptable acid or base salts, and in such cases administration of a compound as a salt may be appropriate.
  • 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 and 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, 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 may be 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.
  • Some compounds of Formula (I) may have 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.
  • the invention further relates to any and all tautomeric forms of the compounds of Formula (I).
  • Additional embodiments of the invention are as follows. These additional embodiments relate to compounds of Formula (I) and pharmaceutically acceptable salts thereof. Such specific substituents may be used, where appropriate, with any of the definitions, claims or embodiments defined hereinbefore or hereinafter. The additional embodiments are illustrative and are not to be read as limiting the scope of the invention as defined by the claims.
  • A is N;
  • D is C-R 7 ;
  • R 7 is selected from H, halo, -CN, C ⁇ aHcyl, C 2 - 6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 7a , -SR 7a , -N(R 7a ) 2 , -N(R 7a )C(O)R 7b , -N(R 7a )N(R 7a ) 2 , -NO 2 , -C(O)H, -C(O)R 7b , -C(O) 2 R 7a , -C(O)N(R 7a ) 2 , -OC(O)N(R 7a ) 2 , -N(R 7a )C(O) 2 R 7a , -N(R 7a )C(O) 2 R 7a , -N(R 7a )C(O)N(R 7a ) 2 , -OC(O)R 7
  • R 7a in each occurrence is independently selected from H, Ci -6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_ 6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 70 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 70* ;
  • R 7b in each occurrence is selected from Ci_ 6 alkyl, C 2-6 alkenyl, C 2- 6alkynyl, carbocyclyl, and heterocyclyl, wherein said C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 70 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 70* ;
  • R 70 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2-6 alkenyl,
  • R 70* in each occurrence is independently selected from carbocyclyl, heterocyclyl,
  • R 70a in each occurrence is independently selected from H, Ci ⁇ alkyl, carbocyclyl, and heterocyclyl;
  • R 70b in each occurrence is independently selected from C h alky!, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 70c in each occurrence is independently selected from carbocyclyl, and heterocyclyl.
  • A is N;
  • D is C-R 7 ;
  • R 7 is selected from H and halo.
  • A is N;
  • D is C-R 7 ;
  • R 7 is selected from H and fluoro.
  • A is N; and D is CH.
  • E is NH
  • G is selected from O and S;
  • E is NH
  • G is O
  • E is O;
  • G is O
  • R 8 and R 9 are each H.
  • E, G, R 8 , and R 9 together with the atoms to which they are attached may form a group selected from:
  • D is selected from C-R 7 and N; and R 7 is selected from H and halo.
  • E, G, R 8 , and R 9 together with the atoms to which they are attached may form a group selected from:
  • D is selected from C-R 7 and N; and R 7 is selected from H and halo
  • J is selected from C-R 4 and N;
  • W is C-R 1 ;
  • R 1 is selected from H, halo, -CN, C ⁇ aUcyl, C2-6alkenyl, 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 , -NO 2 , -C(O)H,
  • R 4 is selected from H, halo, -CN, d ⁇ alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 4a , -SR 4a , -N(R 4a ) 2 , -N(R 4a )C(O)R 4b , -N(R 4a )N(R 4a ) 2 , -NO 2 , -C(O)H,
  • -C(R 4a ) N(OR 4a ), wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 40* ;
  • R 4a in each occurrence is independently selected from H, Ci -6 alkyl, carbocyclyl, and heterocyclyl, wherein said C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 40* ;
  • R 4b in each occurrence is selected from C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 40* ;
  • R 10 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2-6 alkenyl,
  • R 10 in each occurrence is independently selected from Ci_ 6 alkyl, carbocyclyl, heterocyclyl,
  • R 1Oa in each occurrence is independently selected from H, Ci -6 alkyl, carbocyclyl, and heterocyclyl;
  • R 1Ob in each occurrence is independently selected from C 1-6 alkyl, C 2 -6alkenyl, C 2 -6alkynyl, carbocyclyl, and heterocyclyl;
  • R 1Oc in each occurrence is independently selected from C ⁇ aHcyl, carbocyclyl, and heterocyclyl;
  • R 40 in each occurrence is independently selected from halo, -CN, Ci -6 alkyl, C 2-6 alkenyl,
  • R 40* in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, heterocyclyl,
  • R 40a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R 40b in each occurrence is independently selected from Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 40c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl.
  • J is selected from C-R 4 and N;
  • W is CH
  • R 4 is selected from H and C 1-6 alkyl.
  • J is selected from C-R 4 and N;
  • W is CH
  • R 4 is selected from H and methyl
  • J is CH; and W is CH.
  • J is N; and W is CH.
  • R 2 is selected from H, halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 2a , -SR 2a , -N(R 2a ) 2 , -N(R 2a )N(R 2a ) 2 , -NO 2 , -C(O)H, -C(O)R 2b ,
  • C 2-6 alkenyl, C 2- 6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R 20 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 20* ;
  • R 2a in each occurrence is independently selected from H, Ci -6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_ 6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 20* ;
  • R 2b in each occurrence is selected from Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 20* ;
  • R 20 in each occurrence is independently selected from halo, -CN, C 2-6 alkenyl,
  • R 20 in each occurrence is independently selected from Ci_ 6 alkyl, carbocyclyl, heterocyclyl,
  • R 20a in each occurrence is independently selected from H, Ci -6 alkyl, carbocyclyl, and heterocyclyl;
  • R 20b in each occurrence is independently selected from Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl; R 20c in each occurrence is independently selected from H, C ⁇ aHcyl, carbocyclyl, and heterocyclyl.
  • R 2 is selected from -CN and -OR 2a ; and R 2a is Ci -6 alkyl.
  • R 2 is selected from -CN and methoxy.
  • R 2 is -CN.
  • R 2 is -OR 2a ; and R 2a is Ci -6 alkyl.
  • R 2 is methoxy
  • R 3 is selected from H, halo, -CN, C ⁇ aHcyl, C 2- 6alkenyl, C 2- 6alkynyl, carbocyclyl, heterocyclyl, -OR 3a , -SR 3a , -N(R 3a ) 2 , -N(R 3a )C(O)R 3b , -N(R 3a )N(R 3a ) 2 , -NO 2 , -C(O)H, -C(O)R 3b , -C(O) 2 R 3a , -C(O)N(R 3a ) 2 , -OC(O)N(R 3a ) 2 , -N(R 3a )C(O) 2 R 3 , -N(R 3a )C(O) 2 , -S(O)R 3b , -S(O) 2 R 3 ,
  • R 30* in each occurrence is independently selected from carbocyclyl, heterocyclyl,
  • R 30a in each occurrence is independently selected from H, Ci. 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 30b in each occurrence is independently selected from Q-ealkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 30c in each occurrence is independently selected from Ci- 6 alkyl, carbocyclyl, and heterocyclyl.
  • R 3 is H.
  • R 5 is selected from H, halo, -CN, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -0R 5a , -SR 5a , -N(R 5a ) 2 , -N(R 5a )C(O)R 5b , -N(R 5a )N(R 5a ) 2 , -NO 2 , -C(O)H, -C(O)R 5b , -C(O) 2 R 5a , -C(O)N(R 5a ) 2 , -OC(O)N(R 5a ) 2 , -N(R 5a )C(O) 2 R 5a , -N(R 5a )C(O) 2 , -OC(O)N(R 5a ) 2 , -N(R 5a )C(O) 2 R 5a ,
  • R 5a in each occurrence is independently selected from H, Ci ⁇ alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_ 6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 50 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 50* ;
  • R 5b in each occurrence is selected from Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C h alky!, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 50 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 50* ;
  • R 50 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl,
  • R 50* in each occurrence is independently selected from Ci_ 6 alkyl, carbocyclyl, heterocyclyl,
  • R 50a in each occurrence is independently selected from H, carbocyclyl, and heterocyclyl;
  • R 50b in each occurrence is independently selected from Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 50a in each occurrence is independently selected from Ci- 6 alkyl, carbocyclyl, and heterocyclyl; and n is 1 or 2.
  • R 5 is selected from H, halo, -CN, Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -0R 5a , -SR 5a , -N(R 5a ) 2 , -N(R 5a )C(O)R 5b , -N(R 5a )N(R 5a ) 2 , -NO 2 , -C(O)H, -C(O)R 5b , -C(O) 2 R 5a , -C(O)N(R 5a ) 2 , -OC(O)N(R 5a ) 2 , -N(R 5a )C(O) 2 R 5a , -N(R 5a )C(O) 2 , -OC(O)N(R 5a ) 2 , -N(R 5a )C(O) 2 R 5a ,
  • R 5a in each occurrence is independently selected from H, Ci ⁇ alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_ 6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 50 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 50* ;
  • R 5b in each occurrence is selected from Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C h alky!, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 50 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 50* ;
  • R 50 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl,
  • R 50* in each occurrence is independently selected from Ci_ 6 alkyl, carbocyclyl, heterocyclyl,
  • R 50a in each occurrence is independently selected from H, carbocyclyl, and heterocyclyl;
  • R 50b in each occurrence is independently selected from Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 50a in each occurrence is independently selected from Ci- 6 alkyl, carbocyclyl, and heterocyclyl; and n is 1 or 2.
  • R 5 is halo; and n is O or 1.
  • R 5 is fluoro; and n is O or 1.
  • R 5 is fluoro; and n is 1.
  • R 6 is Ci_ 6 alkyl, wherein said Ci -6 alkyl is optionally substituted with one or more R 60 ;
  • R 60 in each occurrence is independently selected from halo, -CN, C h alky!, C 2-6 alkenyl,
  • R 60a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R 60b in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 60c in each occurrence is independently selected from Ci_6alkyl, carbocyclyl, and heterocyclyl.
  • R 6 is Ci- 6 alkyl.
  • R 6 is methyl
  • n 0.
  • n 1 or 2.
  • n 1
  • R 2 is selected from H, halo, -CN, Ci- ⁇ alkyl, C 2- 6alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -0R 2a , -SR 2a , -N(R 2a ) 2 , -N(R 2a )N(R 2a ) 2 , -NO 2 , -C(O)H, -C(O)R 2b , -C(O)N(R 2a ) 2 , -OC(O)N(R 2a ) 2 , -N(R 2a )C(O) 2 R 2a , -N(R 2a )C(O)N(R 2a ) 2 , -OC(O)R 2b , -S(O)R 2b , -S(O) 2 R 2b , -N(R 2a )S(O) 2 R 2 ⁇ -C(R 2a
  • R 2a in each occurrence is independently selected from H, carbocyclyl, and heterocyclyl, wherein said carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 20* ;
  • R 2b in each occurrence is selected from Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 20* ;
  • R 3 is selected from H, halo, -CN, Ci- ⁇ alkyi, C 2- 6alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -0R 3a , -SR 3a , -N(R 3a ) 2 , -N(R 3a )C(O)R 3b , -N(R 3a )N(R 3a ) 2 , -NO 2 , -C(O)H, -C(O)R 3b , -C(O) 2 R 3a , -C(O)N(R 3a ) 2 , -OC(O)N(R 3a ) 2 , -N(R 3a )C(O) 2 R 3 , -N(R 3a )C(O) 2 , -S(O)R 3b , -S(O) 2 R 3 ,
  • R 4 is selected from H, halo, -CN, Ci- ⁇ alkyl, C 2- 6alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 4a , -SR 4a , -N(R 4a ) 2 , -N(R 4a )C(O)R 4b , -N(R 4a )N(R 4a ) 2 , -NO 2 , -C(O)H, -C(O)R 4b , -C(O) 2 R 4a , -C(O)N(R 4a ) 2 , -OC(O)N(R 4a ) 2 , -N(R 4a )C(O) 2 R 4a , -N(R 4a )C(O) 2 R 4a , -N(R 4a )C(O)N(R 4a ) 2 , -OC(O)R 4b ,
  • R 5 is selected from H, halo, -CN, Ci_ 6 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 , -NO 2 , -C(O)H, -C(O)R 5b , -C(O) 2 R 5a , -C(O)N(R 5a ) 2 , -OC(O)N(R 5a ) 2 , -N(R 5a )C(O) 2 R 5a , -N(R 5a )C(O) 2 , -OC(O)N(R 5a ) 2 , -N(R 5a )C(O) 2 R 5a , -
  • R 5a in each occurrence is independently selected from H, carbocyclyl, and heterocyclyl, wherein said Ci_ 6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 50 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 50* ;
  • R 5b in each occurrence is selected from C h alky!, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 50 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 50* ;
  • R 6 is Ci- 6 alkyl, wherein said Ci_ 6 alkyl is optionally substituted with one or more R 60 ;
  • R 7 is selected from H, halo, -CN, Ci-6alkyl, C 2- 6alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 7a , -SR 7a , -N(R 7a ) 2 , -N(R 7a )C(O)R 7b , -N(R 7a )N(R 7a ) 2 , -NO 2 , -C(O)H, -C(O)R 7b , -C(O) 2 R 7a , -C(O)N(R 7a ) 2 , -OC(O)N(R 7a ) 2 , -N(R 7a )C(O) 2 R 7a , -N(R 7a )C(O)N(R 7a )
  • R 7a in each occurrence is independently selected from H, Ci -6 alkyl, carbocyclyl, and heterocyclyl, wherein said carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 70 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 70* ;
  • R 7b in each occurrence is selected from Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein said C 2-6 alkenyl
  • R 10* in each occurrence is independently selected from C ⁇ aUcyl, carbocyclyl, heterocyclyl,
  • R 1Oa in each occurrence is independently selected from H, Ci. 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 1Ob in each occurrence is independently selected from C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 1Oc in each occurrence is independently selected from carbocyclyl, and heterocyclyl;
  • R 20 in each occurrence is independently selected from halo, -CN, C 2-6 alkenyl,
  • R 20* in each occurrence is independently selected from Ci_ 6 alkyl, carbocyclyl, heterocyclyl,
  • R 20a in each occurrence is independently selected from H, Ci ⁇ alkyl, carbocyclyl, and heterocyclyl;
  • R 20b in each occurrence is independently selected from C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 20c in each occurrence is independently selected from H, Ci ⁇ alkyl, carbocyclyl, and heterocyclyl;
  • R 30 in each occurrence is independently selected from halo, -CN, C 2-6 alkenyl,
  • R 30* in each occurrence is independently selected from C ⁇ aHcyl, carbocyclyl, heterocyclyl,
  • R 30a in each occurrence is independently selected from H, Ci. 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 30b in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 30c in each occurrence is independently selected from C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R 40 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2 - 6 alkenyl,
  • R 40* in each occurrence is independently selected from Ci_ 6 alkyl, carbocyclyl, heterocyclyl,
  • R 40a in each occurrence is independently selected from H, Ci -6 alkyl, carbocyclyl, and heterocyclyl;
  • R 40b in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 40c in each occurrence is independently selected from Ci- 6 alkyl, carbocyclyl, and heterocyclyl;
  • R 50 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2-6 alkenyl,
  • R 50 in each occurrence is independently selected from carbocyclyl, heterocyclyl,
  • R 50a in each occurrence is independently selected from H, carbocyclyl, and heterocyclyl
  • R 50b in each occurrence is independently selected from C ⁇ aHcyl, C 2 - 6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 50a in each occurrence is independently selected from Ci- ⁇ alkyl, carbocyclyl, and heterocyclyl;
  • R 60 in each occurrence is independently selected from halo, -CN, C 1-6 alkyl, C 2 - 6 alkenyl,
  • R 60a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl;
  • R 60b in each occurrence is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl
  • R 60c in each occurrence is independently selected from carbocyclyl, and heterocyclyl;
  • R 70 in each occurrence is independently selected from halo, -CN, Ci_ 6 alkyl, C 2-6 alkenyl,
  • R 70* in each occurrence is independently selected from carbocyclyl, heterocyclyl,
  • R 70a in each occurrence is independently selected from H, Ci -6 alkyl, carbocyclyl, and heterocyclyl;
  • R 70b in each occurrence is independently selected from Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl;
  • R 70c in each occurrence is independently selected from carbocyclyl, and heterocyclyl; and n is selected from O, 1, 2, and 3.
  • R 1 is selected from H, halo, -CN, Ci_6alkyl, C2-6alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR la , -SR la , -N(R la ) 2 , -N(R la )C(O)R lb , -N(R la )N(R la ) 2 , -NO 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 1 ⁇ C(O) 2 R 1 a , -N(R 1 ⁇ C(O)N(R 1 a ) 2 , -OC(O)R lb , -S(O)R lb , -S(O) 2 R lb
  • R 2 is selected from H, halo, -CN, Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -0R 2a , -SR 2a , -N(R 2a ) 2 , -N(R 2a )N(R 2a ) 2 , -NO 2 , -C(O)H, -C(O)R 2 ⁇ -C(O)N(R 2a ) 2 , -OC(O)N(R 2a ) 2 , -N(R 2a )C(O) 2 R 2a , -N(R 2a )C(O)N(R 2a ) 2 , -OC(O)R 2b , -S(O)R 2b , -S(O) 2 R 2b , -S(O) 2 R 2b , -N(R 2a )S(O) 2
  • R 2a in each occurrence is independently selected from H, Ci ⁇ alkyl, carbocyclyl, and heterocyclyl, wherein said C h alky!, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 20* ;
  • R 2b in each occurrence is selected from C 2-6 alkenyl, C 2 -6alkynyl, carbocyclyl, and heterocyclyl, wherein said C 1-6 alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 20 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 20* ;
  • R 3 is selected from H, halo, -CN, Ci- ⁇ alkyl, C2-6alkenyl, C 2 - 6 alkynyl, carbocyclyl, heterocyclyl, -OR 3a , -SR 3a , -N(R 3a ) 2 , -N(R 3a )C(O)R 3b , -N(R 3a )N(R 3a ) 2 , -NO 2 , -C(O)H, -C(O)R 3b , -C(O) 2 R 3a , -C(O)N(R 3a ) 2 , -OC(O)N(R 3a ) 2 , -N(R 3a )C(O) 2 R 3 , -N(R 3a )C(O) 2 , -S(O)R 3b , -S(O) 2 R
  • R 4 is selected from H, halo, -CN, Ci_ 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 4a , -SR 4a , -N(R 4a ) 2 , -N(R 4a )C(O)R 4b , -N(R 4a )N(R 4a ) 2 , -NO 2 , -C(O)H, -C(O)R 4b , -C(O) 2 R 4a , -C(O)N(R 4a ) 2 , -OC(O)N(R 4a ) 2 , -N(R 4a )C(O) 2 R 4a , -N(R 4a )C(O) 2 R 4a , -N(R 4a )C(O)N(R 4a ) 2 , -OC(O)R 4b ,
  • R 4b in each occurrence is selected from Ci_ 6 alkyl, C 2 - 6 alkenyl, C 2 -6alkynyl, carbocyclyl, and heterocyclyl, wherein said C ⁇ alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 40 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 40* ;
  • R 5 is selected from H, halo, -CN, C2-6alkenyl, 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 , -NO 2 , -C(O)H,
  • -C(R 5a ) N(OR 5a ), wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R 50 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 50* wherein two R 5 substituents on the 2 and 6 carbon atoms may together optionally form an ethylene bridge;
  • R 5a in each occurrence is independently selected from H, C 1-6 alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_ 6 alkyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 50 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 50* ;
  • R 5b in each occurrence is 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- 6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 50 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 50* ;
  • R 6 is Ci -6 alkyl, wherein said is optionally substituted with one or more R 60 ;
  • R 7 is selected from H, halo, -CN, Ci-6alkyl, C 2- 6alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, -OR 7a , -SR 7a , -N(R 7a ) 2 , -N(R 7a )C(O)R 7b , -N(R 7a )N(R 7a ) 2 , -NO 2 , -C(O)H,
  • Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl are optionally substituted on carbon with one or more R 70 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 70* ;
  • R 7a in each occurrence is independently selected from H, Ci ⁇ alkyl, carbocyclyl, and heterocyclyl, wherein said C ⁇ aHcyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 70 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 70* ;
  • R 7b in each occurrence is selected from Ci -6 alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted on carbon with one or more R 70 , and wherein if said heterocyclyl contains an -NH- moiety, that nitrogen is optionally substituted with R 70* ;
  • A is N;
  • D is C-R 7 ;
  • J is selected from C-R 4 and N; W is CH;
  • R 2 is selected from -CN and -OR 2a ;
  • R 2a is Ci-ealkyl;
  • R 3 is H;
  • R 4 is selected from H and R 5 is halo;
  • R 6 is Ci -6 alkyl;
  • R 7 is selected from H and halo
  • A is N;
  • D is C-R 7 ;
  • J is selected from C-R 4 and N;
  • W is CH
  • R 2 is selected from -CN and -OR 2a ;
  • R 2a is Ci- ⁇ alkyl
  • R 3 is H
  • R 4 is selected from H and Ci- 6 alkyl
  • R 5 is halo
  • R 6 is Ci- ⁇ alkyl
  • R 7 is selected from H and halo
  • A is N;
  • D is C-R 7 ;
  • J is selected from C-R 4 and N;
  • W is CH
  • R 2 is selected from -CN and methoxy
  • R 3 is H
  • R 4 is selected from H and methyl
  • R 5 is fluoro
  • R 6 is methyl
  • R 7 is selected from H and fluoro
  • A is N;
  • D is C-R 7 ;
  • J is selected from C-R 4 and N;
  • W is CH
  • R 2 is selected from -CN and methoxy
  • R 3 is H
  • R 4 is selected from H and methyl
  • R 5 is fluoro
  • R 6 is methyl
  • R 7 is selected from H and fluoro
  • A is N;
  • D is CH
  • J is selected from C-R 4 and N;
  • W is CH
  • R 2 is selected from cyano and -0R 2a ;
  • R 2a is Ci- ⁇ alkyl
  • R 3 is H
  • R 4 is selected from H and C 1-6 alkyl
  • R 6 is Ci -6 alkyl
  • A is N;
  • D is CH
  • J is selected from C-R 4 and N;
  • W is CH
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 4 is selected from H and methyl
  • R 6 is methyl
  • the present invention provides compounds of Formula (I), or pharmaceutically acceptable salts thereof, as illustrated by the Examples, each of which provides a further independent aspect of the invention.
  • 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 compounds of Formula (I) may be evaluated with regard to their ability to inhibit the
  • the assay utilizes the ATPase activity of the ParE subunit of reconstituted Escherichia coli ParC/ParE tetramer protein. Inhibition of ATPase activity may be monitored by reduced production of inorganic phosphate, a product of the ATPase reaction. Inorganic phosphate may be quantified using the ammonium molybdate/malachite green-based detection system. For determination of IC50 values, assays may be performed 384-well microtiter plates. Each well preferably contains a dilution range of the compound dissolved in DMSO.
  • each well preferably contains: 20 rnM 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 is preferably 30 ⁇ L. Reactions may be incubated 24 hours at room temperature and then quenched with the addition of 45 ⁇ L malachite green reagent (Lanzetta, P. A., L.
  • the compounds of Formula (I) may be evaluated with regard to their antimicrobial activity using Assay 2, described below.
  • Assay 2 Assay 2
  • 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 and Moraxella catarrhalis.
  • Gram-positive species including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Enterococcus faecium
  • Gram-negative species including Haemophilus influenzae, Escherichia coli and Moraxella catarrhalis.
  • 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 4 (mg/L) against Escherichia coli, when tested in an assay based on the Assay 2 described above
  • the terms “infection” and “bacterial infection” may refer to a gynecological infection.
  • the terms “infection” and “bacterial infection” may refer to a respiratory tract infection (RTI).
  • the terms “infection” and “bacterial infection” may refer to a sexually transmitted disease.
  • the terms “infection” and “bacterial infection” may refer to a urinary tract infection.
  • the terms “infection” and “bacterial infection” may refer to acute exacerbation of chronic bronchitis (ACEB).
  • the terms “infection” and “bacterial infection” may refer to acute otitis media.
  • the terms “infection” and “bacterial infection” may refer to acute sinusitis.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by drug resistant bacteria.
  • the terms “infection” and “bacterial infection” may refer to catheter-related sepsis.
  • the terms “infection” and “bacterial infection” may refer to chancroid.
  • the terms “infection” and “bacterial infection” may refer to chlamydia.
  • the terms “infection” and “bacterial infection” may refer to community- acquired pneumoniae (CAP).
  • the terms “infection” and “bacterial infection” may refer to complicated skin and skin structure infection.
  • the terms “infection” and “bacterial infection” may refer to uncomplicated skin and skin structure infection.
  • the terms “infection” and “bacterial infection” may refer to endocarditis.
  • the terms “infection” and “bacterial infection” may refer to febrile neutropenia.
  • the terms “infection” and “bacterial infection” may refer to gonococcal cervicitis.
  • the terms “infection” and “bacterial infection” may refer to gonococcal urethritis.
  • the terms “infection” and “bacterial infection” may refer to hospital-acquired pneumonia (HAP).
  • the terms “infection” and “bacterial infection” may refer to osteomyelitis. In yet a further aspect, the terms “infection” and “bacterial infection” may refer to sepsis. In one aspect, the terms “infection” and “bacterial infection” may refer to syphilis.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Acinetobacter baumanii. In another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Acinetobacter haemolyticus . In still another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Acinetobacter junii. In yet another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Acinetobacter johnsonii. In a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Acinetobacter Iwoffi.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Bacteroides bivius. In yet a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Bacteroides fragilis. In one aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Burkholderia cepacia. In another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Campylobacter jejuni. In still another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Chlamydia pneumoniae.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Chlamydia urealyticus. In a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Chlamydophila pneumoniae. In still a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Clostridium difficili. In yet a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Enterobacter aerogenes. In one aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Enterobacter cloacae.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Enterococcus faecalis. In still another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Enterococcus faecium. In yet another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Escherichia coli. In a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Gardnerella vaginalis. In still a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Haemophilus parainfluenzae.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Haemophilus influenzae. In one aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Helicobacter pylori. In another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Klebsiella pneumoniae. In still another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Legionella pneumophila. In yet another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Methicillin-resistant Staphylococcus aureus.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Methicillin-susceptible Staphylococcus aureus. In still a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Moraxella catarrhalis. In yet a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Morganella morganii. In one aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Mycoplasma pneumoniae. In another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Neisseria gonorrhoeae.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Penicillin-resistant Streptococcus pneumoniae. In yet another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Penicillin-susceptible Streptococcus pneumoniae. In a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Peptostreptococcus magnus. In still a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Peptostreptococcus micros. In yet a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Peptostreptococcus anaerobius.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Peptostreptococcus asaccharolyticus .
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Peptostreptococcus prevotii.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Peptostreptococcus tetradius.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Peptostreptococcus vaginalis.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Proteus mirabilis.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Pseudomonas aeruginosa. In yet a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Quinolone-Resistant Staphylococcus aureus. In one aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Quinolone-Resistant Staphylococcus epidermis. In another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Salmonella typhi. In still another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Salmonella paratyphi.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Salmonella enteritidis. In a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Salmonella typhimurium. In still a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Serratia marcescens. In yet a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Staphylococcus aureus. In one aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Staphylococcus epidermidis.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Staphylococcus saprophyticus. In still another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Streptoccocus agalactiae. In yet another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Streptococcus agalactiae. In a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Streptococcus pneumoniae. In still a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Streptococcus pyogenes.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Stenotrophomonas maltophilia. In one aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Ureaplasma urealyticum. In another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Vancomycin-Resistant Enterococcus faecium. In still another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Vancomycin-Resistant Enterococcus faecalis.
  • infection and bacterial infection may refer to an infection caused by Vancomycin- Resistant Staphylococcus aureus.
  • infection and bacterial infection may refer to an infection caused by Vancomycin-Resistant Staphylococcus epidermis.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Acinetobacter spp.. In another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Bacteroides spp.. In still another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Burkholderia spp.. In yet another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Campylobacter spp.. In a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Chlamydia spp..
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Chlamydophila spp.. In yet a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Clostridium spp.. In one aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Enterobacter spp.. In another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Enterococcus spp.. In still another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Escherichia spp..
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Gardnerella spp.. In one aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Haemophilus spp.. In another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Helicobacter spp.. In still another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Klebsiella spp.. In yet another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Legionella spp.. In one aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Moraxella spp..
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Morganella spp.. In still another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Mycoplasma spp.. In yet another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Neisseria spp.. In a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Peptostreptococcus spp.. In still a further aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Proteus spp..
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Pseudomonas spp.. In one aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Salmonella spp.. In another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Serratia spp.. In still another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Staphylococcus spp.. In yet another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Strep toccocus spp..
  • the terms “infection” and “bacterial infection” may refer to an infection caused by Stenotrophomonas spp.. In another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by Ureaplasma spp.. In still another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by aerobes. In yet another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by obligate anaerobes. In one aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by facultative anaerobes. In another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by gram-positive bacteria.
  • the terms “infection” and “bacterial infection” may refer to an infection caused by gram-negative bacteria. In yet another aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by gram-variable bacteria. In one aspect, the terms “infection” and “bacterial infection” may refer to an infection caused by atypical respiratory pathogens.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for 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 the production of an anti-bacterial effect 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 producing an anti-bacterial effect in a warm-blooded 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 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 the production of an anti-bacterial effect in a warm-blooded animal, such as man.
  • a compound of Formula (I), or a pharmaceutically-acceptable salt thereof, for the therapeutic (including prophylactic) treatment of mammals including humans, in particular in treating infection, is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • 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.
  • a pharmaceutical composition including a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a bacterial infection in a warm-blooded animal such as man.
  • a pharmaceutical composition including a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the production of an anti-bacterial effect 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 pharmaceutical composition including a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for producing an anti-bacterial effect in a warm-blooded animal including administering to said animal an effective amount of a pharmaceutical composition including a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition including 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 pharmaceutical composition including a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the production of an anti-bacterial effect in a warm-blooded animal, such as man.
  • 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).
  • the 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
  • 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 p-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.
  • 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 p_- 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 p_- hydroxybenzoate
  • anti-oxidants such as ascorbic acid
  • coloring agents such as ascorbic acid
  • flavoring agents such as ascorbic acid
  • sweetening agents such as sucrose, 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.
  • Suitable classes and substances may be selected from one or more of the following: i) other antibacterial agents for example macrolides e.g. erythromycin, azithromycin or clarithromycin; quinolones e.g. ciprofloxacin or levofloxacin; ⁇ -lactams e.g. penicillins e.g.
  • amoxicillin or piperacillin cephalosporins e.g. ceftriaxone or ceftazidime
  • carbapenems e.g. meropenem or imipenem etc
  • aminoglycosides e.g. gentamicin or tobramycin; or oxazolidinones
  • anti-infective agents for example, an antifungal triazole e.g. or amphotericin
  • biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability-increasing protein (BPI) products; and/or iv) efflux pump inhibitors.
  • a chemotherapeutic agent selected from: i) one or more additional antibacterial agents; and/or ii) one or more anti-infective agents; and/or iii) biological protein therapeutics for example antibodies, cytokines, bactericidal/permeability- increasing protein (BPI) products; and/or iv) one or more efflux pump inhibitors.
  • 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.
  • Compounds of Formula (I) may be prepared in a variety of ways.
  • the Processes, Schemes, and Examples shown below illustrate some methods for synthesizing compounds of Formula (I) and intermediates which may be used for the synthesis of compounds of Formula (I) (wherein A, D, E, G, J, W, R 1 , R 2 , R 3 , R 5 , R 6 , R 8 , R 9 , and n, unless otherwise defined, are as defined hereinabove; and wherein PG denotes a protecting group, and wherein L is a leaving group).
  • Process A provides a process for preparing compounds of Formula (I), the process including reacting a compound of Formula (AA):
  • Process A may be performed under standard peptide coupling conditions, which are described in the literature (for example, Coste, Jacques; Frerot, Eric; Jouin, Patrick. "Coupling N-Methylated Amino Acids Using PyBroP and PyCIoP Halogenophosphonium Salts: Mechanism and Fields of Application.” Journal of Organic Chemistry (1994), 59(9), 2437-46.
  • Process B provides a process for preparing compounds of Formula (I), the process including reacting a compound of Formula (AC):
  • Suitable solvents for the reaction shown in Process B include THF, DMC, chloroform and methanol.
  • the reaction may typically be performed at room temperature, but may require heating to solubilize the starting materials.
  • the reduction may typically be performed at room temperature.
  • Reducing agents suitable for Process B include boron reducing agents such as sodium triacetoxyborohydride, borane -pyridine complexes, and sodium cyanoborohydride.
  • Process C provides a process for preparing compounds of (AD), the process including reacting a compound of Formula (BF):
  • Formula (BF) with an acid and thereafter if appropriate: i) converting a compound of Formula (BF) into another compound of Formula (BF); and ii) removing any protecting groups, wherein R y and R z may each, independently, be selected from Ci_ 6 alkyl, wherein R y and R z may join to form a ring.
  • Acids suitable for use in Process C include HCl, anhydrous or aqueous, in an organic solvent such as acetonitrile or THF.
  • Process C may be performed at room temperature or under heating, depending on the particular nature of the compound of the Formula (BF).
  • R y and R z may each be methyl.
  • Scheme 1 depicts a procedure by which compounds of Formula (AA) may be prepared.
  • Formula (AA) Alkylation of a compound (AE) may be accomplished by reaction with a compound of Formula (AF) in the presence of a base. Deprotection of the resulting compound provides a compound of Formula (AA).
  • Examples of leaving groups suitable for use in such a reaction include mesylate, chloro, bromo and iodo.
  • Examples of protecting groups suitable for use in such a reaction include t-butoxycarbonyl, which may be removed by reaction with an acid such as HCl.
  • Scheme 2 depicts an alternative process by which compounds of Formula (AG) may be prepared.
  • Scheme 3 depicts another process by which compounds of Formula (AA) may be prepared.
  • Scheme 4 depicts another process by which compounds of Formula (AA) may be prepared.
  • a compound of Formula (AE) may be reacted with an alkylating reagent such as bromo- or chloroethanol, bromo or chloro acetaldehyde, or 2-bromo-l,l-diethoxyethane, or with a protected derivative thereof, in the presence of a base such as NaH or Cs 2 CO 3 .
  • Treatment of the resulting compound resulting compound with an acid such as HCl may be used to provide a compound of Formula (AD).
  • the compound of Formula (AD) may then be reductively aminated with a compound of Formula (AJ), to provide a compound of Formula (AG).
  • Deprotection of the amino group provides a compound of Formula (AA).
  • Scheme 5 depicts a process by which compounds of Formula (AL), which are compounds of Formula (AF) in which the leaving group is a mesylate group, may be prepared.
  • a compound of Formula (AK), for which examples of a suitable protecting group include t- butxoycarbonyl, may be reacted with a compound such as bromoethanol or a derivative thereof in the presence of a base, providing a compound of Formula (AH).
  • a compound of Formula (AH) Reaction of the compound of Formula (AH) with mesyl chloride, in the presence of a base, such as trialkyl amine or an immobilized version thereof on a resin, provides a compound of Formula (AL).
  • a similar process is suitable for the preparation of compounds of the Formula (AFA). The process may also involve standard protection group manipulations on nitrogen and alcohol functionalities. It should be understood that compounds of Formula (AL) are potentially unstable, and may be present as part of a mixture which includes the corresponding chloroethylene compound. Accordingly, compounds of Formula (AL) should be prepared freshly under carefully controlled conditions.
  • Reaction of a compound of Formula (AM) with a compound of Formula (AN) in the presence of a suitable base may be used to obtain compounds of Formula (AO).
  • a suitable base examples of which include bases such as 2,6-lutidine
  • Compounds of Formula (AO) may be converted to compounds of Formula (AP) using a suitable Lewis acid, such as AlCl 3 .
  • compounds of Formula (AP) may be obtained by reacting compound of Formula (AM) with 3-ethoxyacryloyl chloride, followed by cyclization with sulfuric acid.
  • Scheme 6 depicts a process by which compounds of Formula (AS), which are compounds of Formula (AE) in which J is a CH group, may be prepared.
  • Reaction of a compound of Formula (AQ) with methacrylate in the presence of a Palladium catalyst may be used to provide a compound of Formula (AR).
  • a compound of Formula (AR) may be converted to a compound of Formula (AS) by treatment with Zinc followed by ultraviolet light.
  • a compound of Formula (AQ) may be reacted with methyl propiolate under Sonogashira coupling conditions, to provide a compound of Formula (AT), which may be reduced under Lindlar conditions to provide a compound of Formula (AU).
  • a compound of Formula (AS) may be obtained by treating the compound of Formula (AU) with Zinc.
  • Scheme 8 depicts a process by which compounds of Formula (AW), which is a compound of Formula (AE) in which J is N, may be prepared.
  • a compound of Formula (AV) may be reacted with ethylglyoxylate to provide a compound of Formula (AW).
  • Scheme 9 depicts a further process by which compounds of Formula (AW) may be prepared.
  • a compound of Formula (AY) may be obtained by reaction of a compound of Formula (AX) with a haloacetic acid ester such as ethyl bromoacetate. Reduction of the nitro group shown in Formula (BA) (using, for example, H 2 and Pd/C) may be used to provide a compound of Formula (AZ). Oxidation with hydrogen peroxide may be used to obtain a compound of Formula (AW).
  • a compound of Formula (AX) may be reacted with ethyl glyoxylate to provide a compound of Formula (BA).
  • Reduction of the nitro group shown in Formula (BA) (using, for example, H 2 and Pd/C) may be used to provide a compound of Formula (AZ), which may be oxidized as discussed above to provide a compound of Formula (AW).
  • Scheme 10 depicts a process by which compounds of the Formula (BE), which are compounds of Formula (AE) in which W is N and J is CH, may be prepared.
  • Formula (BE) Compounds of Formula (BE) are may be prepared following techniques known in the literature (such as J.A. Turner, J. Org. Chem. 1990, 55, 4744-4750). For example, compounds of Formula (BE) may be prepared by formylation of a suitably protected compound of Formula (BB), followed by condensation with lithiated t-butylacetate and then cyclization under acidic conditions (using an acid such as HCl).
  • Scheme 11 depicts a procedure by which compounds of Formula (BF) may be prepared.
  • Compounds of Formula (AE) may be reacted with a base and an appropriate alkylating reagent, such as 2-bromo-l,l-diethoxyethane.
  • alkylating reagent such as 2-bromo-l,l-diethoxyethane.
  • suitable bases include cesium carbonate.
  • 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 has to be given to solubility as well as resolution.
  • resolution may be obtained by 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.
  • a pure regioisomer of a compound of the invention when required, it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by resolution of a mixture of the regioisomers or intermediates using a standard procedure.
  • temperatures are quoted as 0 C; operations were carried out at room temperature, that is typically in the range 18-26 0 C and without the exclusion of air unless otherwise stated, or unless the skilled person would otherwise work under an inert atmosphere;
  • 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 racemic mixture was separated on a Chiralpak AD column (500 x 20 mm, 20micron) with ethanol/ methanol (1:1), containing 0.1% diethyl amine.
  • Trans enantiomer A (Intermediate 19) eluted first, followed by trans enantiomer B (Intermediate 20).
  • the chiral purity (using an analytical method equivalent to the preparative method described above) was determined to be >98% e.e. for both enantiomers.
  • reaction mixture was then treated with di-tert-butyl dicarbonate (4.0 mL, 17.4 mmol) and stirred under nitrogen for 1 hour. TLC indicated the complete disappearance of starting material.
  • the reaction mixture was filtered through celite. The filtrate was concentrated to dryness and subjected to chromatography on silica gel eluting with a gradient of 0-5% methanol/dichloromethane followed by an isocratic gradient of 5% methanol/dichloromethane containing 0.25% ammonium hydroxide to give 2.86 g (75%) of the product as a yellow oil.
  • trans enantiomer A (Intermediate 24, 90 mg, 0.21 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL) with cooling in an ice bath. The reaction mixture was removed from the ice bath and stirred at room temperature for 30 minutes. An additional 1 mL of trifluoroacetic acid was added. After 30 min the reaction mixture was concentrated in vacuo.
  • the crude product was partitioned between 15% methanol / dichloromethane and saturated sodium bicarbonate.
  • the aqueous phase was adjusted to pH ⁇ 10 by the addition of saturated sodium carbonate solution.
  • the layers were separated and the aqueous phase was re-extracted Ix with 15% methanol/dichloromethane.
  • the aqueous phase was re-extracted twice with 15% methanol/chloroform.
  • the combined organic phases were washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated to dryness giving 1.2 g (73%) of the crude product as a yellow solid that was used without further purification.
  • WO 2007016610 48 mg, 0.24 mmol in dry DMF (5 mL) was added ethyl-diisopropyl-amine (142 ⁇ L, 0.82 mmol) followed by (3-dimethylamino-propyl)-ethyl-carbodiirnide (EDC) hydrochloride (59 mg, 0.31 mmol) and benzotriazol-1-ol (HOBt) (41 mg, 0.31 mmol). The reaction mixture was stirred at room temperature for 15 minutes under nitrogen.
  • EDC (3-dimethylamino-propyl)-ethyl-carbodiirnide
  • HOBt benzotriazol-1-ol
  • reaction mixture was then treated with l-[2- (3-fluoro-4-methylamino-piperidin-l-yl)-ethyl]-2-oxo-l,2-dihydro-quinoline-7-carbonitrile, trans enantiomer A (Intermediate 25, 67 mg, 0.20 mmol) in 3 mL of dry DMF along with a minimal amount of dichloromethane (for solubility).
  • the reaction mixture was stirred at room temperature overnight followed by heating at 50 0 C for an additional 24 hours. Solvent was removed in vacuo. The crude residue was partitioned between 15% methanol/chloroform and saturated sodium bicarbonate solution.
  • reaction mixture was stirred at room temperature for 24 hours and the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was diluted with dichloromethane (10.0 mL) and poured into a saturated sodium bicarbonate solution (10 mL). The organic layer was separated, washed with water, brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude residue was triturated from diethyl ether to give 150 mg of product as pale yellow solid.

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Abstract

La présente invention porte sur des composés de Formule (I): et sur des sels pharmaceutiquement acceptables de ceux-ci, et sur leur utilisation dans le traitement d'infections bactériennes.
PCT/GB2008/050482 2007-06-27 2008-06-24 Dérivés de pipéridine substitués et leur utilisation comme agents antibactériens WO2009001126A1 (fr)

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US8071592B2 (en) 2006-07-20 2011-12-06 Glaxo Group Limited Derivatives and analogs of N-ethylquinolones and N-ethylazaquinolones
US8211908B2 (en) 2006-05-26 2012-07-03 Toyama Chemical Co., Ltd. Heterocyclic compound or salt thereof and intermediate thereof
WO2012108376A1 (fr) 2011-02-07 2012-08-16 第一三共株式会社 Dérivé de pyrrolidinone contenant un groupe amino
US8329694B2 (en) 2005-06-24 2012-12-11 Toyama Chemical Co., Ltd. Quinoxalinones as antibacterial composition
US8415375B2 (en) 2009-04-09 2013-04-09 Actelion Pharmaceuticals Ltd. 2-hydroxyethyl-1H-quinolin-2-one derivatives and their azaisosteric analogues with antibacterial activity
EP2628722A1 (fr) 2012-02-16 2013-08-21 Bayer CropScience AG Énaminocétones à base de CF3O et leur utilisation pour la préparation de pyrazoles à base de CF3O
WO2014024056A1 (fr) 2012-08-06 2014-02-13 Daiichi Sankyo Company, Limited Dérivés de pyrrolidine possédant des propriétés antibactériennes
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
US11001588B2 (en) 2018-09-19 2021-05-11 Forma Therapeutics, Inc. Activating pyruvate kinase R and mutants thereof
WO2021110656A1 (fr) 2019-12-02 2021-06-10 Janssen Pharmaceutica Nv Composés inhibiteurs d'oga

Citations (1)

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WO2006137485A1 (fr) * 2005-06-24 2006-12-28 Toyama Chemical Co., Ltd. Nouveau composé hétérocyclique azoté et sel de celui-ci

Patent Citations (1)

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WO2006137485A1 (fr) * 2005-06-24 2006-12-28 Toyama Chemical Co., Ltd. Nouveau composé hétérocyclique azoté et sel de celui-ci

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8329694B2 (en) 2005-06-24 2012-12-11 Toyama Chemical Co., Ltd. Quinoxalinones as antibacterial composition
US8524738B2 (en) 2005-06-24 2013-09-03 Toyama Chemical Co., Ltd. Quinolinones and quinoxalinones as antibacterial composition
US8211908B2 (en) 2006-05-26 2012-07-03 Toyama Chemical Co., Ltd. Heterocyclic compound or salt thereof and intermediate thereof
US8367831B2 (en) 2006-05-26 2013-02-05 Toyama Chemical Co., Ltd. Heterocyclic compound or salt thereof and intermediate thereof
US8071592B2 (en) 2006-07-20 2011-12-06 Glaxo Group Limited Derivatives and analogs of N-ethylquinolones and N-ethylazaquinolones
US8415375B2 (en) 2009-04-09 2013-04-09 Actelion Pharmaceuticals Ltd. 2-hydroxyethyl-1H-quinolin-2-one derivatives and their azaisosteric analogues with antibacterial activity
WO2012108376A1 (fr) 2011-02-07 2012-08-16 第一三共株式会社 Dérivé de pyrrolidinone contenant un groupe amino
EP2628722A1 (fr) 2012-02-16 2013-08-21 Bayer CropScience AG Énaminocétones à base de CF3O et leur utilisation pour la préparation de pyrazoles à base de CF3O
WO2013120876A1 (fr) 2012-02-16 2013-08-22 Bayer Intellectual Property Gmbh Énaminocétones contenant cf3o et leur utilisation pour la préparation de pyrazoles contenant cf3o
WO2014024056A1 (fr) 2012-08-06 2014-02-13 Daiichi Sankyo Company, Limited Dérivés de pyrrolidine possédant des propriétés antibactériennes
US10208052B1 (en) 2017-03-20 2019-02-19 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
US10472371B2 (en) 2017-03-20 2019-11-12 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
US10836771B2 (en) 2017-03-20 2020-11-17 Forma Therapeutics, Inc. Compositions for activating pyruvate kinase
US11014927B2 (en) 2017-03-20 2021-05-25 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
US11649242B2 (en) 2017-03-20 2023-05-16 Forma Therapeutics, Inc. Pyrrolopyrrole compositions as pyruvate kinase (PKR) activators
US10675274B2 (en) 2018-09-19 2020-06-09 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
US11071725B2 (en) 2018-09-19 2021-07-27 Forma Therapeutics, Inc. Activating pyruvate kinase R
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
WO2021110656A1 (fr) 2019-12-02 2021-06-10 Janssen Pharmaceutica Nv Composés inhibiteurs d'oga

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