EP2121702A1 - 2-chinolinon- und 2-chinoxalinonderivate und deren verwendung als antibakterielle mittel - Google Patents

2-chinolinon- und 2-chinoxalinonderivate und deren verwendung als antibakterielle mittel

Info

Publication number
EP2121702A1
EP2121702A1 EP07848510A EP07848510A EP2121702A1 EP 2121702 A1 EP2121702 A1 EP 2121702A1 EP 07848510 A EP07848510 A EP 07848510A EP 07848510 A EP07848510 A EP 07848510A EP 2121702 A1 EP2121702 A1 EP 2121702A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
pharmaceutically acceptable
acceptable salt
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07848510A
Other languages
English (en)
French (fr)
Inventor
Janelle Comita-Prevoir
Mark Cronin
Bolin Geng
Andrew Aydon Godfrey
Folkert Reck
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP2121702A1 publication Critical patent/EP2121702A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

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 applicants have hereby discovered compounds that possess the ability to act as antimicrobials. Accordingly, the present invention relates to compounds that demonstrate antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, their use as medicaments, and their use in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans.
  • Formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is substantially free of a cis ( ⁇ ) mixture of its enantiomers, and wherein A is selected from CH and N; D is selected from C-R 7 and N; wherein at least one of A and D is carbon; E is selected from O, NH, and S, wherein: i) E is NH if R 8 and R 9 together from 0; and ii) E is O or S if R 8 and R 9 are each H; G is selected from O and S; J is selected from C-R 4 and N;
  • R 1 is selected from H, halo, cyano, C 2-6 alkenyl, and C 2-6 alkynyl, OR la , and -N(R 1 a ) 2 , wherein said Ci- ⁇ alkyl, C 2 -6alkenyl, and C 2-6 alkynyl are optionally substituted with one or more R 10 ;
  • R la in each occurrence is independently selected from H and wherein said C ⁇ aHcyl is optionally substituted with one or more R 20 ;
  • R 2 is selected from H, halo, cyano, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -0R 2a , and -N(R 2a ) 2 wherein said Ci. 6 alkyl, C 2 . 6 alkenyl, and C 2-6 alkynyl are optionally substituted with one or more R 20 ;
  • R 2a in each occurrence is independently selected from H and Ci ⁇ alkyl, wherein said Ci- ⁇ alkyl are optionally substituted with one or more R 20 ;
  • R 3 is selected from H, halo, cyano, Ci- ⁇ alkyl, C 2- 6alkenyl, and C 2- 6alkynyl, -0R 3a , and -N(R 3a ) 2 , wherein said d- ⁇ alkyl, C 2- 6alkenyl, and C 2- 6alkynyl are optionally substituted with one or more R 30 ;
  • R 3a in each occurrence is independently selected from H and Ci- ⁇ alkyl, wherein said Ci- ⁇ alkyl is optionally substituted with one or more R 30 ;
  • R 4 is selected from H, halo, -CO 2 H, cyano, Ci -6 alkyl, C 2-6 alkenyl, and C 2- 6alkynyl, wherein said C 2-6 alkenyl, and C 2 - 6 alkynyl are optionally substituted with one or more R 40 ;
  • R 6 is selected from fluoro, C 2 _ 6 alkenyl, C 2-6 alkynyl, -0R 6a , wherein said C 2 .
  • R 6 alkenyl, and C 2-6 alkynyl are optionally substituted with one or more R 60 ;
  • R 6a in each occurrence is independently selected from H and Ci-6alkyl, wherein said are optionally substituted with one or more R 60 ;
  • R 7 is selected from H, halo, cyano, Ci_6alkyl, C 2 -6alkenyl, and C 2 - 6 alkynyl, wherein said
  • Ci- ⁇ alkyl, C 2 - 6 alkenyl, and C 2- 6alkynyl are optionally substituted with one or more R 70 ;
  • R 10 , R 20 , R 30 , R 40 , R 60 , and R 70 in each occurrence are each, independently, selected from halo, hydroxy, cyano, -CO 2 H, Ci -6 alkyl, C 2 - 6 alkenyl, and C 2 - 6 alkynyl.
  • the present invention provides a compound of Formula (II):
  • R 1 is selected from H, halo, cyano, Ci- ⁇ alkyl, C 2 - 6 alkenyl, and C 2-6 alkynyl, OR la , and -N(R la ) 2 , wherein said Ci- ⁇ alkyl, C 2- 6alkenyl, and C 2 -6alkynyl are optionally substituted with one or more R 10 ;
  • R la in each occurrence is independently selected from H and Ci galley 1, wherein said C h alky! is optionally substituted with one or more R 20 ;
  • R 2 is selected from H, halo, cyano, Ci -6 alkyl, C 2-6 alkenyl, C 2- 6alkynyl, -0R 2a , and -N(R 2a ) 2 wherein said C 2-6 alkenyl, and C 2-6 alkynyl are optionally substituted with one or more R 20 ;
  • R 2a in each occurrence is independently selected from H and wherein said Ci ⁇ alkyl are optionally substituted with one or more R 20 ;
  • R 3 is selected from H, halo, cyano, C 2- 6alkenyl, and C 2-6 alkynyl, -OR 3a , and
  • R 3a in each occurrence is independently selected from H and wherein said is optionally substituted with one or more R 30 ;
  • R 4 is selected from H, halo, -CO 2 H, cyano, C h alky., C 2-6 alkenyl, and C 2-6 alkynyl, wherein said Ci- 6 alkyl, C 2 - 6 alkenyl, and C 2-6 alkynyl are optionally substituted with one or more R 40 ;
  • R 6 is selected from fluoro, Ci- ⁇ alkyl, C 2 - 6 alkenyl, C 2 -6alkynyl, -OR 6a , wherein said Ci- ⁇ alkyl,
  • C 2-6 alkenyl, and C 2 - 6 alkynyl are optionally substituted with one or more R 60 ;
  • R a in each occurrence is independently selected from H and wherein said Ci ⁇ alkyl are optionally substituted with one or more R 60 ;
  • R 7 is selected from H, halo, cyano, Ci- ⁇ alkyl, C 2- 6alkenyl, and C 2 - 6 alkynyl, wherein said
  • Ci- 6 alkyl, C 2 - 6 alkenyl, and C 2 -6alkynyl are optionally substituted with one or more R 70 ;
  • R 10 , R 20 , R 30 , R 40 , R 60 , and R 70 in each occurrence are each, independently, selected from halo, hydroxy, cyano, -CO 2 H, Ci-galkyl, C 2-6 alkenyl, and C 2 - 6 alkynyl.
  • the compounds of Formulas (I) and (II) and pharmaceutically acceptable salts thereof are believed to be effective in treating bacterial infections. Accordingly, the present invention relates to compounds of Formulas (I) and (H) that demonstrate antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, methods for their us in the treatment of bacterial infections, their use as medicaments for the treatment of bacterial infections, and their use in the manufacture of such medicaments.
  • C x-y indicates the numerical range of carbon atoms that are present in the group; for example, includes Cialkyl (methyl), C 2 alkyl (ethyl), C 3 alkyl (propyl and isopropyl) and C 4 alkyl (butyl, 1-methylpropyl, 2-methylpropyl, and f-butyl).
  • alkyl refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms. References to individual alkyl groups such as "propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only.
  • 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 2-8 alkenyl includes, but is not limited to, groups such as C 2-6 alkenyl, C 2-4 alkenyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, and 2-methyl- 1 -heptenyl.
  • 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 2-8 alkynyl includes, but is not limited to, groups such as C 2 . 6 alkynyl, C 2-4 alkynyl, ethynyl, 2-propynyl, 2-methyl-2-propynyl, 3-butynyl, 4-pentynyl, 5-hexynyl, 2-heptynyl, and 4-methyl-5-heptynyl.
  • halo refers to fluoro, chloro, and bromo. In one aspect, “halo" may refer to fiuoro.
  • carrier refers to a saturated, partially saturated, or unsaturated, mono or bicyclic carbon ring that contains 3-12 ring atoms, wherein one or more -CH 2 - groups can optionally be replaced by a corresponding number of -C(O)- groups.
  • the term “carbocyclyl” may refer to a monocyclic ring containing 3 to 6 ring atoms or a bicyclic ring containing 9 or 10 atoms.
  • the term “carbocyclyl” may refer to a monocyclic ring containing 5 or 6 atoms.
  • Carbocyclyl include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1-oxocyclopentyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.
  • a particular example of a "carbocyclyl” group is phenyl.
  • heterocyclyl refers to a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 ring atoms of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group can optionally be replaced by a -C(O)-.
  • Ring sulfur atoms may be optionally oxidized to form S-oxides.
  • Ring nitrogen atoms may be optionally oxidized to form N-oxides.
  • heterocyclyl include, but are not limited to, 1,3-benzodioxolyl, 3,5-dioxopiperidinyl, imidazolyl, indolyl, isoquinolone, isothiazolyl, isoxazolyl, morpholino, 2-oxopyrrolidinyl, 2-oxo-l,3-thiazolidinyl, piperazinyl, piperidyl, pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, pyrimidyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridone, quinolyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thienyl, thiomorpholino, thiophenyl,
  • heterocyclyl may refer to a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 atoms of which at least one atom is selected from nitrogen, sulfur, and oxygen, and may, unless otherwise specified, be carbon or nitrogen linked, and a ring nitrogen atom may be optionally oxidized to form an ⁇ -oxide.
  • (+) is intended to signify a racemic mixture; i.e. an optically inactive mixture of equal amounts of (+) and (-) enantiomers of the indicated compound.
  • 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.
  • substantially free is intended to indicate that the specified entity is present in an amount less than 10%, more particularly less than 5%, in particular less than 2%, more particularly less than 1%, in particular less then 0.5%, particularly less than 0.2%.
  • the term "optionally substituted,” indicates that substitution is optional and therefore it is possible for the designated group to be either substituted or unsubstituted. In the event a substitution is desired, 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 which exhibits an antibacterial effect.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the phrase "effective amount” means an amount of a compound or composition which is sufficient 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.
  • a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, citric or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation
  • a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxye
  • the compounds of Formulas (I) and (II) have two chiral carbons on the central piperidine ring, carbon "a” and carbon "b.” Additionally, the compounds of Formulas (I) and (II) may have other chiral centers and/or geometric isomeric centers (E- and Z- isomers) It is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess antibacterial activity.
  • the invention further relates to any and all tautomeric forms of the compounds of Formula (I) and (II) and pharmaceutically acceptable salts thereof that possess antibacterial activity.
  • the R 6 group on carbon "a” and the -NH- group on carbon "b” of the compounds of Formula (I) are in a cis (+) relationship to each other, wherein the compound of Formula (I) is substantially free of a cis ( ⁇ ) mixture of its enantiomers.
  • the R 6 group on carbon "a” and the -NH- group on carbon "b” of the compounds of Formula (I) are in a cis (-) relationship to each other, the compound of Formula (I) is substantially free of a cis ( ⁇ ) mixture of its enantiomers.
  • R 6 group on carbon "a” and the -NH- group on carbon "b” of the compounds of Formula (I) are in a trans (+) relationship to each other.
  • R 6 group on carbon "a” and the -NH- group on carbon "b” of the compounds of Formula (I) are in a trans (-) relationship to each other.
  • A is N.
  • A is CH.
  • D is N.
  • D is CH.
  • D is selected from N and CH.
  • A is CH; and D is N.
  • E and G are each O; and R 8 and R 9 are each H.
  • J is N.
  • J is CH.
  • J is selected from N and CH.
  • J is selected from N and C-R 4 ; and R 4 is selected from H and Ci- ⁇ alkyl.
  • J is selected from N and C-R 4 ; and R 4 is selected from H and methyl.
  • J is selected from C-R 4 ;. and R 4 is selected from H and methyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • A, D, E, G, R , and R together with the ring atoms to which they are attached, form:
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form:
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form:
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • R 1 is H.
  • R 2 is selected from cyano and -OR 2a ; and R 2a is Ci- ⁇ alkyl.
  • R 2 is selected from cyano and methoxy.
  • R 2 is cyano
  • R 2 is -OR 2a ; and R 2a is Ci- ⁇ alkyl.
  • R is methoxy
  • R 3 is H.
  • R 6 is selected from fluoro and -OR 6a ; and R 6a is selected from H and Ci- ⁇ alkyl.
  • R 6 is selected from fluoro, hydroxy, and methoxy.
  • R 6 is fluoro
  • R 6 is hydroxy
  • R 6 is methoxy.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof may be a compound of Formula (Ia):
  • R 1 , R 2 , R 3 , R 6 , G, and J are as defined hereinabove, and wherein the compound of Formula (Ia) is substantially free of a cis ( ⁇ ) mixture of its enantiomers.
  • G is selected from O and S;
  • J is selected from N and CH;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is C,. 6 alkyl
  • R 3 is H
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and
  • G is selected from O and S; J is selected from N and CH; R 1 is H; R 2 is selected from cyano and methoxy;
  • R 3 is H
  • R 6 is selected from fluoro, hydroxy, and methoxy.
  • G is selected from O and S;
  • J is selected from N and C-R 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is Ci- ⁇ alkyl
  • R 3 is H
  • R 4 is selected from H and C ⁇ aUcyl
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and Ci- ⁇ alkyl.
  • G is selected from O and S;
  • J is selected from N and C-R 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is methyl
  • R 3 is H
  • R 4 is selected from H and methyl
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and methyl.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (Ib):
  • R 1 , R 2 , R 3 , R 6 , and J are as defined hereinabove, wherein the compound of Formula (Ib) is substantially free of a cis ( ⁇ ) mixture of its enantiomers.
  • J is selected from N and CH; R 1 is H;
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is C 1-6 alkyl;
  • R 3 is H
  • R 6a is selected from H and C h alky!.
  • J is selected from N and CH;
  • R 1 is H
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 6 is selected from fluoro, hydroxy, and methoxy.
  • J is selected from N and CH;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is C, -6 alkyl;
  • R 3 is H
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and Ci_ 6 alkyl.
  • J is selected from N and CH; R 1 is H;
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 6 is selected from fluoro, hydroxy, and methoxy.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof may be a compound of Formula (Ic):
  • R 1 , R 2 , R 3 , R 6 , R 8 , R 9 , A, D, E, G, and J are as defined hereinabove, wherein the compound of Formula (Ic) is substantially free of a cis ( ⁇ ) mixture of its enantiomers.
  • R 1 is H
  • R is selected from cyano and -OR 2a a .
  • R 2a is C 1-6 alkyl
  • R 3 is H
  • R 4 is selected from H and
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and Ci -6 alkyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is C, -6 alkyl
  • R 3 is H
  • R 4 is selected from H and
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and C h alky!.
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -0R 2a ;
  • R 2a is methyl
  • R 3 is H
  • R 4 is selected from H and methyl
  • R 6 is selected from fluoro and -0R 6a ;
  • R 6a is selected from H and methyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -0R 2a ;
  • R 2a is methyl
  • R 3 is H
  • R 4 is selected from H and methyl
  • R 6 is selected from fluoro and -0R 6a ;
  • R 6a is selected from H and methyl.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof may be a compound of Formula (Id):
  • R 1 , R 2 , R 3 , R 6 , R 8 , R 9 , A, D, E, G, and J are as defined hereinabove, and wherein the compound of Formula (Id) is substantially free of a cis ( ⁇ ) mixture of its enantiomers.
  • J is selected from and CR ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is Ci -6 alkyl
  • R 3 is H
  • R 4 is selected from H and C ⁇ aUcyl
  • R* is selected from fluoro and -OR 6a ;
  • R ,6 o a a is selected from H and Ci -6 alkyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from: and
  • J is selec ed from N and CR ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is Ci- ⁇ alkyl
  • R 3 is H
  • R 4 is selected from H and Ci -6 alkyl
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and Ci -6 alkyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from and CR 4 ; ...
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is methyl
  • R 3 is H
  • R 4 is selected from H and methyl
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and methyl.
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is methyl
  • R 3 is H
  • R 4 is selected from H and methyl
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and methyl.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof may be a compound of Formula (Ie):
  • R 1 , R 2 , R 3 , R 6 , R 8 , R 9 , A, D, E, G, and J are as defined hereinabove, and wherein the compound of Formula (Ie) is substantially free of a cis ( ⁇ ) mixture of its enantiomers.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ; R 1 is H;
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is Ci -6 alkyl;
  • R 3 is H; and
  • R 4 is selected from H and
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is Ci. 6 alkyl
  • R 3 is H
  • R 4 is selected from H and Ci- ⁇ alkyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 4 is selected from H and methyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 4 is selected from H and methyl.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof may be a compound of Formula (If):
  • R 1 , R 2 , R 3 , R 8 , R 9 , A, D, E, G, and J are as defined hereinabove, wherein the fluoro group on carbon "a” and the -NH- group on carbon "b” are in a cis relationship to each other, and wherein the compound of Formula (If) is substantially free of a cis ( ⁇ ) mixture of its enantiomers.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is Ci- ⁇ alkyl
  • R 3 is H
  • R 4 is selected from H and d- ⁇ alkyl.
  • J is selected from N and CR 4 ; R 1 is H;
  • R is selected from cyano and -OR 2a ;.
  • R 2a is Ci- ⁇ alkyl
  • R 3 is H
  • R 4 is selected from H and Ci- ⁇ alkyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ; R 1 is H;
  • R 2 is selected from cyano and methoxy; R 3 is H; and R 4 is selected from H and methyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 4 is selected from H and methyl.
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof may be a compound of Formula (Ig):
  • R 1 , R 2 , R 3 , R 8 , R 9 , A, D, E, G, and J are as defined hereinabove, wherein the compound of Formula (Ig) is substantially free of a cis ( ⁇ ) mixture of its enantiomers.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is C 1-6 alkyl
  • R 3 is H
  • R 4 is selected from H and C h alky!.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R ,2"a is Ci- ⁇ alkyl
  • R 3 is H
  • R 4 is selected from H and Ci -6 alkyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 4 is selected from H and methyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 4 is selected from H and methyl.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof may be a compound of Formula (Ih):
  • R 1 , R 2 , R 3 , R 8 , R 9 , A, D, E, G, and J are as defined hereinabove, wherein the compound of Formula (Ii) is substantially free of a cis ( ⁇ ) mixture of its enantiomers.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is Ci- ⁇ alkyl
  • R 3 is H
  • R 4 is selected from H and Ci- ⁇ alkyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is Ci- ⁇ alkyl
  • R 3 is H
  • R 4 is selected from H and Ci- 6 alkyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ; R 1 is H;
  • R 2 is selected from cyano and methoxy; R 3 is H; and R 4 is selected from H and methyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ; R 1 is H;
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 4 is selected from H and methyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is Ci -6 alkyl
  • R 3 is H
  • R 4 is selected from H and Ci- ⁇ alkyl
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and Ci- 6 alkyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from: ,
  • J is selec ed from N and CR 4 ;
  • R' is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is Ci -6 alkyl
  • R 3 is H
  • R 4 is selected from H and Ci- ⁇ alkyl
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and C h alky!.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is methyl
  • R 3 is H
  • R 4 is selected from H and methyl
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and methyl.
  • J is selected from and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is methyl
  • R 3 is H
  • R 4 is H
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and methyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is methyl
  • R 3 is H
  • R 4 is selected from H and methyl
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and methyl.
  • the compound of Formula (II), or a pharmaceutically acceptable salt thereof may be a compound of Formula (Ha):
  • R 1 , R 2 , R 3 , R 6 , R 8 , R 9 , A, D, E, G, and J are as defined hereinabove.
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is C,. 6 alkyl
  • R 3 is H
  • R 4 is selected from H and Ci- ⁇ alkyl
  • R 6 is selected from fluoro and -OR 6a ;
  • R >6a is selected from H and C i -6 alkyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R ia is Ci- ⁇ alkyl
  • R 3 is H
  • R 4 is selected from H and Ci- ⁇ alkyl
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and Ci- 6 alkyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R" is Ci- ⁇ alkyl
  • R 3 is H
  • R 4 is H
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and Ci- ⁇ alkyl.
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is methyl
  • R 3 is H
  • R 4 is selected from H and methyl
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and methyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is methyl
  • R 3 is H
  • R 4 is H
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and methyl.
  • the compound of Formula (II), or a pharmaceutically acceptable salt thereof may be a compound of Formula (lib):
  • R 1 , R 2 , R 3 , R 6 , R 8 , R 9 , A, D, E, G, and J are as defined hereinabove.
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is Ci- ⁇ alkyl
  • R 3 is H
  • R 4 is selected from H and Ci-6alkyl
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and C ]-6 alkyl.
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is C,. 6 alkyl
  • R 3 is H
  • R 4 is selected from H and
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and Ci- 6 alkyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is Ci-ealkyl
  • R 3 is H
  • R 4 is selected from H
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and Ci. 6 alkyl. 3.4) In yet another aspect of the compound of Formula (lib), or a pharmaceutically acceptable salt thereof,
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is methyl
  • R 3 is H
  • R 4 is selected from H and methyl
  • R 6 is selected from fluoro and -OR 6a ;
  • R 6a is selected from H and methyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is methyl
  • R 3 is H
  • R 4 is H; R is selected from fluoro and -OR a : and
  • R ,6a a is selected from H and methyl.
  • the compound of Formula (II), or a pharmaceutically acceptable salt thereof may be a compound of Formula (lie)
  • R 1 , R 2 , R 3 , R 8 , R 9 , A, D, E, G, and J are as defined hereinabove, and wherein the fluoro group on carbon "a” and the -NH- group on carbon "b" are in a trans relationship to each other.
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is C 1-6 alkyl
  • R 3 is H
  • R 4 is selected from H and 4.2) In another aspect of the compound of Formula (lie), or a pharmaceutically acceptable salt thereof,
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is Ci -6 alkyl
  • R 3 is H
  • R 4 is selected from H and C ⁇ aUcyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is C!. 6 alkyl
  • R 3 is H
  • R 4 is H. 4.4
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 4 is selected from H and methyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 4 is H.
  • the compound of Formula (II), or a pharmaceutically acceptable salt thereof may be a compound of Formula (Hd):
  • 1 , ⁇ R>2 , R ⁇ )3 , R ri8 , R ⁇ »9 , A, D, E, G, and J are as defined hereinabove.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is C 1-6 alkyl
  • R 3 is H
  • R 4 is selected from H and Q ⁇ allcy!.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is C ⁇ alkyl
  • R 3 is H
  • R 4 is selected from H and Ci- ⁇ alkyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -0R 2a ;
  • R 2a is Ci- ⁇ alkyl
  • R 3 is H
  • R 4 is H.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR ;
  • R 1 is H
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 4 is selected from H and methyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 4 is H.
  • the compound of Formula (II), or a pharmaceutically acceptable salt thereof may be a compound of Formula (He):
  • R 1 , R 2 , R 3 , R 8 , R 9 , A, D, E, G, and J are as defined hereinabove.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R ,2"a is Ci -6 alkyl
  • R 3 is H
  • R »4 is selected from H and C h alky!.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ; R 1 is H;
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is C,. 6 alkyl;
  • R 3 is H; and
  • R 4 is selected from H and
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is Ci- ⁇ alkyl
  • R 3 is H
  • R 4 is H.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 4 is selected from H and methyl.
  • A, D, E, G, R 8 , and R 9 together with the ring atoms to which they are attached, form a group selected from:
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 4 is methyl
  • the compound of Formula (II), or a pharmaceutically acceptable salt thereof may be a compound of Formula (Hf):
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is C,. 6 alkyl
  • R 3 is H
  • R 4 is selected from H and
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is Ci -6 alkyl
  • R 3 is H
  • R 4 is H.
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 4 is selected from H and methyl.
  • J is selected from N and CR ;
  • R 1 is H
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 4 is H.
  • the compound of Formula (Hg), or a pharmaceutically acceptable salt thereof may be a compound of Formula (Hg):
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is C 1-6 alkyl
  • R 3 is H
  • R 4 is selected from H and Ci_6alkyl.
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and -OR 2a ;
  • R 2a is C,. 6 alkyl;
  • R 3 is H;
  • R 4 is H.
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 4 is selected from H and methyl.
  • J is selected from N and CR 4 ;
  • R 1 is H
  • R 2 is selected from cyano and methoxy
  • R 3 is H
  • R 4 is H.
  • the present invention provides compounds of Formulas (I) and (H) and pharmaceutically acceptable salts thereof, as illustrated by the Examples, each of which provides a further independent aspect of the invention.
  • the compounds of Formulas (I) (II) and pharmaceutically acceptable salts thereof 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.
  • 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 adjusted to be equal to a 0.5 McFarland and a further 1 in 10 dilution may be 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) was determined as the lowest drug concentration able to reduce growth by 80% or more.
  • Compounds were evaluated against a panel of Gram-positive species, including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Enterococcus faecium. In addition, compounds were evaluated against a panel of Gram- negative species including Haemophilus influenzae, Escherichia coli and Moraxella catarrhalis. Compounds of the present invention and pharmaceutically acceptable salts thereof are believed to generally have MICs less than or equal to 8 ⁇ g/ml versus one or more of the organisms named above.
  • the compound of Example 2 had an MIC of 0.25 (mg/L) against Staphylococcus aureus and an MIC of 0.5 (mg/L) against Escherichia coli.
  • Compounds may be tested for antimicrobial activity by susceptibility testing using microbroth dilution methods recommended by CSLI.
  • Compounds may be dissolved in dimethylsulfoxide and tested in 10 doubling dilutions in the susceptibility assays such that the final dimethylsulfoxide concentration in the assay is 2% (v/v).
  • the Staphylococcus aureus (Sau) 516 cells used in the assay may be grown overnight on appropriate agar media and then suspended in the NCCLS-recommended liquid susceptibility-testing media.
  • each suspension may be adjusted to be equal to a 0.5 McFarland standard, and a further 1-in- 200 dilution may be made into the same liquid medium to prepare the final organism suspension, and 100 ⁇ L of this suspension may be added to each well of a microti ter plate containing compound dissolved in 2 ⁇ L of dimethylsulfoxide. Plates may be incubated under appropriate conditions of atmosphere and temperature and for times according to NCCLS standard methods prior to being read. As used in Table 1 below, the term “inhibition” refers to the percentage of Staphylococcus aureus 516 cell growth that is suppressed (compared to an untreated sample) by the compound of the indicated example number.
  • the compounds and salts of the example numbers listed below were tested at the indicated concentrations, providing the indicated inhibitions.
  • the highest concentrations at which the compounds were tested was 8 ⁇ g/mL.
  • compounds were tested at concentrations higher than 8 ⁇ g/mL typically when the concentration was first measured in ⁇ M and was subsequently converted to ⁇ g/mL.
  • concentration closest to 8 ⁇ g/mL is provided below.
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a bacterial infection caused by one or more pathogenic organisms such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogene
  • pathogenic organisms such as Acineto
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of an infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man.
  • an infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a bacterial infection
  • the bacteria is of a genus selected from Aeromonas, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavo bacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, in a warm-blood
  • a method for treating a bacterial infection in a warmblooded animal comprising administering to said animal an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof.
  • a method for treating a bacterial infection caused by one or more pathogenic organisms such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorr
  • a method for treating a bacterial infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof.
  • a bacterial infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinus
  • a method for treating a bacterial infection wherein the bacteria is of a genus selected from Aeromonas, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I) or (II), or
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof for use in treating a bacterial infection caused by one or more pathogenic organisms such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof for use in treating infections such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intraabdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man.
  • infections such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intraabdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, for use in treating a bacterial infection wherein the bacteria is of a genus selected from Aeromonas, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, and Munnheimia, in a warm-blooded animal such as man.
  • the bacteria is of a
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Acinetobacter baumanii. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Aeromis hydrophila. In still another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Bacillus anthracis. In yet another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Bacteroidesfragilis. In a further aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Bordatella pertussis.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Burkholderia cepacia. In yet a further aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Chlamyida pneumoniae. In one aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Citrobacter freundii. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Clostridium difficile. In still another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Enterobacter cloacae.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Enterococcus faecalis. In a further aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Enterococcus faecium. In still a further aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Enterobacter aerogenes. In yet a further aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Escherichia coli. In one aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Fusobacterium necrophorum.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Haemophilus influenzae.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Haemophilus parainfluenzae.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Haemophilus somnus.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Klebsiella oxytoca.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Klebsiella pneumoniae.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Legionella pneumophila.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Listeria monocytogenes.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Moraxella catarrhalis.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Morganella morganii.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Mycoplasma pneumoniae.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Neisseria gonorrhoeae. In still a further aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Neisseria meningitidis. In yet a further aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Pasteurella multocida. In one aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Proteus mirabilis. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Proteus vulgaris.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Pseudomonas aeruginosa. In yet another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Salmonella typhi. In a further aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Salmonella typhimurium. In still a further aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Serratia marcesens. In yet a further aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Shigella flexneria.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Shigella dysenteriae.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Staphylococcus aureus.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Staphylococcus epidermidis.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Staphylococcus haemolyticus.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Staphylococcus intermedius.
  • the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Staphylococcus saprophyticus. In yet a further aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Stenotrophomonas maltophila. In one aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Streptococcus agalactiae. In another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Streptococcus mutans. In a still another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Streptococcus pneumoniae. In yet another aspect, the terms “infection” and “bacterial infection” may refer to a bacterial infection caused by Streptococcus pyrogenes.
  • the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Aeromonas. In another aspect, the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Acinetobacter. In still another aspect, the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Bacillus. In yet another aspect, the terms “infection and “bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Bacteroides. In a further aspect, the terms “infection and “bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Bordetella.
  • the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Burkholderia. In yet a further aspect, the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Chlamydophila. In one aspect, the terms “infection and “bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Citrobacter. In another aspect, the terms “infection and “bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Clostridium.
  • the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Enterobacter. In yet another aspect, the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Enterococcus. In a further aspect, the terms “infection and “bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Escherichia. In still a further aspect, the terms “infection and “bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Flavobacterium.
  • the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Fusobacterium. In one aspect, the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Haemophilus. In one aspect, the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Klebsiella. In another aspect, the terms “infection and “bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Legionella. In still another aspect, the terms “infection and “bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Listeria.
  • the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Morganella. In a further aspect, the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Moraxella. In still a further aspect, the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Mycoplasma. In yet a further aspect, the terms “infection and “bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Neisseria. In one aspect, the terms “infection and “bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Pasteurella.
  • the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Peptococci. In still another aspect, the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Peptostreptococci. In yet another aspect, the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Prevotella. In a further aspect, the terms “infection and “bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Proteus.
  • the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Pseudomonas. In still another aspect, the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Salmonella. In yet a further aspect, the terms “infection and “bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Serratia. In one aspect, the terms “infection and “bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Shigella.
  • the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Staphylococcus. In another aspect, the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Stenotrophomonas. In still another aspect, the terms “infection and "bacterial infection” may refer to a bacterial infection caused by a bacteria of the genus Streptococcus. In one aspect, the terms “infection” and “bacterial infection” may refer to a gynecological infection. In another aspect the terms “infection” and “bacterial infection” may refer to a respiratory tract infection (RTI).
  • RTI respiratory tract infection
  • 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. In a further aspect, the terms “infection” and “bacterial infection” may refer to chlamydia. In still a further aspect, the terms “infection” and “bacterial infection” may refer to community- acquired pneumonia (CAP). In yet a further aspect, the terms “infection” and “bacterial infection” may refer to complicated skin and skin structure infection. In one aspect, the terms “infection” and “bacterial infection” may refer to uncomplicated skin and skin structure infection. In another aspect, the terms “infection” and “bacterial infection” may refer to endocarditis. In still another aspect, the terms “infection” and “bacterial infection” may refer to febrile neutropenia.
  • the terms “infection” and “bacterial infection” may refer to gonococcal cervicitis. In a further aspect, the terms “infection” and “bacterial infection” may refer to gonococcal urethritis. In still a further aspect, the terms “infection” and “bacterial infection” may refer to hospital-acquired pneumonia (HAP). In yet another aspect, the terms “infection” and “bacterial infection” may refer to osteomyelitis. In a further aspect, the terms “infection” and “bacterial infection” may refer to sepsis. In still a further aspect, the terms “infection” and “bacterial infection” may refer to syphilis.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (Ib), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (Ic), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (Id), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (Ie), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (If), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (Ig), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (Ih), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (Ha), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (lib), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (lie), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (He), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (Uf), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a pharmaceutical composition comprising a compound of Formula (Hg), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • 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 ⁇ - hydroxybenzoate; anti-oxidants such as ascorbic acid); coloring agents; flavoring agents; and/or sweetening agents such as sucrose, saccharine or aspartame.
  • preservatives such as ethyl or propyl ⁇ - hydroxybenzoate
  • anti-oxidants such as ascorbic acid
  • coloring agents such as ascorbic acid
  • flavoring agents such as 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 pharmaceutical composition of this invention may also contain or be co-administered (simultaneously, sequentially or separately) with one or more known drugs selected from other clinically useful classes of antibacterial agents (for example, macrolides, quinolones, ⁇ -lactams or aminoglycosides) and/or other anti- infective agents (for example, an antifungal triazole or amphotericin).
  • drugs for example, macrolides, quinolones, ⁇ -lactams or aminoglycosides
  • other anti- infective agents for example, an antifungal triazole or amphotericin.
  • carbapenems for example meropenem or imipenem, to broaden the therapeutic effectiveness.
  • Compounds of this invention may also contain or be co-administered with bactericidal/permeability-increasing protein (BPl) products or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.
  • the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.
  • a daily dose in the range of 1-50 mg/kg is employed. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • the compound of Formulas (I) and its pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of antibacterial effects in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • any of the alternate embodiments of the compounds of the invention described herein also apply.
  • 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.
  • suitable protecting groups for a hydroxy group are, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, a silyl group such as trimethylsilyl or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon.
  • a suitable protecting group for an amino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or J-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • 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 f-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 fr ⁇ (trifluoroacetate).
  • a suitable acid as hydrochloric, sulfuric, phosphoric acid or trifluoroacetic acid
  • an arylmethoxycarbonyl group such as a benzyloxycarbonyl group
  • a Lewis acid for example boron fr ⁇ (trifluoroacetate
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine.
  • Another suitable protecting group for an amine is, for example, a cyclic ether such as tetrahydrofuran, which may be removed by treatment with a suitable acid such as trifluoroacetic acid.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.
  • the present invention provides a process for preparing a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, said process comprising reacting a compound of Formula (AA):
  • the compound of Formula (AA) may be reacted with the compound of Formula (AB) under typical reductive amination conditions.
  • the first step of the reaction typically takes place in the presence of a dehydrating agent such as molecular sieves (MS 3A), though the reaction will generally proceed without a dehydrating agent.
  • a suitable solvent is methanol or methanol/chloroform mixtures.
  • the imine intermediate is typically not isolated; rather, the reducing agent is generally added to the reaction mixture after imine formation.
  • Suitable reducing agents for the second (reduction) step of the process include boron reducing agents such as NaB(OAc) 3 H or NaBH 3 CN.
  • the present invention provides a process for preparing a compound of Formula (I) or (II) in which R 6 is F, or a pharmaceutically acceptable salt thereof, said process comprising reacting a compound of Formula (AC):
  • the present invention provides a process for preparing a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, said process comprising reacting a compound of Formula (BI):
  • Suitable reducing agents for the reduction of the compound of Formula (BI) include boron reducing agents such as NaB(OAc) 3 H or NaBH 3 CN.
  • a suitable solvent is methanol or methanol/chloroform mixtures
  • Suitable leaving groups include leaving groups such as mesylate, chloro, bromo, and iodo.
  • Suitable protecting groups include alkoxycarbonyl groups such as f-butoxycarbonyl, which may be deprotected using acids such as HCl.
  • Reaction of a compound of Formula (AD) under Mitsunobu conditions with a compound of Formula (AG) may be used to obtain a compound of Formula (AF).
  • Deprotection provides a compound of Formula (AA).
  • Suitable protecting groups include alkoxycarbonyls such as t- butoxycarbonyl, which may be removed using acids such as HCl.
  • Scheme 3 depicts another method for preparing compounds of Formula (AA).
  • a compound of Formula (AD) may be reacted with a base such as NaH, followed by reaction with bromo- or chloroethanol or bromo-or chloro acetaldehyde, or with a protected derivative thereof, (followed by deprotection and oxidation in case of an alcohol derivative), providing a compound of Formula (AH).
  • the compound of Formula (AH) may be reacted with the compound of Formula (AI) under typical reductive amination conditions.
  • the imine-formation typically takes place in the presence of a dehydrating agent such as molecular sieves (MS 3A), though the reaction will generally proceed just as well without a dehydrating agent.
  • a suitable solvent is tetrahydrofuran, dichloromethane or chloroform/methanol mixtures.
  • the imine intermediate is typically not isolated; rather, the reducing agent is generally added to the reaction mixture after imine formation.
  • Suitable reducing agents for the second step of the reaction include boron reducing agents such as NaB(OAc) 3 H or NaBH 3 CN. Deprotection of the compound of Formula (AF) provides a compound of Formula (AA).
  • Suitable protecting groups for the amino group substituent on the piperidine ring of the compound of Formula (AI) include alkoxycarbonyls such as ⁇ -butoxycarbonyl, which may be removed using acids such as HCl; and azides, which may be converted to the amine reductively, either with triphenyl phosphine (Staudinger Reaction) or by hydrogenation.
  • a compound of Formula (AL) may be prepared by reaction of a compound of Formula (AI) with bromoethanol or a derivative thereof in the presence of a base such as triethylamine, providing a compound of Formula (AG).
  • the compound of Formula (AG) may be reacted with mesyl chloride, in the presence of a base, such as trialkyl amine or an immobilized version thereof on a resin, providing a compound of Formula (AL).
  • the compound of Formula (AL) is potentially unstable, and may be present as part of a mixture with the corresponding chloride (arising from attack of chloride on the mesyl group) and needs to be prepared fresh under careful controlled conditions.
  • a compound of Formula (AO), which is a compound of Formula (AD) in which J is CH may be prepared according to Scheme 5.
  • a compound of Formula (AO) may be prepared from commercially available compounds of Formula (AM) by reaction with cinnamoylchloride in the presence of a suitable base such as 2,6-lutidine, followed by cyclization with aluminum trichloride.
  • a suitable base such as 2,6-lutidine
  • cinnamoyl chloride may be replaced with E-ethoxyacryloyl chloride and cyclization of the intermediate E-ethoxyacryloylamides affected with sulfuric acid instead of aluminium trichloride (E. Baston et al, European Journal of Medicinal Chemistry 35 (2000) 931).
  • Unsymmetrical substituted anilines generally lead to regioisomeric quinolin-2(lH)-one derivatives, which may be difficult to separate by chromatography due to limited solubility.
  • Such mixtures may be separated either by crystallization or may be converted to the corresponding 2-chloroquinoline derivatives (for example with phosphorusIII oxychloride), which may be separated by chromatography or by crystallization and can then be hydrolyzed back with refluxing hydrochloride acid to the single regioisomers of the compound of Formula (AO).
  • a compound of Formula (AO) may also be prepared according to Scheme 6.
  • a compound of Formula (AO) may be prepared from a compound of Formula (AP) by forming a carbon-carbon bond, followed by intramolecular amide bond formation of an appropriately set up cis unsaturated system.
  • the isomerization of a trans double bond may be performed thermically or photochemically under uv light.
  • the carbon-carbon bond formation may be performed as a Sonogashira Coupling to an alkyne intermediate, which may be partially hydrogenated to a cis double bond under Lindlar conditions.
  • a compound of Formula (AO) may also be prepared according to Scheme 7.
  • a compound of the Formula (AO) may be prepared from a compound of Formula (BE) by deprotonation with a base such as sodium ethoxide, followed by reaction with diethyl oxalate to form a compounds of the Formula (BF). This intermediate may then be reduced with a suitable reducing agent such as sodium borohydride, providing a compound of Formula (BG). The compound of Formula (BG) may then be cyclized to a compound of Formula (BH), after reduction of the nitro group with a suitable reducing agent such as iron in acetic acid or tin dichloride. Finally, elimination with a base such as DBU, provides a compound of Formula (AO).
  • a base such as sodium ethoxide
  • diethyl oxalate to form a compounds of the Formula (BF).
  • This intermediate may then be reduced with a suitable reducing agent such as sodium borohydride, providing a compound of Formula (BG).
  • the compound of Formula (BG) may then be cyclized to a compound of Formula
  • a compound of Formula (AU), which is a compound of Formula (AD) in which J is N, may be prepared according to Scheme 8.
  • Scheme 9 depicts another method for preparing compound of Formula (AU).
  • a compound of Formula (AU) may be obtained by oxidation of a compound of Formula (AX) with oxidants such as hydrogen peroxide.
  • the compound of Formula (AX) may be obtained by reacting a compound a compound of Formula (AV) with bromoacetic acid esters, or with ethylgloxylate, followed by reduction of the nitro group and spontaneous cyclization.
  • Suitable reducing agents include Pd/C and H 2 , iron in acetic acid, and tin chloride.
  • a compound of Formula (AZ) which is a compound of Formula (AG) in which the protecting group is t-butoxycarbonyl, may be prepared according to scheme 10.
  • a compound of Formula (BA) may be reacted with a compound of Formula (BB) in the presence of a base providing a compound of Formula (BC).
  • a base providing a compound of Formula (BC).
  • Suitable leaving groups for this reaction include mesylate and halo groups such as chloro and bromo.
  • Suitable protecting groups for this reaction include silyl protecting groups such as t-butyl-dimethylsilyl.
  • the protecting group of the compound of Formula (BC) may be removed using t-butylammonium fluoride, providing a compound of Formula (BD).
  • the compound of Formula (BD) may be deprotected by hydrogenation.
  • suitable catalysts for such a reaction include Pd(OH) 2 , Platinum black, and PtO 2 , followed by reaction with di-t-butylcarbonate, providing a compound of Formula (AZ).
  • an optically active form of a compound of the invention 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.
  • 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 (250 x 20 mm, 10 micron) with 60% hexanes and 40% ethanol/ methanol (1:1), containing 0.1% diethyl amine.

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EP07848510A 2006-12-15 2007-12-13 2-chinolinon- und 2-chinoxalinonderivate und deren verwendung als antibakterielle mittel Withdrawn EP2121702A1 (de)

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MY150958A (en) 2005-06-16 2014-03-31 Astrazeneca Ab Compounds for the treatment of multi-drug resistant bacterial infections
EP1900732A4 (de) 2005-06-24 2009-11-18 Toyama Chemical Co Ltd Neue nitrogenierte heterocyclische verbindung und salz davon
EP1992628A1 (de) 2007-05-18 2008-11-19 Glaxo Group Limited Derivate und Analoge von N-Ethylquinolonen und N-Ethylazaquinolonen
RU2516701C2 (ru) 2008-10-10 2014-05-20 Актелион Фармасьютиклз Лтд Оксазолидиниловые антибиотики
AR076222A1 (es) 2009-04-09 2011-05-26 Actelion Pharmaceuticals Ltd Derivados 2-hidroxietil-1h-quinolin-ona y sus analogos azaisotericos con actividad antibacteriana y composiciones farmaceuticas que los contienen
EP2646567A4 (de) * 2010-10-04 2014-03-26 British Columbia Cancer Agency Nachweis von fusobacterium in einer gastrointestinalen probe zur diagnose von gastrointestinalem karzinom
WO2019040104A2 (en) * 2017-08-21 2019-02-28 Acadia Pharmaceuticals Inc. COMPOUNDS, RELATED SALTS AND METHODS OF TREATING DISEASES
SG11202001062XA (en) 2017-08-21 2020-03-30 Acadia Pharm Inc Compounds, salts thereof and methods for treatment of diseases

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AR040336A1 (es) 2002-06-26 2005-03-30 Glaxo Group Ltd Compuesto de piperidina, uso del mismo para la fabricacion de un medicamento, composicion farmaceutica que lo comprende y procedimiento para preparar dicho compuesto
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MY150958A (en) * 2005-06-16 2014-03-31 Astrazeneca Ab Compounds for the treatment of multi-drug resistant bacterial infections
EP1900732A4 (de) * 2005-06-24 2009-11-18 Toyama Chemical Co Ltd Neue nitrogenierte heterocyclische verbindung und salz davon
AU2007268749B2 (en) * 2006-05-26 2012-07-26 Taisho Pharmaceutical Co., Ltd. Novel heterocyclic compound or salt thereof and intermediate thereof
JP2009539807A (ja) * 2006-06-09 2009-11-19 グラクソ グループ リミテッド 抗菌薬としての置換１−メチル−１ｈ−キノリン−２−オンおよび１−メチル−１ｈ−１，５−ナフチリジン−２−オン
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PE20081551A1 (es) * 2006-07-20 2009-01-09 Glaxo Group Ltd Derivados de quinolona como antibacterianos
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CL2007003641A1 (es) 2008-09-22
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ECSP099506A (es) 2009-08-28
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