WO2015066413A1 - Composés d'acide oxazolidinone-hydroxamique pour le traitement d'infections bactériennes - Google Patents

Composés d'acide oxazolidinone-hydroxamique pour le traitement d'infections bactériennes Download PDF

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WO2015066413A1
WO2015066413A1 PCT/US2014/063325 US2014063325W WO2015066413A1 WO 2015066413 A1 WO2015066413 A1 WO 2015066413A1 US 2014063325 W US2014063325 W US 2014063325W WO 2015066413 A1 WO2015066413 A1 WO 2015066413A1
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crc
alkyl
halogen
alkoxy
optionally substituted
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PCT/US2014/063325
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English (en)
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Jiping Fu
Patrick Lee
Ann Marie Madera
Zachary Kevin Sweeney
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Novartis Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention pertains generally to compounds and compositions for treating bacterial infections.
  • the invention pertains to treating infections caused by Gram-negative bacteria. More specifically, the invention pertains to treating Gram- negative infections by inhibiting the activity of UDP-3-0-(R-3-hydroxydecanoyl)-N- acetylglucosamine deacetylase (LpxC).
  • the invention provides small molecule inhibitors of LpxC, pharmaceutical compositions containing such inhibitors, methods of treating patients with such compounds and pharmaceutical compounds, and methods of preparing such pharmaceutical compositions and inhibitors.
  • the inhibitors can be used to treat Gram- negative infections of patients, either alone or in combination with other antibacterials.
  • nosocomial infections Over the past several decades, the frequency of antimicrobial resistance and its association with serious infectious diseases have increased at alarming rates. The increasing prevalence of resistance among nosocomial pathogens is particularly disconcerting. It is currently estimated that, of the over 2 million nosocomial infections occurring each year in the United States, 50 to 60% are caused by antimicrobial-resistant strains of bacteria. The high rate of resistance to commonly used antibacterial agents increases the morbidity, mortality, and costs associated with nosocomial infections. In the United States, nosocomial infections are thought to contribute to or cause more than 77,000 deaths per year while costing approximately $5 to $10 billion dollars.
  • the most important resistant pathogens are methicillin-(oxacillin-) resistant Staphylococcus aureus, ⁇ -lactam-resistant and multidrug-resistant pneumococci, and vancomycin-resistant enterococci.
  • Gram-negative resistance Important causes of Gram-negative resistance include extended-spectrum ⁇ -lactamases (ESBLs) in Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis, high-level third-generation cephalosporin (Amp C) ⁇ -lactamase resistance among Enterobacter species and Citrobacter freundii, and multidrug-resistance genes observed in Pseudomonas, Acinetobacter, and Stenotrophomonas.
  • ESBLs extended-spectrum ⁇ -lactamases
  • Amp C cephalosporin
  • Gram-negative bacteria are in general more resistant to a large number of antibactenals and chemotherapeutic agents than are Gram-positive bacteria.
  • the present invention provides novel compounds, pharmaceutical formulations including the compounds, methods of inhibiting UDP-3-0-(R-3-hydroxydecanoyl)-N- acetylglucosamine deacetylase (LpxC), and methods of treating Gram-negative bacterial infections.
  • Compounds acting on this target site have been reported as antibactenals, see e.g., WO2014/160649.
  • the present invention provides novel inhibitory compounds and compositions, and methods for their use as antibactenals, particularly for Gram-negative bacterial infections.
  • the invention provides compounds of Formula (I):
  • X is N or C, wherein when X is N, R 4 is absent;
  • Y is N or C, wherein when Y is N, R 5 is absent;
  • R 1 , R 2 , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, -CH 3 , and -Cihaloalkyl;
  • R 3 is L-R
  • L is a divalent bond, or -CH 2 -;
  • R is selected from group consisting of
  • -C C 4 alkyl optionally substituted with one or more groups selected from halogen, d- C 4 alkoxy, -CN and -OH;
  • -CrC 4 alkoxy optionally substituted with one or more groups selected from halogen, C C 4 alkoxy, -CN and -OH;
  • alkyl wherein the alkyl is optionally substituted with one or more groups selected from halogen, CrC 4 alkoxy, -CN and -OH;
  • -C 2 -C 6 alkynyl optionally substituted with one or more groups selected from halogen, C C 4 alkoxy, -CN and -OH;
  • cycloalkyl optionally substituted with one or more groups selected from halogen, C Calkyl, -Ci-C alkylCrCalkoxy, C C alkoxy, CrC haloalkyl, nitrile, -S(0) 2 C C 4 alkyl and -OH;
  • aryl is optionally substituted with one or more groups selected from halogen, C Calkoxy, CrC haloalkoxy, CrC haloalkyl and C C alkyl;
  • aryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, C C haloalkoxy, CrC haloalkyl and C C alkyl;
  • cycloalkyl is optionally substituted with one or more groups selected from halogen, Ci-Calkoxy, C C haloalkoxy, CrC haloalkyl and C C 4 alkyl;
  • cycloalkenyl optionally substituted with one or more groups selected from halogen, C Calkoxy, CrC haloalkoxy, CrC haloalkyl and C C alkyl;
  • heterocyclyl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more groups selected from halogen, C Calkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, -S(0) 2 CrCalkyl and -OH, and said heterocyclyl may contain one unsaturated bond;
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more groups selected from halogen, C Calkoxy, Ci-C haloalkoxy, Ci-C haloalkyl, Ci-C alkyl, nitrile, -S(0) 2 Ci-Calkyl and -OH;
  • R is selected from group consisting of
  • -CrCealkyl optionally substituted with one or more groups selected from halogen, Ci- C alkoxy, -CN, -OH and a 5-6 membered heterocyclyl containing one or two heteroatoms selected from N, O and S as ring members and optionally substituted with up to two halo, oxo or C1-C3 alkyl;
  • -C 2 -C alkynyl optionally substituted with one or more groups selected from halogen, C C 4 alkoxy, -CN and -OH;
  • cycloalkyl optionally substituted with one or more groups selected from halogen, C C alkyl, -Ci-C alkylCrC alkoxy, C C alkoxy, CrC haloalkyl, nitrile, -S(0) 2 C C 4 alkyl, -OH, and C1-C3 alkyl substituted with a group selected from CN, OH, -S0 2 R', - NHC(0)R', and a 5-6 membered heterocyclyl containing one or two heteroatoms selected from N, O and S as ring members and optionally substituted with up to two halo, oxo or R', and wherein R' is C1-C3 alkyl;
  • aryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl and C C alkyl;
  • aryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, C C haloalkoxy, CrC haloalkyl and C C alkyl;
  • heterocyclyl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, -S(0) 2 C C alkyl and -OH;
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, -S(0) 2 CrC alkyl and -OH;
  • R 2 and R 3 taken together form a 4 to 7 membered heteroaryl containing 1 to 3 heteroatoms selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, CrC haloalkoxy, Ci-C haloalkyl and C C 4 alkyl.
  • the invention provides a method of inhibiting a deacetylase enzyme in Gram-negative bacteria, thereby affecting bacterial growth, comprising administering to a patient in need of such inhibition a compound of formula I.
  • the invention provides a method of inhibiting LpxC, thereby modulating the virulence of a bacterial infection, comprising administering to a patient in need of such inhibition a compound of formula I.
  • the invention provides a method for treating a subject with a Gram-negative bacterial infection, which comprises administering to the subject in need thereof an antibacterial effective amount of a compound of formula I with a pharmaceutically acceptable carrier.
  • the subject is a mammal and in some other embodiments, the subject is a human.
  • the invention provides a method of administering an inhibitory amount of a compound of formula I to fermentative or non-fermentative Gram-negative bacteria.
  • the Gram-negative bacteria are selected from the group consisting of Pseudomonas aeruginosa and other Pseudomonas species, Stenotrophomonas maltophilia, Burkholderia cepacia and other Burkholderia species, Alcaligenes xylosoxidans, species of Acinetobacter, Enterobacteriaceae, Haemophilus, Moraxella, Bacteroides, Fransicella, Shigella, Proteus, Vibrio, Salmonella, Bordetella, Helicobactor, Legionella, Citrobactor, Serratia,
  • Campylobactor, Yersinia and Neisseria Campylobactor, Yersinia and Neisseria.
  • the invention provides a method of administering an inhibitory amount of a compound of formula I to Gram-negative bacteria, such as
  • Enterobacteriaceae which is selected from the group consisting of organisms such as Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Providencia,
  • Another embodiment of the invention provides a pharmaceutical composition comprising an effective amount of a compound of Formula I with a pharmaceutically acceptable carrier thereof.
  • compositions according to the present invention are provided which include any of the compounds described above and a pharmaceutically acceptable carrier.
  • LpxC is an abbreviation that stands for UDP-3-0-(R-3-hydroxydecan- oyl)-N- acetylglucosamine deacetylase.
  • the term "subject" refers to an animal.
  • the animal is a mammal.
  • a subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
  • primates e.g., humans
  • the subject is a human.
  • the term “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • treating refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • treating refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • treating or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • antibacterial agent refers to agents synthesized or modified in the laboratory that have either bactericidal or bacteriostatic activity.
  • An "active” agent in this context will inhibit the growth of P. aeruginosa and / or other Gram-negative bacteria.
  • the term “inhibiting the growth” indicates that the rate of increase in the numbers of a population of a particular bacterium is reduced. Thus, the term includes situations in which the bacterial population increases but at a reduced rate, as well as situations where the growth of the population is stopped, as well as situations where the numbers of the bacteria in the population are reduced or the population even eliminated. If an enzyme activity assay is used to screen for inhibitors, one can make modifications in bacterial uptake/efflux, solubility, half-life, etc. to compounds in order to correlate enzyme inhibition with growth inhibition.
  • Optionally substituted means the group referred to can be substituted at one or more positions by any one or any combination of the radicals listed thereafter.
  • Halo or "halogen”, as used herein, may be fluorine, chlorine, bromine or iodine.
  • CrC 4 -Alkyl denotes straight chain or branched alkyl having 1-4 carbon atoms. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly, such as "CrC 4 -Alkyl” will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • CrC 4 -Alkoxy denotes straight chain or branched alkoxy having 1-4 carbon atoms. If a different number of carbon atoms is specified, such as Ce or C3, then the definition is to be amended accordingly, such as "CrC 4 -Alkoxy” will represent methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • CrC -Haloalkyl denotes straight chain or branched alkyl having 1- 4 carbon atoms with at least one hydrogen substituted with a halogen. If a different number of carbon atoms is specified, such as C 6 or C 3 , then the definition is to be amended accordingly, such as "Ci-C 4 -Haloalkyl” will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl that have at least one hydrogen substituted with halogen, such as where the halogen is fluorine: CF 3 CF 2 -, (CF 3 ) 2 CH-, CH 3 -CF 2 -, CF 3 CF 2 -, CF 3 , CF 2 H-, CF 3 CF 2 CHCF 3 or CF 3 CF 2 CF 2 CF 2 -.
  • C 3 -C 7 -cycloalkyl refers to a saturated monocyclic hydrocarbon ring of 3 to 7 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. If a different number of carbon atoms is specified, such as C 3 -C 6 , then the definition is to be amended accordingly.
  • heterocyclyl and "5- to 14-membered heterocyclyl”, refers, respectively, to 4- to 8- membered, 5- to 6-membered, 3- to 10-membered, 3- to 14-membered, 4- to 14-membered and 5- to 14-membered heterocyclic rings containing 1 to 7, 1 to 5 or 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulphur, which may be saturated, or partially saturated.
  • the heterocyclic group can be attached at a heteroatom or a carbon atom.
  • heterocyclyl includes single ring groups, fused ring groups and bridged groups.
  • heterocyclyl examples include, but are not limited to pyrrolidine, piperidine, piperazine, pyrrolidine, pyrrolidinone, morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydrothiopyran, tetrahydropyran, 1 ,4-dioxane, 1 ,4-oxathiane, 8-aza- bicyclo[3.2.1 ]octane, 3,8-diazabicyclo[3.2.1 ]octane, 3-Oxa-8-aza-bicyclo[3.2.1 ]octane, 8- Oxa-3-aza-bicyclo[3.2.1 ]octane, 2-Oxa-5-aza-bicyclo[2.2.1 ]heptane, 2,5-Diaza- bicyclo[2.2.1 ]heptane, azetidine, ethylenedioxo, oxtane or thiazole.
  • Heteroaryl is a completely unsaturated (aromatic) ring.
  • the term “heteroaryl” refers to a 5-14 membered monocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to 8 heteroatoms selected from N, O or S.
  • the heteroaryl is a 5-10 membered ring system (e.g., 5-7 membered monocycle or an 8-10 membered bicycle) or a 5-7 membered ring system.
  • Typical heteroaryl groups include furan, isotriazole, thiadiazole, oxadiazole, indazole, indazole, indole, quinoline, 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5- imidazolyl, 3-, 4-, or 5- pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5- oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-(1 ,2,4-triazolyl), 4- or 5-(1 ,2, 3-triazolyl), tetrazolyl, triazine, pyrimidine, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl.
  • hydroxy or "hydroxyl” includes groups with an -OH.
  • the invention provides compounds of Formula (I) as described in the following embodiments, including pharmaceutical salts of these compounds, pharmaceutical compositions and combinations containing these compounds and salts, and methods of using these compounds and compositions to inhibit growth of certain bacteria and to treat infections caused by such bacteria.
  • Particular embodiments of the invention include these:
  • X is N or C, wherein when X is N, R 4 is absent;
  • Y is N or C, wherein when Y is N, R 5 is absent;
  • R 1 , R 2 , R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, -CH 3 , and -Cihaloalkyl;
  • R 3 is L-R
  • L is a divalent bond, or -CH 2 -;
  • R is selected from group consisting of
  • -CrC 4 alkyl optionally substituted with one or more groups selected from halogen, d- C 4 alkoxy, -CN and -OH;
  • -CrC 4 alkoxy optionally substituted with one or more groups selected from halogen, C C 4 alkoxy, -CN and -OH;
  • -S-CrC alkyl wherein the alkyl is optionally substituted with one or more groups selected from halogen, C C alkoxy, -CN and -OH;
  • -C2-Cealkynyl optionally substituted with one or more groups selected from halogen, C C 4 alkoxy, -CN and -OH;
  • -C 3 -C 7 cycloalkyl optionally substituted with one or more groups selected from halogen, CrC 4 alkyl, -Ci-C4alkylCrC 4 alkoxy, CrC 4 alkoxy, CrC 4 haloalkyl, nitrile, -S(0) 2 C C 4 alkyl and -OH;
  • aryl is optionally substituted with one or more groups selected from halogen, C Calkoxy, CrC haloalkoxy, CrC haloalkyl and C C alkyl;
  • aryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, C C haloalkoxy, CrC haloalkyl and C C alkyl;
  • cycloalkyl is optionally substituted with one or more groups selected from halogen, Ci-Calkoxy, C C haloalkoxy, CrC haloalkyl and C1-C4 alkyl;
  • -Cs-Cecycloalkenyl optionally substituted with one or more groups selected from halogen, C Calkoxy, CrC haloalkoxy, Ci-C haloalkyl and C C alkyl;
  • heterocyclyl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more groups selected from halogen, C Calkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, -S(0) 2 CrCalkyl and -OH, and said heterocyclyl may contain one unsaturated bond;
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more groups selected from halogen, C C 4 alkoxy, CrC 4 haloalkoxy, CrC 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 C C 4 alkyl and -OH;
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more groups selected from halogen, C Calkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, - S(0) 2 C C 4 alkyl and -OH; or
  • R is selected from group consisting of
  • -CrC 6 alkyl optionally substituted with one or more groups selected from halogen, d- C4alkoxy, -CN, -OH and a 5-6 membered heterocyclyl containing one or two heteroatoms selected from N, O and S as ring members and optionally substituted with up to two halo, oxo or C1-C3 alkyl;
  • -C 2 -Cealkenyl optionally substituted with one or more groups selected from halogen, - CN, -OH and C C 4 alkoxy;
  • -C 2 -C 4 alkynyl optionally substituted with one or more groups selected from halogen, C C 4 alkoxy, -CN and -OH;
  • cycloalkyl optionally substituted with one or more groups selected from halogen, C C alkyl, -Ci-C alkylCrC alkoxy, C C alkoxy, CrC haloalkyl, nitrile, -S(0) 2 C C alkyl, -OH, and C C 3 alkyl substituted with a group selected from CN, OH, -S0 2 R', - NHC(0)R', and a 5-6 membered heterocyclyl containing one or two heteroatoms selected from N, O and S as ring members and optionally substituted with up to two halo, oxo or R', and wherein R' is C1-C3 alkyl;
  • aryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl and C C alkyl;
  • aryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, C C haloalkoxy, CrC haloalkyl and C C alkyl;
  • heterocyclyl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more groups selected from halogen, C C 4 alkoxy, CrC 4 haloalkoxy, CrC 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 C C 4 alkyl and -OH;
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more groups selected from halogen, CrC 4 alkoxy, CrC 4 haloalkoxy, CrC 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 CrC alkyl and -OH;
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, - S(0) 2 C C 4 alkyl and -OH; or
  • R 2 and R 3 taken together form a 4 to 7 membered heteroaryl containing 1 to 3 heteroatoms selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, CrC haloalkoxy, Ci-C haloalkyl and C C 4 alkyl.
  • alkyl, alkenyl, alkynyl, cycloalkyi, aryl, heteroaryl, heterocyclyl, or cycloalkenyl that is described as optionally substituted with one or more groups may be unsubstituted, or it may be substituted with one or more of the designated groups, up to the number of hydrogen atoms on the unsusbstituted alkyl, alkenyl, alkynyl, cycloalkyi, aryl, heteroaryl, heterocyclyl, or cycloalkenyl.
  • the alkyl, alkenyl, alkynyl, cycloalkyi, aryl, heteroaryl, heterocyclyl, or cycloalkenyl is substituted with one, two or three of the designated groups, unless otherwise specified.
  • R is -C 3 - C 7 cycloalkyl optionally substituted with one to three groups selected from halogen, -OH, d- C alkyl, -Ci-C alkylCrC alkoxy, CrC alkoxy, CrC haloalkyl, nitrile, and -S(0) 2 CrC alkyl.
  • R is phenyl optionally substituted with one or more groups selected from halogen, d-C 4 alkoxy, CrC 4 haloalkoxy, CrC 4 haloalkyl and C1-C4 alkyl.
  • phenyl is unsubstituted or substituted with up to three groups selected from F, CI, Br, CrC 4 alkoxy, CrC 4 haloalkoxy, CrC haloalkyl and C C alkyl.
  • X is N or C, wherein when X is N, R 4 is absent;
  • Y is N or C, wherein when Y is N, R 5 is absent;
  • R 1 , R 2 , R 4 or R 5 are independently selected from the group consisting of hydrogen, halogen, -CH 3 , and -Cihaloalkyl;
  • R 3 is L-R
  • L is a divalent bond, or -CH 2 -;
  • R is selected from group consisting of
  • -CrC alkyl optionally substituted with halogen, C C alkoxy, -CN or -OH,
  • heterocyclyl is optionally substituted with one or more halogen, C C alkoxy,
  • heterocyclyl is optionally substituted with one or more halogen, Ci-C alkoxy, C C haloalkoxy, CrC haloalkyl, Ci-C alkyl, nitrile, -S(0) 2 Cr C 4 alkyl or -OH, 5 to 10 membered heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more halogen, d-C 4 alkoxy, C C 4 haloalkoxy, C C 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 CrC 4 alkyl or -OH,
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more halogen, C C 4 alkoxy, C C 4 haloalkoxy, C C 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH; or '
  • R is selected from group consisting of
  • -CrC 4 alkyl optionally substituted with halogen, Ci-C 4 alkoxy, -CN or -OH,
  • heterocyclyl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, C C alkoxy, CrC 4 haloalkoxy, Ci-C 4 haloalkyl, d-C 4 alkyl, nitrile, -S(0) 2 Ci-C 4 alkyl or -OH,
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O
  • said heteroaryl is optionally substituted with one or more halogen, Ci-C alkoxy, C C 4 haloalkoxy, C C 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH, -CrC 4 alkyl-5 to 10 membered heteroaryl containing 1 to 3 heteroatom selected from N, S, and O
  • said heteroaryl is optionally substituted with one or more halogen, d- C 4 alkoxy, CrC 4 haloalkoxy, CrC 4 haloalkyl, C C alkyl, nitrile, -S(0) 2 CrC alkyl or -OH, and
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more halogen, C C 4 alkoxy, C C 4 haloalkoxy, C C 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH; or
  • R 2 and R 3 taken together form a 4 to 7 membered heteroaryl containing 1 to 3 heteroatoms selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, Ci-C alkoxy, C C haloalkoxy, Ci-C haloalkyl or C C alkyl.
  • the compound or a pharmaceutically acceptable salt is represented by formulae I or II of any of the preceding embodiments, wherein
  • X is N or C, wherein when X is N, R 4 is absent;
  • Y is N or C, wherein when Y is N, R 5 is absent;
  • R 1 , R 2 , R 4 or R 5 are independently selected from the group consisting of hydrogen, halogen, -CH 3 , and Cihaloalkyl;
  • R 3 is L-R
  • L is a divalent bond, or -CH 2 -;
  • R is selected from group consisting of
  • -CrC alkyl optionally substituted with halogen, C C alkoxy, -CN or -OH,
  • cycloalkyl optionally substituted with halogen, d-C 4 alkyl, -CrC alkylCr C 4 alkoxy, C C 4 alkoxy, C C 4 haloalkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH,
  • aryl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl,
  • heterocyclyl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, C C alkoxy, C C 4 haloalkoxy, C C 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH,
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more halogen, Ci-C alkoxy, C C 4 haloalkoxy, C C 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH,
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more halogen, C C 4 alkoxy, C C 4 haloalkoxy, C C 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH; or '
  • R is selected from group consisting of
  • -CrC alkyl optionally substituted with halogen, C C alkoxy, -CN or -OH,
  • cycloalkyl optionally substituted with halogen, CrC 4 alkyl, -Ci-C 4 alkylCr C 4 alkoxy, C C 4 alkoxy, C C 4 haloalkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH, -C 6 -Ci 0 aryl, wherein the aryl is optionally substituted with one or more halogen, C C 4 alkoxy, CrC 4 haloalkoxy, CrC 4 haloalkyl or C1-C4 alkyl,
  • heterocyclyl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, C C alkoxy, C C 4 haloalkoxy, C C 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH,
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more halogen, Ci-C alkoxy, C C 4 haloalkoxy, C C 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH,
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more halogen, C C 4 alkoxy, C C 4 haloalkoxy, C C 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH; or
  • R 2 and R 3 taken together form a 4 to 7 membered heteroaryl containing 1 to 3 heteroatoms selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, Ci-C alkoxy, C C haloalkoxy, Ci-C haloalkyl or C C alkyl.
  • the compound or a pharmaceutically acceptable salt is represented by formula I or II according to any of the preceding embodiments, wherein:
  • X is N or C, wherein when X is N, R 4 is absent;
  • Y is N or C, wherein when Y is N, R 5 is absent;
  • R 1 , R 2 , R 4 or R 5 are independently selected from the group consisting of hydrogen, halogen, -CH 3 , and Cihaloalkyl;
  • R 3 is L-R; L is a divalent bond, or -CH 2 -;
  • R is selected from group consisting of
  • -CrC 4 alkyl optionally substituted with halogen, CrC 4 alkoxy, -CN or -OH,
  • heterocyclyl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, C C alkoxy, C C 4 haloalkoxy, C C 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH,
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more halogen, C C alkoxy, C C 4 haloalkoxy, C C 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH,
  • R 2 and R 3 taken together form a 4 to 7 membered heteroaryl containing 1 to 3 heteroatoms selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, d-C 4 alkoxy, CrC 4 haloalkoxy, CrC 4 haloalkyl or C C 4 alkyl.
  • the compound or a pharmaceutically acceptable salt is any of the preceding embodiments where the compound is represented by formula III:
  • X is N or C, wherein when X is N, R 4 is absent;
  • Y is N or C, wherein when Y is N, R 5 is absent;
  • R 1 , R 2 , R 4 or R 5 are independently selected from the group consisting of hydrogen, halogen, -CH 3 , and Cihaloalkyl;
  • R is selected from group consisting of
  • -CrC alkyl optionally substituted with halogen, C C alkoxy, -CN or -OH,
  • heterocyclyl is optionally substituted with one or more halogen, CrC 4 alkoxy,
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more halogen, d-C 4 alkoxy, C C 4 haloalkoxy, C C 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH,
  • R 2 and R 3 taken together form a 4 to 7 membered heteroaryl containing 1 to 3 heteroatoms selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, Ci-C alkoxy, C C haloalkoxy, Ci-C haloalkyl or C C alkyl.
  • Y is N or C, wherein when Y is N, R 5 is absent;
  • R 1 , R 2 , R 4 or R 5 are independently selected from the group consisting of hydrogen, halogen, -CH 3 , and Cihaloalkyl;
  • R is selected from group consisting of
  • -CrC alkyl optionally substituted with halogen, C C alkoxy, -CN or -OH,
  • cycloalkyl optionally substituted with halogen, Ci-C alkyl, -CrC alkylCr C 4 alkoxy, C C 4 alkoxy, C C 4 haloalkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH,
  • aryl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl,
  • heterocyclyl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, CrC 4 alkoxy, C C 4 haloalkoxy, C C 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH,
  • -CrC alkyl-4 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, S, and O wherein said heterocyclyl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, -S(0) 2 C C alkyl or -OH, -C 3 -C 5 cycloalkyl-4 to 7 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, d-C 4 alkoxy, CrC 4 haloalkoxy, CrC 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 Cr C 4 alkyl or -OH,
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, Ci-C haloalkyl or C C alkyl, and
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more halogen, d- C alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl.
  • the compound or a pharmaceutically acceptable salt is represented by formula III as described above, wherein:
  • R 1 , R 2 , R 4 or R 5 are independently selected from the group consisting of hydrogen and halogen
  • R is selected from group consisting of
  • -C C alkyl optionally substituted with halogen, C C alkoxy, -CN or -OH,
  • cycloalkyl optionally substituted with halogen, Ci-C alkyl, -CrC alkylCr C 4 alkoxy, C C 4 alkoxy, C C 4 haloalkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH,
  • aryl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl,
  • heterocyclyl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, C C alkoxy, C C 4 haloalkoxy, C C 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH,
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more halogen, d-C 4 alkoxy, CrC 4 haloalkoxy, CrC 4 haloalkyl or CrC 4 alkyl, and
  • heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heteroaryl is optionally substituted with one or more halogen, d- C alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl.
  • R 1 , R 2 , R 4 or R 5 are independently selected from the group consisting of hydrogen and halogen;
  • R is -CrC alkyl optionally substituted with halogen, C C alkoxy, -CN or -OH.
  • the compound or a pharmaceutically acceptable salt thereof is any of the preceding embodiments represented by formula III above, wherein:
  • R 1 , R 2 , R 4 or R 5 are independently selected from the group consisting of hydrogen and halogen;
  • R is -C 3 -C 7 cycloalkyl optionally substituted with halogen, C C alkyl, -CrC alkylCr C 4 alkoxy, C C 4 alkoxy, C C 4 haloalkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH.
  • R 1 , R 2 , R 4 or R 5 are independently selected from the group consisting of hydrogen and fluorine;
  • R is -C 3 -C 7 cycloalkyl optionally substituted with halogen, C C alkyl, -CrC alkylCr C 4 alkoxy, Ci-C 4 alkoxy, C C 4 haloalkyl, nitrile, -S(0) 2 C C 4 alkyl or -OH.
  • the compound or a pharmaceutically acceptable salt thereof is any of the preceding embodiments represented by formula III, wherein:
  • X is C
  • Y is C
  • R 1 , R 2 , R 4 or R 5 are independently selected from the group consisting of hydrogen and halogen;
  • R is selected from group consisting of
  • heterocyclyl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, C C 4 alkoxy, C C 4 haloalkoxy, C C 4 haloalkyl, C C 4 alkyl, nitrile, -S(0) 2 CrC 4 alkyl or -OH,
  • the compound or a pharmaceutically acceptable salt thereof is any of the preceding embodiments represented by formula III, wherein:
  • R 1 , R 2 , R 4 or R 5 are independently selected from the group consisting of hydrogen, halogen, -CH 3 , and Cihaloalkyl;
  • R is selected from group consisting of
  • Y is N or C, wherein when Y is N, R 5 is absent;
  • R 1 , R 2 , R 4 or R 5 are independently selected from the group consisting of hydrogen, halogen, -CH 3 , and Cihaloalkyl;
  • L is a divalent bond
  • R is selected from group consisting of
  • R 1 , R 2 , R 4 or R 5 are independently selected from the group consisting of hydrogen, halogen, -CH 3 and Cihaloalkyl;
  • R 3 is L-R
  • L is a divalent bond, or -CH 2 -;
  • R is halogen
  • -CrC 4 alkyl optionally substituted with halogen, CrC 4 alkoxy, -CN or -OH,
  • R 2 and R 3 taken together form a 4 to 7 membered heteroaryl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, Ci-C alkoxy, C C haloalkoxy, Ci-C haloalkyl or C C alkyl.
  • the compound is selected from:
  • a compound or pharmaceutically acceptable salt according to any of the above embodiments is combined with a pharmaceutically acceptable carrier to provide a pharmaceutical composition.
  • a compound or pharmaceutically acceptable salt according to any of the above embodiments is used in combination with a second therapeutic agent. Suitable therapeutic agents for use in such combinations, including immunomodulators, are disclosed herein.
  • a compound (including pharmaceutically acceptable salts) or pharmaceutical composition according to any of the embodiments above can be used in a method to treat a bacterial infection.
  • the infection is caused by a Gram-negative bacterium.
  • the method comprises administering such compound to a subject in need of treatment for a Gram-negative bacterial infection, generally in an amount sufficient to treat the infection.
  • the bacterial infection can suitably be caused by a bacterium selected from the group consisting of Pseudomonas aeruginosa and other Pseudomonas species, Stenotrophomonas maltophilia, Burkholderia cepacia and other Burkholderia species, Alcaligenes xylosoxidans, species of Acinetobacter, Enterobacteriaceae, Haemophilus, Moraxella, Bacteroides, Fransicella, Shigella, Proteus, Vibrio, Salmonella, Bordetella, Helicobactor, Legionella, Citrobactor, Serratia, Campylobactor, Yersinia and Neisseria.
  • a bacterium selected from the group consisting of Pseudomonas aeruginosa and other Pseudomonas species, Stenotrophomonas maltophilia, Burkholderia cepacia and other Burkholderia
  • the compounds and compositions described herein, including any of the particular embodiments of Formula (I), (III) or (III) described above, can be used or administered in combination with one or more therapeutic agents that act as immunomodulators, e.g., an activator of a costimulatory molecule, or an inhibitor of an immune-inhibitory molecule, or a vaccine.
  • the Programmed Death 1 (PD-1 ) protein is an inhibitory member of the extended CD28/CTLA4 family of T cell regulators (Okazaki et al. (2002) Curr Opin Immunol 14:
  • PD-1 is expressed on activated B cells, T cells, and monocytes.
  • PD-1 is an immune-inhibitory protein that negatively regulates TCR signals (Ishida, Y. ef al. (1992) EMBO J. 1 1 :3887-3895; Blank, C. ef al. (Epub 2006 Dec. 29) Immunol. Immunother. 56(5):739-745), and is up-regulated in chronic infections.
  • the interaction between PD-1 and PD-L1 can act as an immune checkpoint, which can lead to, e.g., a decrease in infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and/or immune evasion by cancerous or infected cells (Dong et al. (2003) J. Mol. Med. 81 :281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100).
  • Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2; the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99:12293-7; Brown et al. (2003) J Immunol. 170:1257-66).
  • Immunomodulation can be achieved by binding to either the immune-inhibitory protein (e.g., PD-1 ) or to binding proteins that modulate the inhibitory protein (e.g., PD-L1 , PD-L2).
  • the combination therapies of the invention include an immunomodulator that is an inhibitor or antagonist of an inhibitory molecule of an immune checkpoint molecule.
  • the immunomodulator binds to a protein that naturally inhibits the immuno-inhibitory checkpoint molecule.
  • these immunomodulators can enhance the antimicrobial response, and thus enhance efficacy relative to treatment with the antibacterial compound alone.
  • Immune checkpoints refers to a group of molecules on the cell surface of CD4 and CD8 T cells. These molecules can effectively serve as “brakes” to down-modulate or inhibit an adaptive immune response. Immune checkpoint molecules include, but are not limited to, Programmed Death 1 (PD-1 ), Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), B7H1 , B7H4, OX-40, CD137, CD40, and LAG 3, which directly inhibit immune cells.
  • PD-1 Programmed Death 1
  • CTL-4 Cytotoxic T-Lymphocyte Antigen 4
  • B7H1 B7H4, OX-40
  • CD137 CD40
  • LAG 3 which directly inhibit immune cells.
  • Immunotherapeutic agents which can act as immune checkpoint inhibitors useful in the methods of the present invention, include, but are not limited to, inhibitors of PD-L1 , PD-L2, CTLA4, TIM3, LAG 3, VISTA, BTLA, TIGIT, LAIR1 , CD160, 2B4 and/or TGFR
  • Inhibition of an inhibitory molecule can be performed by inhibition at the DNA, RNA or protein level.
  • an inhibitory nucleic acid e.g., a dsRNA, siRNA or shRNA
  • the inhibitor of an inhibitory signal is a polypeptide, e.g., a soluble ligand, or an antibody or antigen-binding fragment thereof, that binds to the inhibitory molecule.
  • immunomodulator can be administered concurrently with, prior to, or subsequent to, one or more compounds of the invention, and optionally one or more additional therapies or therapeutic agents.
  • the therapeutic agents in the combination can be administered in any order. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. It will further be appreciated that the therapeutic agents utilized in this combination may be administered together in a single composition or administered separately in different compositions. In general, it is expected that each of the therapeutic agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • the antibacterial compounds described herein are administered in combination with one or more immunomodulators that are inhibitors of PD-1 , PD-L1 and/or PD-L2.
  • Each such inhibitor may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or an oligopeptide. Examples of such immunomodulators are known in the art.
  • the immunomodulator is an anti-PD-1 antibody chosen from MDX-1 106, Merck 3475 or CT- 01 1 .
  • the immunomodulator is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-LI or PD-L2 fused to a constant region (e.g. , an Fc region of an immunoglobulin sequence).
  • an immunoadhesin e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-LI or PD-L2 fused to a constant region (e.g. , an Fc region of an immunoglobulin sequence).
  • the immunomodulator is a PD-1 inhibitor such as AMP-224.
  • the immunomodulator is a PD-LI inhibitor such as anti- PD-LI antibody.
  • the immunomodulator is an anti-PD-LI binding antagonist chosen from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1 105.
  • MDX-1 105 also known as BMS-936559, is an anti-PD-LI antibody described in
  • Antibody YW243.55.S70 is an anti-PD-LI described in WO 2010/077634.
  • the immunomodulator is nivolumab (CAS Registry Number: 946414-94-4).
  • Alternative names for nivolumab include MDX-1 106, MDX-1 106-04, ONO- 4538, or BMS-936558.
  • Nivolumab is a fully human lgG4 monoclonal antibody which specifically blocks PD-1 .
  • Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD-1 are disclosed in US 8,008,449, EP2161336 and
  • the immunomodulator is an anti-PD-1 antibody
  • Pembrolizumab is a humanized lgG4 monoclonal antibody that binds to PD-1 .
  • Pembrolizumab and other humanized anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, US 8,354,509,
  • the immunomodulator is Pidilizumab (CT-01 1 ; Cure Tech), a humanized lgG1 k monoclonal antibody that binds to PD1 .
  • Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in WO2009/10161 1 .
  • anti-PD1 antibodies useful as immunomodulators for use in the methods disclosed herein include AMP 514 (Amplimmune), and anti-PD1 antibodies disclosed in US 8,609,089, US 2010028330, and/or US 201201 14649.
  • the anti-PD- L1 antibody is MSB0010718C.
  • MSB0010718C also referred to as A09-246-2; Merck Serono
  • the immunomodulator is MDPL3280A (Genentech / Roche), a human Fc optimized lgG1 monoclonal antibody that binds to PD-L1 .
  • MDPL3280A and other human monoclonal antibodies to PD-L1 are disclosed in U.S. Patent No.: 7,943,743 and U.S Publication No. : 20120039906.
  • Other anti-PD-L1 binding agents useful as immunomodulators for methods of the invention include YW243.55.S70 (see
  • WO2010/077634 MDX-1 105 (also referred to as BMS-936559), and anti-PD-L1 binding agents disclosed in WO2007/005874.
  • the immunomodulator is AMP-224 (B7-DCIg; Amplimmune; e.g., disclosed in WO2010/027827 and WO201 1/066342), is a PD-L2 Fc fusion soluble receptor that blocks the interaction between PD1 and B7-H1 .
  • the immunomodulator is an anti-LAG-3 antibody such as BMS-986016.
  • BMS-986016 (also referred to as BMS986016) is a monoclonal antibody that binds to LAG-3.
  • BMS-986016 and other humanized anti-LAG-3 antibodies are disclosed in US 201 1/0150892, WO2010/019570, and WO2014/008218
  • the combination therapies disclosed herein include a modulator of a costimulatory molecule or an inhibitory molecule, e.g., a co-inhibitory ligand or receptor.
  • the costimulatory modulator, e.g., agonist, of a costimulatory molecule is chosen from an agonist (e.g., an agonistic antibody or antigen-binding fragment thereof, or soluble fusion) of OX40, CD2, CD27, CDS, ICAM-1 , LFA-1 (CD1 1 a/CD18), ICOS (CD278), 4-1 BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or CD83 ligand.
  • an agonist e.g., an agonistic antibody or antigen-binding fragment thereof, or soluble fusion
  • OX40 e.g., CD2, CD27, CDS, ICAM-1 , LFA-1 (CD1 1 a/CD18), ICOS (CD278), 4-1 BB (CD137), GITR, CD30, CD40, BAF
  • the combination therapies disclosed herein include an immunomodulator that is a costimulatory molecule, e.g., an agonist associated with a positive signal that includes a costimulatory domain of CD28, CD27, ICOS and/or GITR.
  • an immunomodulator that is a costimulatory molecule, e.g., an agonist associated with a positive signal that includes a costimulatory domain of CD28, CD27, ICOS and/or GITR.
  • Exemplary GITR agonists include, e.g., GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as, a GITR fusion protein described in U.S. Patent No.: 6, 1 1 1 ,090, European Patent No.: 090505B1 , U.S Patent No.: 8,586,023, PCT Publication Nos.: WO 2010/0031 18 and 201 1/090754, or an anti-GITR antibody described, e.g., in U.S. Patent No. : 7,025,962, European Patent No.: 1947183B1 , U.S. Patent No.: 7,812, 135, U.S. Patent No.: 8,388,967, U.S.
  • anti-GITR antibodies e.g., bivalent anti-GITR antibodies
  • the immunomodulator used is a soluble ligand (e.g., a CTLA-4- Ig), or an antibody or antibody fragment that binds to PD-L1 , PD-L2 or CTLA4.
  • a soluble ligand e.g., a CTLA-4- Ig
  • the anti-PD-1 antibody molecule can be administered in combination with an anti-CTLA-4 antibody, e.g., ipilimumab, for example.
  • anti-CTLA4 antibodies include
  • Tremelimumab (lgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206); and Ipilimumab (CTLA-4 antibody, also known as MDX-010, CAS No. 477202-00-9).
  • an anti-PD-1 antibody molecule is administered after treatment with a compound of the invention as described herein.
  • an anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-LAG-3 antibody or an antigen-binding fragment thereof.
  • the anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-TIM-3 antibody or antigen-binding fragment thereof.
  • the anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-LAG-3 antibody and an anti-TIM-3 antibody, or antigen-binding fragments thereof.
  • the combination of antibodies recited herein can be administered separately, e.g., as separate antibodies, or linked, e.g., as a bispecific or trispecific antibody molecule.
  • a bispecific antibody that includes an anti-PD-1 or PD-L1 antibody molecule and an anti-TIM-3 or anti- LAG-3 antibody, or antigen-binding fragment thereof is administered.
  • the combination of antibodies recited herein is used to treat a cancer, e.g., a cancer as described herein (e.g., a solid tumor).
  • a cancer e.g., a cancer as described herein (e.g., a solid tumor).
  • the efficacy of the aforesaid combinations can be tested in animal models known in the art. For example, the animal models to test the synergistic effect of anti-PD-1 and anti-LAG-3 are described, e.g., in Woo et al. (2012) Cancer Res. 72(4):917-27).
  • immunomodulators that can be used in the combination therapies include, but are not limited to, e.g., afutuzumab (available from Roche®); pegfilgrastim (Neulasta®); lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®), actimid
  • cytokines e.g., IL-21 or IRX-2 (mixture of human cytokines including interleukin 1 , interleukin 2, and interferon ⁇ , CAS 951209-71-5, available from IRX
  • Exemplary doses of such immunomodulators that can be used in combination with the antibacterial compounds of the invention include a dose of anti-PD-1 antibody molecule of about 1 to 10 mg/kg, e.g., 3 mg/kg, and a dose of an anti-CTLA-4 antibody, e.g., ipilimumab, of about 3 mg/kg.
  • a method to treat a bacterial infection in a subject comprising administering to the subject a compound of Formula (I) as described herein, and an immunomodulator.
  • the activator of the costimulatory molecule is an agonist of one or more of OX40, CD2, CD27, CDS, ICAM-1 , LFA-1 (CD1 1 a/CD18), ICOS (CD278), 4-1 BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 and CD83 ligand.
  • inhibitor of the immune checkpoint molecule is chosen from PD-1 , PD-L1 , PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1 , CD160, 2B4 and TGFR beta.
  • inhibitor of the immune checkpoint molecule is chosen from an inhibitor of PD-1 , PD-L1 , LAG-3, TIM-3 or CTLA4, or any combination thereof.
  • the antibody molecule is a bispecific or multispecific antibody molecule that has a first binding specificity to PD-1 or PD- L1 and a second binding specifity to TIM-3, LAG-3, or PD-L2.
  • the immunomodulator is an anti-PD-1 antibody chosen from Nivolumab, Pembrolizumab or Pidilizumab.
  • the immunomodulator is an anti-PD-L1 antibody chosen from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-
  • intravenously at a dose of about 1 to 30 mg/kg, e.g., about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg, or about 3 mg/kg., e.g., once a week to once every 2, 3, or 4 weeks.
  • the anti-PD-1 antibody molecule e.g., Nivolumab
  • the anti-PD-1 antibody molecule e.g., Nivolumab
  • the compounds as defined in embodiments may be synthesized by the general synthetic routes below, specific examples of which are described in more detail in the Examples.
  • the invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure material.
  • protecting group a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention.
  • the protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J.
  • Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known to those skilled in the art.
  • salts of compounds of the present invention having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used.
  • metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid
  • organic alkali metal or alkaline earth metal compounds such as the corresponding hydroxides, carbonates or hydrogen carbonates
  • Acid addition salts of compounds of the present invention are obtained in customary manner, e.g. by treating the compounds with an acid or a suitable anion exchange reagent.
  • Internal salts of compounds of the present invention containing acid and basic salt-forming groups, e.g. a free carboxy group and a free amino group, may be formed, e.g. by the neutralisation of salts, such as acid addition salts, to the isoelectric point, e.g. with weak bases, or by treatment with ion exchangers.
  • Salts can be converted into the free compounds in accordance with methods known to those skilled in the art.
  • Metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.
  • diastereo isomers can be separated, for example, by partitioning between polyphasic solvent mixtures, recrystallisation and/or chromatographic separation, for example over silica gel or by e.g. medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, for example by means of fractional crystallisation, or by chromatography over optically active column materials.
  • Intermediates and final products can be worked up and/or purified according to standard methods, e.g. using chromatographic methods, distribution methods, (re-) crystallization, and the like.
  • mixtures of isomers that are formed can be separated into the individual isomers, for example diastereo isomers or enantiomers, or into any desired mixtures of isomers, for example racemates or mixtures of diastereo isomers, for example analogously to the methods described under "Additional process steps”.
  • solvents from which those solvents that are suitable for any particular reaction may be selected include those mentioned specifically or, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethylformamide or dimethyl acetamide, bases, such as heterocyclic nitrogen bases, for example pyridine or N-methylpyrrolidin-2- one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride,
  • the compounds of the present invention may also be obtained in the form of hydrates, or their crystals may, for example, include the solvent used for crystallization. Different crystalline forms may be present.
  • the invention relates also to those forms of the process in which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
  • an optical isomer or "a stereoisomer” refers to any of the various stereoisomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom.
  • the term “chiral” refers to molecules which have the property of non-superimposability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound.
  • Enantiomers are a pair of stereoisomers that are non- superimposable mirror images of each other.
  • a 1 : 1 mixture of a pair of enantiomers is a "racemic” mixture. The term is used to designate a racemic mixture where appropriate.
  • Diastereoisomers are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the compounds can be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as isomer mixtures, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.
  • the present invention is meant to include all such possible stereoisomers, including racemic mixtures, diasteriomeric mixtures and optically pure forms.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
  • any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
  • Racemic products can also be resolved by chiral
  • HPLC high pressure liquid chromatography
  • the compounds of the present invention can also be obtained in the form of their hydrates, or include other solvents used for their
  • solvate refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules.
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like.
  • hydrate refers to the complex where the solvent molecule is water.
  • the compounds of the present invention including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.
  • salt refers to an acid addition or base addition salt of a compound of the present invention.
  • Salts include in particular “pharmaceutically acceptable salts”.
  • pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable.
  • the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds of the present invention.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 CI, 125 l respectively.
  • the invention includes various isotopically labeled compounds of the present invention, for example those into which radioactive isotopes, such as 3 H and 14 C, or those into which non-radioactive isotopes, such as 2 H and 13 C are present.
  • isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F labeled compound of the present invention may be particularly desirable for PET or SPECT studies.
  • Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), or at least 6600 (99% deuterium incorporation).
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, de-acetone, d 6 -DMSO.
  • co-crystals may be capable of forming co-crystals with suitable co- crystal formers.
  • These co-crystals may be prepared from compounds of the present invention by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of the invention with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed.
  • Suitable co-crystal formers include those described in WO 2004/078163. Hence the invention further provides co-crystals comprising a compound of the present invention.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • deuterium substitution at non-exchangeable hydrocarbon bonds e.g., C-H
  • Isotopically-labeled compounds of the invention i.e. compounds of formula (I)
  • compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations Sections using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously.
  • the invention provides a method of inhibiting a deacetylase enzyme in a Gram-negative bacterium, the method comprising the step of contacting the Gram-negative bacteria with a compound of the invention, e.g., a compound of Formula I or salt thereof.
  • the invention provides a method for treating a subject with a Gram-negative bacterial infection, the method comprising the step of administering to the subject in need thereof an antibacterial effective amount of a compound of the invention, e.g., a compound of Formula I or salt thereof with a pharmaceutically acceptable carrier.
  • a compound of the invention e.g., a compound of Formula I or salt thereof with a pharmaceutically acceptable carrier.
  • the compounds of the invention can be used for treating conditions caused by the bacterial production of endotoxin and, in particular, by Gram-negative bacteria and bacteria that use LpxC in the biosynthesis of lipopolysaccharide (LPS) or endotoxin.
  • LPS lipopolysaccharide
  • the compounds of the invention also are useful in the treatment of patients suffering from or susceptible to pneumonia, sepsis, cystic fibrosis, wound, complicated diabetic foot or complicated urinary tract infections and sexually transmitted diseases caused by Gram- negative pathogens.
  • the compounds of the invention also are useful in the conditions that are caused or exacerbated by the bacterial production of lipid A and LPS or endotoxin, such as sepsis, septic shock, systemic inflammation, localized inflammation, chronic obstructive pulmonary disease (COPD) and acute exacerbations of chronic bronchitis (AECB).
  • treatment includes the administration of a compound of the invention, or a combination of compounds of the invention, optionally with a second agent wherein the second agent is a second antibacterial agent or a second non-antibacterial agent.
  • preferred second non-antibacterial agents include antiendotoxins including endotoxin receptor-binding antibodies, endotoxin-binding antibodies, antiCD14-binding protein antibodies antilipopolysaccharide-binding protein antibodies and tyrosine kinase inhibitors.
  • the compounds of the present invention may also be used with second non-antibacterial agents administered via inhalation.
  • Preferred non-antibacterial agents used in this treatment include antiinflammatory steroids, non-steroidal anti-inflammatory agents, bronchodilators, mucolytics, anti-asthma therapeutics and lung fluid surfactants.
  • the non-antibacterial agent may be selected from a group consisting of albuterol, salbuterol, budesonide,
  • beclomethasone dexamethasone, nedocromil, beclomethasone, fluticasone, flunisolide, triamcinolone, ibuprofen, rofecoxib, naproxen, celecoxib, nedocromil, ipratropium, metaproterenol, pirbuterol, salneterol, bronchodilators, mucolytics, calfactant, beractant, poractant alfa, surfaxin and pulmozyme (also called domase alfa).
  • the compounds of the invention can be used, alone or in combination with a second antibacterial agent for the treatment of a serious or chronic respiratory tract infection including serious lung and nosocomial infections such as those caused by Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Serratia marcescens, Stenotrophomonas maltophilia,
  • Pseudomonas aeruginosa Burkholderia cepacia, Acinetobacter baumanii, Alcaligenes xylosoxidans, Flavobacterium meningosepticum, Providencia stuartii and Citrobacter freundi, community lung infections such as those caused by Haemophilus influenzae, Legionella species, Moraxella catarrhalis, Enterobacter species, Acinetobacter species, Klebsiella species, and Proteus species, and infections caused by other bacterial species such as Neisseria species, Shigella species, Salmonella species, Helicobacter pylori, Vibrionaceae and Bordetella species as well as the infections is caused by a Brucella species, Francisella tularensis and/or Yersinia Pestis.
  • a compound of the present invention may also be used in combination with other agents, e.g., an additional antibiotic agent that is or is not of the formula I, for treatment of a bacterial infection in a subject.
  • combination is meant either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound of the present invention and a combination partner may be administered independently at the same time or separately within time intervals that especially allow that the combination partners show a cooperative, e.g., synergistic, effect, or any combination thereof.
  • the compounds of the present invention can be used to sensitize Gram-negative bacteria to the effects of a second agent.
  • An embodiment of the present invention is compounds of the present invention used in combination with a second antibacterial agent, non-limiting examples of antibacterial agents may be selected from the following groups:
  • Beta-lactams including penicillin such as penicillin G, penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, azlocillin, temocillin, cephalosporin such as cepalothin, cephapirin, cephradine, cephaloridine, cefazolin, cefamandole, cefuroxime, cephalexin, cefprozil, cefaclor, loracarbef, cefoxitin, cefinetazole, cefotaxime, ceftizoxime, ceftriaxone,
  • cefoperazone ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir, cefpirome, cefepime, and carbapenems such as carbapenem, imipenem, meropenem and PZ-601 ;
  • Quinolones such as nalidixic acid, oxolinic acid, norfloxacin, pefloxacin, enoxacin, ofloxacin, levofloxacin, ciprofloxacin, temafloxacin, lomefloxacin, fleroxacin, grepafloxacin, sparfloxacin, trovafloxacin, clinafloxacin, gatifloxacin, moxifloxacin, sitafloxacin,
  • Antibacterial sulfonamides and antibacterial sulphanilamides including para- aminobenzoic acid, sulfadiazine, sulfisoxazole, sulfamethoxazole and sulfathalidine;
  • Aminoglycosides such as streptomycin, neomycin, kanamycin, paromycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin, sisomicin, dibekalin and isepamicin;
  • Tetracyclines such as tetracycline, chlortetracycline, demeclocycline, minocycline, oxytetracycline, methacycline, doxycycline, tegacycline;
  • Rifamycins such as rifampicin (also called rifampin), rifapentine, rifabutin, bezoxazinorifamycin and rifaximin;
  • Lincosamides such as lincomycin and clindamycin
  • Glycopeptides such as vancomycin and teicoplanin
  • the second antibacterial agent may be administered in combination with the compounds of the present inventions wherein the second antibacterial agent is administered prior to, simultaneously, or after the compound or compounds of the present invention.
  • a compound of the invention may be formulated with a second agent into the same dosage form.
  • An example of a dosage form containing a compound of the invention and a second agent is a tablet or a capsule.
  • the compounds of the invention may be used alone or in combination with a second antibacterial agent administered via inhalation.
  • a preferred second antibacterial agent is selected from a group consisting of tobramycin, gentamicin, aztreonam, ciprofloxacin, polymyxin, colistin, colymycin, azithromycin and clarithromycin.
  • BLI beta-lactamase inhibitor
  • Suitable BLI's include clavulanic acid, sulbactam, tazobactam, avibactam, and various BLIs disclosed in WO2014/152996, WO2013/149136, and US2013/02813459.
  • compositions comprising a compound of Formula I, II or III as described herein, in combination with a beta-lactamase inhibitor such as those named above, and methods of using a compound of Formula I, II or III in combination with a beta- lactamase inhibitor to treat drug-resistant bacterial infections.
  • an effective amount of the compound is that amount necessary or sufficient to treat or prevent a bacterial infection and/or a disease or condition described herein.
  • an effective amount of the LpxC inhibitor is the amount sufficient to treat bacterial infection in a subject.
  • an effective amount of the LpxC inhibitor is an amount sufficient to treat a bacterial infection, such as, but not limited to Pseudomonas aeruginosa and the like in a subject.
  • the effective amount can vary depending on such factors as the size and weight of the subject, the type of illness, or the particular compound of the invention. For example, the choice of the compound of the invention can affect what constitutes an "effective amount.”
  • One of ordinary skill in the art would be able to study the factors contained herein and make the determination regarding the effective amount of the compounds of the invention without undue experimentation.
  • the regimen of administration can affect what constitutes an effective amount.
  • the compound of the invention can be administered to the subject either prior to or after the onset of a bacterial infection. Further, several divided dosages, as well as staggered dosages, can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus injection. Further, the dosages of the compound(s) of the invention can be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
  • Compounds of the invention may be used in the treatment of states, disorders or diseases as described herein, or for the manufacture of pharmaceutical compositions for use in the treatment of these diseases.
  • the invention provides methods of use of compounds of the present invention in the treatment of these diseases or pharmaceutical preparations having compounds of the present invention for the treatment of these diseases.
  • composition includes preparations suitable for administration to mammals, e.g., humans.
  • pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • phrases "pharmaceutically acceptable carrier” is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, suitable for administering compounds of the present invention to mammals.
  • the carriers include liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, - tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin,
  • Formulations of the present invention include those suitable for oral, nasal, inhalation, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as, for example, cetyl alcohol and glycerol monostea
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluent commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • various antibacterial and antifungal agents for example, paraben, chlorobutanol, phenol sorbic acid, and the like.
  • isotonic agents such as sugars, sodium chloride, and the like into the compositions.
  • prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenteral-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc., administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administration is preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • intravenous and subcutaneous doses of the compounds of this invention for a patient when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per day, and still more preferably from about 1.0 to about 100 mg per kg per day.
  • An effective amount is that amount treats a bacterial infection.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • a compound of the present invention While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical composition.
  • the compounds as defined in embodiments may be synthesized by the general synthetic routes below, specific examples of which are described in more detail in the Examples.
  • the intermediate A-4 could also be synthesis by general method described in
  • Scheme C described another general method for the synthesis of intermediate A-6.
  • Amine C-1 could be converted to C-2 using methods described in either Scheme A or Scheme B.
  • Intermediate A-6 could be prepared from compound C-2 via deprotecting PMB group and then coupling with various aryl groups.
  • protecting group a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention.
  • the protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as e.g., Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 pp. (URL: http://www.science-of-synthesis.com (Electronic Version, 48 Volumes)); J. F. W. McOmie, "Protective Groups in Organic
  • Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known per se.
  • salts of compounds of the present invention having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g., the sodium salt of 2-ethyl hexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used.
  • metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g., the sodium salt of 2-ethyl hexanoic acid
  • organic alkali metal or alkaline earth metal compounds such as the corresponding hydroxides, carbonates or hydrogen carbonates
  • Acid addition salts of compounds of the present invention are obtained in customary manner, e.g., by treating the compounds with an acid or a suitable anion exchange reagent.
  • Internal salts of compounds of the present invention containing acid and basic salt-forming groups, e.g., a free carboxy group and a free amino group, may be formed, e.g., by the neutralisation of salts, such as acid addition salts, to the isoelectric point, e.g., with weak bases, or by treatment with ion exchangers.
  • Salts can be converted in customary manner into the free compounds; metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.
  • diastereoisomers can be separated in a manner known per se into the individual isomers; diastereoisomers can be separated, for example, by partitioning between polyphasic solvent mixtures, recrystallisation and/or chromatographic separation, for example over silica gel or by, e.g., medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, for example by means of fractional crystallisation, or by chromatography over optically active column materials.
  • Intermediates and final products can be worked up and/or purified according to standard methods, e.g., using chromatographic methods, distribution methods, (re-) crystallization, and the like.
  • the process steps to synthesize the compounds of the invention can be carried out under reaction conditions that are known per se, including those mentioned specifically, in the absence or, customarily, in the presence of solvents or diluents, including, for example, solvents or diluents that are inert towards the reagents used and dissolve them, in the absence or presence of catalysts, condensation or neutralizing agents, for example ion exchangers, such as cation exchangers, e.g., in the H + form, depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, for example in a temperature range of from about -100 °C to about 190°C, including, for example, from approximately -80°C to approximately 150°C, for example at from -80 to -60°C, at room temperature, at from -20 to 40°C or at reflux temperature, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under an argon or
  • mixtures of isomers that are formed can be separated into the individual isomers, for example diastereoisomers or enantiomers, or into any desired mixtures of isomers, for example racemates or mixtures of diastereoisomers, for example analogously to the methods described in Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005.
  • solvents from which those solvents that are suitable for any particular reaction may be selected include those mentioned specifically or, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethylformamide or dimethyl acetamide, bases, such as heterocyclic nitrogen bases, for example pyridine or N-methylpyrrolidin-2- one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride,
  • the compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may, for example, include the solvent used for crystallization. Different crystalline forms may be present.
  • the invention relates also to those forms of the process in which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
  • the present invention also relates to pro-drugs of a compound of the present invention that are converted in vivo to the compounds of the present invention as described herein. Any reference to a compound of the present invention is therefore to be understood as referring also to the corresponding pro-drugs of the compound of the present invention, as appropriate and expedient.
  • a pharmaceutical combination comprising a) a first agent which is a compound of the invention, e.g. a compound of formula I or any subformulae thereof, and b) a co- agent, e.g. a second drug agent as defined above, or a beta-lactamase inhibitor.
  • a method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of a compound of the invention, e.g. a compound of formula I or any subformulae thereof, and a co-agent, e.g. a second drug agent as defined above, or a beta-lactamase inhibitor.
  • a compound of the invention e.g. a compound of formula I or any subformulae thereof
  • a co-agent e.g. a second drug agent as defined above, or a beta-lactamase inhibitor.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. Fixed combinations are also within the scope of the present invention.
  • the administration of a pharmaceutical combination of the invention results in a beneficial effect, e.g. a synergistic therapeutic effect, compared to a monotherapy applying only one of its pharmaceutically active ingredients.
  • Each component of a combination according to this invention may be administered separately, together, or in any combination thereof.
  • the compound of the invention and any additional agent may be formulated in separate dosage forms.
  • the compound of the invention and any additional agent may be formulated together in any combination.
  • the compound of the invention inhibitor may be formulated in one dosage form and the additional agent may be formulated together in another dosage form. Any separate dosage forms may be administered at the same time or different times.
  • composition of this invention comprises an additional agent as described herein.
  • Each component may be present in individual compositions, combination compositions, or in a single composition.
  • Step 1 CBZ-CI, NaHC0 3, Acetone, Water, 5 °C to room temperature.
  • Step 2 n- BuLi, THF, -75 °C to room temperature.
  • Step 3 Iodine, triphenylphosphine, imidazole, rt.
  • Step 4 NaH (60 %), N,N-dimethylformamide, 0 °C to room temperature.
  • Step 5 LiOH, THF, MeOH, Water, room temperature.
  • Step 6 NH 2 OTHP, EDC.HCI, HOBt, TEA, dichloromethane, room temperature.
  • Step 7 35.5% aq. HCI, EtOH, room temperature.
  • Step 2 Synthesis of (R)-3-(4-bromophenyl)-5-(hydroxymethyl) oxazolidin-2-one [1.1 b] 1.1a (6.0 g, 19.6 mmol, 1.0 equiv) was dissolved in THF (60 ml.) and cooled to -75 °C. n- BuLi (1.51 g, 23.5 mmol, 1.2 equiv) was gradually added and the reaction mixture was stirred at -75 °C for 1 hour.
  • Triphenylphosphine (2.5 g, 95.6 mmol, 1.3 equiv) and imidazole (0.70 g, 10.3 mmol, 1.4 equiv) were dissolved in dichloromethane (20 ml_).
  • Iodine (2.42 g, 9.5 mmol, 1.3 equiv) was added and the reaction mixture was stirred at room temperature for 15 minutes.
  • 1.1 b 2.0 g, 73.5 mmol, 1.0 equiv was added portion wise. The reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to obtain a residue.
  • 1.1 d was obtained as a mixture of diastereomers (R)-ethyl 3-((S)-3-(4- bromophenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanoate and (S)-ethyl 3- ((S)-3-(4-bromophenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanoate.
  • the mixture of diastereromers was carried through the following steps and the separation of diastereomers was conducted at the hydroxamic acid stage.
  • Step 1 CBZ-CI, NaHC0 3, Acetone:Water, 0°C to room temperature.
  • Step 2 n- BuLi(2.5M in hexane), THF, -78°C to room temperature.
  • Step 3 Iodine, triphenylphosphine, imidazole, rt.
  • Step 4 NaH (60%), ⁇ , ⁇ -dimethylformamide, 0°C to room temperature.
  • Step 5 LiOH, THF, MeOH, Water, room temperature.
  • Step 6 NH 2 OTHP, EDC.HCI, HOBt, TEA, DCM, room temperature.
  • Step 7 Methanolic-HCI (8%w/w), MeOH, room temperature.
  • Step 1 Synthesis of benzyl (4-bromo-2-methylphenyl)carbamate [1.2a]
  • Step 2 Synthesis of (R)-3-(4-bromo-2-methylphenyl)-5-(hydroxymethyl)oxazolidin-2- one [1.2b].
  • 1. 2a (2.0 g, 6.2 mmol, 1.0 equiv) was dissolved in THF (60 mL) and cooled to - 78°C.
  • n-BuLi (2.5M in hexane) (0.40 g , 6.3 mmol, 1.01 equiv) was added and the reaction mixture was stirred at -78° for 45 minutes.
  • Step 1 CBZ-CI, NaHC0 3, Acetone: Water, 5 °C to room temperature.
  • Step 2 n- BuLi (23 % in hexane), THF, -75 °C to room temperature.
  • Step 3 Iodine, triphenylphosphine, imidazole, THF, room temperature.
  • Step 4 NaH (60%), N,N- dimethylformamide, 0 °C to room temperature.
  • Step 5 LiOH.H 2 0, THF, MeOH, Water, room temperature.
  • Step 6 NH 2 OTHP, EDC.HCI, HOBt, NMM, THF, room temperature.
  • Step 7 35.5% aq. HCI, EtOH, room temperature.
  • Step 4 Synthesis of (R)-ethyl 3-((S)-3-(4-bromo-2-fluorophenyl)-2-oxooxazolidin-5-yl)- 2-methyl-2-(methylsulfonyl)propanoate [1.3d].
  • Step 5 Synthesis of (R)-3-((S)-3-(4-bromo-2-fluorophenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoic acid [1.3e]. 1.3d (0.13 g, 0.29 mmol, 1.0 equiv) was dissolved in THF (3.0 mL), MeOH (1.0 mL). LiOH (0.036 g, 0.86 mmol, 3.0 equiv) in water (1 ml_) was added. The resulting mixture was stirred at room temperature for 3 hours.
  • Step 7 Synthesis of (R)-3-((S)-3-(4-bromo-2-fluorophenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide [1.3]. 1.3f (0.09 g, 0.17 mmol, 1.0 equiv) was dissolved in ethanol (3 ml_), 35.5 % aqueous HCI (0.5 ml_) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched in to water, neutralized with sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to obtain the crude product.
  • Step 1 CBZ-CI, NaHC0 3, Acetone:Water, 0°C to room temperature.
  • Step 2 n- BuLi (23 % in hexane), THF, -78°C to room temperature.
  • Step 3 Iodine, triphenylphosphine, imidazole, THF, room temperature.
  • Step 4 NaH (60%), ⁇ , ⁇ -dimethylformamide, 0°C to room temperature.
  • Step 5 LiOH.H 2 0, THF, MeOH, Water, rt.
  • Step 6 NH 2 OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, rt.
  • Step 7 35.5% aq. HCI, EtOH, room temperature.
  • Step 1 CBZ-CI, NaHC0 3, Acetone:Water, 0°C to room temperature.
  • Step 3 Iodine, triphenylphosphine, imidazole, THF, room temperature.
  • Step 4 Na
  • Step 2 Synthesis of (R)-3-(4-bromo-2,6-difluorophenyl)-5-(hydroxymethyl)oxazolidin- 2-one [1.4b].
  • 1. 4a (1.23 g, 3.6 mmol, 1.0 equiv) was dissolved in THF (35 mL) and cooled to -78°C.
  • n-BuLi 23 % in hexane (0.34 g, 5.39 mmol, 1.5 equiv) was gradually added and the reaction mixture was stirred at -78° for 1 hour.
  • Triphenylphosphine (0.80 g, 3.04 mmol, 1.3 equiv) was dissolved in THF (10 mL), imidazole (0.21 g, 3.04 mmol, 1.3 equiv) was added and the reaction mixture was stirred at room temperature for 5 minutes.
  • Iodine (0.77 g, 3.04 mmol, 1.3 equiv) was added and the reaction mixture was stirred at room temperature for 10 minutes.
  • 1.4b (0.72 g, 2.34 mmol, 1.0 equiv) in THF (10 mL) was added dropwise and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with water and extracted with EtOAc.
  • Step 4 Synthesis of ethyl 3-((S)-3-(4-bromo-2,6-difluorophenyl)-2-oxooxazolidin-5-yl)- 2-methyl-2-(methylsulfonyl)propanoate [1.4d].
  • Ethyl 2-(methylsulfonyl)propanoate (1.21 g, 6.7 mmol, 4.0 equiv) was dissolved in N,N-dimethylformamide (15 mL) and cooled to 0-5 °C. NaH (60%) (0.08 g, 3.35 mmol, 2.0 equiv) was added portion wise and the reaction mixture was stirred at room temperature for 2 hours.
  • reaction mixture was concentrated to dryness, diluted with water, acidified by 1 N HCI aqueous solution to the pH 2 to 3 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford compound 1.4e (0.259 g, 70% yield). The crude material was used in the next step with no further purification.
  • Step 7 Synthesis of (R)-3-((S)-3-(4-bromo-2,6-difluorophenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide [1.4]. 1.4f (0.160 g, 0.29 mmol, 1.0 equiv) was dissolved in ethanol (6 ml_), 35.5% aq. HCI (0.16 ml_) was added and reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, neutralized by saturated sodium bicarbonate solution and extracted with EtOAc.
  • Step 1 CH 3 COOK, PdCI 2 (dppf),1 ,4-dioxane, 1 10°C.
  • Step 2 LiOH.H 2 0, THF, MeOH, Water, room temperature.
  • Step 3 NH 2 OTHP, EDC.HCI, HOBt, TEA, dichloromethane, room temperature.
  • Step 4 Conc.HCI , EtOH, room temperature.
  • Step 1 Synthesis of (R)-ethyl 3-((S)-3-(biphenyl-4-yl)-2-oxooxazolidin-5-yl)-2-methyl-2- (methylsulfonyl)propanoate [2.1a].
  • 1.1 d (0.25 g, 0.6 mmol, 1.0 equiv)
  • phenylboronic acid 0.084 g, 0.7 mmol, 1.2 equiv
  • potassium acetate 0.17 g, 1.7 mmol, 3.0 equiv
  • Step 1 K 2 C0 3 , PdCI 2 (dppf), N, N-dimethylformamide, 80°C.
  • Step 2 LiOH.H 2 0, THF, MeOH, Water, room temperature.
  • Step 3 NH 2 OTHP, EDC.HCI, HOBt, TEA, dichloromethane, room temperature.
  • Step 4 35.5% aq. HCI, EtOH, room temperature.
  • Step 1 Synthesis of ethyl 3-((S)-3-(4-(3-fluoropyridin-4-yl)phenyl)-2-oxooxazolidin-5- yl)-2-methyl-2-(methylsulfonyl)propanoate [2.2a].
  • Step 2 Synthesis of 3-((S)-3-(4-(3-fluoropyridin-4-yl)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoic acid [2.2b].
  • 2.2a (0.15 g, 0.33 mmol, 1.0 equiv) was dissolved in THF (8 ml_), methanol (1 ml_).
  • LiOH.H 2 0 (0.04 g, 0.99 mmol, 3.0 equiv) in water (1 ml_) was added. The resulting mixture was stirred at room temperature for 2 hours.
  • Step 1 Synthesis of benzyl naphthalen-2-ylcarbamate [2.3a] Naphthalen-2-amine (2.5 g, 17.4 mmol, 1.0 equiv) was dissolved in acetone: water (2:1 , 30 ml_). NaHC0 3 (3.07 g, 36.6 mmol, 2.1 equiv) was added and the reaction mixture was cooled to 0 °C. CBZ-CI (3.12 g, 18.3 mmol, 1.05 equiv) was added and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was quenched with water and extracted with EtOAc.
  • Triphenylphosphine (0.56 g, 2.13 mmol, 1.3 equiv) and imidazole (0.156 g, 2.3 mmol, 1.4 equiv) were dissolved in dichloromethane (10 ml_) and the reaction mixture was stirred at room temperature for 10 minutes.
  • Iodine (0.54 g, 2.13 mmol, 1.3 equiv) and 2.3b (0.4 g, 1.64 mmol, 1.0 equiv) were added and the reaction mixture was stirred at rt for 3 hours. The mixture was concentrated and the residue was purified by silica gel chromatography (0-40% EtOAc in Hexane) to afford product 2.3c (0.4 g, 68.6% yield).
  • Step 7 Synthesis of (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-3-(naphthalen-2- yl)-2-oxooxazolidin-5-yl)propanamide [2.3].
  • 2.3f (0.15 g, 0.3 mmol, 1.0 equiv) was dissolved in ethanol (1 mL). 35.5% aq. HCI (0.5 mL) was added to the solution and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to afford a crude product. The crude product was purified by preparative HPLC purification to afford 2.3 as desired diastereomer (0.016 g, 13 % yield).
  • Step 1 Cul, Cs 2 C0 3 , trans-cyclohexane-1 ,2-diamine, 1 ,4-dioxane, 125 °C.
  • Step 2 LiOH.H 2 0, THF, MeOH, Water, room temperature.
  • Step 3 NH 2 OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, room temperature.
  • Step 4 HCI (in IPA), dichloromethane, MeOH, room temperature.
  • Step 1 Synthesis of ethyl 3-((S)-3-(benzo[d]thiazol-6-yl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoate [2.4a]. 6.1e mix diastereomers (0.3 g, 1.07 mmol, 1.0 equiv), 6-bromobenzo[c ]thiazole (0.25 g, 1.1 mmol, 1 .1 equiv) were dissolved in 1 ,4- dioxane (8 mL).
  • Step 1 CBZ-CI, NaHC0 3, Acetone: Water, 0 °C to room temperature.
  • Step 2 n- BuLi (2.5M in hexane), THF, -70°C to room temperature.
  • Step 3 Iodine, triphenylphosphine, imidazole, dichloromethane, room temperature.
  • Step 4 NaH (60%), N,N- dimethylformamide, 0 °C to room temperature.
  • Step 5 LiOH.H 2 0, THF, MeOH, Water, room temperature.
  • Step 6 NH 2 OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, room temperature.
  • Step 7 35.5% aq. HCI, EtOH, room temperature.
  • Triphenylphosphine (2.75 g, 10.5 mmol, 1.3 equiv) was dissolved in dichloromethane (10 mL). imidazole (0.71 g, 10.5 mmol, 1.3 equiv) and iodine (2.66 g, 10.5 mmol, 1.3 equiv) were added and the reaction mixture was stirred at room temperature for 15 minutes. A solution of 2.5b (2.0 g, 8.08 mmol, 1.0 equiv) in dichloromethane (5 mL) was drop wise added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with dichloromethane.
  • Step 4 Synthesis of ethyl-2-methyl-3-((S)-3-(1-methyl-1 H-indazol-5-yl)-2- oxooxazolidin-5-yl)-2-(methylsulfonyl)propanoate [2.5d].
  • Ethyl 2-(methylsulfonyl) propanoate (4.03 g, 22.4 mmol, 4.0 equiv) was dissolved in N,N-dimethylformamide (8 mL) and cooled to 0-5 °C. NaH (60%) (0.45 g, 1 1.20 mmol, 2.0 equiv) was added in portions and the reaction mixture was stirred at rt for 1.5 hours.
  • Step 1 Cul, Cs 2 C0 3 , trans-cyclohexane-1 ,2-diamine, 1 ,4-dioxane, 125 °C.
  • Step 2 LiOH.H 2 0, THF, MeOH, Water, room temperature.
  • Step 3 NH 2 OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, room temperature.
  • Step 4 35.5% aq. HCI, EtOH, room temperature.
  • Step 1 Synthesis of (R)-ethyl-3-((S)-3-(benzo[b]thiophen-6-yl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoate [2.6a]. 6.1e (0.25 g, 0.9 mmol, 1.0 equiv), 6- bromobenzo[0]thiophene (0.23 g, 1.0 mmol, 1.1 equiv) were dissolved in 1 ,4-dioxane (5 ml_).
  • Step 1 DBU, dppb, PdCI 2 (PPh 3 ) 2 , DMSO, 100°C.
  • Step 2 LiOH.H 2 0, THF, MeOH, Water, room temperature.
  • Step 3 N-methyl morpholine, NH 2 OTHP, EDC.HCI, HOBt, THF, room temperature.
  • Step 4 35.5% aq. HCI HCI, EtOH, room temperature.
  • Step 1 Synthesis of ethyl 2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(prop-1-ynyl) phenyl) oxazolidin-5-yl)propanoate [3.1.1a].
  • Step 2 Synthesis of 2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(prop-1-ynyl)phenyl) oxazolidin-5-yl)propanoic acid [3.1.1 b].
  • 3.1.1a (2.71 g, 6.91 mmol, 1.0 equiv) was dissolved in THF (25 mL), MeOH (12 mL).
  • LiOH.H 2 0 (0.85 g, 20.72 mmol, 3.0 equiv) solution in water (1 mL) was added to the reaction mixture. The resulting mixture was stirred at rt for 2 hours.
  • reaction mixture was concentrated to dryness and the residue was diluted with water, acidified by 1 N HCI aqueous solution to pH 4 to 5 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 3.1.1 b (2.30 g, 91.3 % yield). The crude material was used in the next step with no further purification.
  • Step 4 Synthesis of (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4- (prop-1-ynyl)phenyl)oxazolidin-5-yl)propanamide [3.1.1].
  • 3.1.1c (2.5 g, 5.39 mmol, 1.0 equiv) was dissolved in ethanol (30 ml_) and 35.5% aq. HCI (1 ml_) was added. The reaction mixture was stirred at rt for 4 hours. The reaction was quenched with water, neutralized by saturated aqueous sodium bicarbonate solution, and extracted with EtOAc.
  • Step 1 DBU, dppb, PdCI 2 (PPh 3 ) 2 , DMSO, 90°C.
  • Step 2 LiOH.H 2 0, THF, MeOH, Water, room temperature.
  • Step 3 NH 2 OTHP, EDC.HCI, HOBt, TEA, dichloromethane, room temperature.
  • Step 4 Conc.HCI , EtOH, room temperature.
  • Step 1 Synthesis of ethyl 3-((S)-3-(4-(cyclopropylethynyl)phenyl)-2-oxooxazolidin-5- yl)-2-methyl-2-(methylsulfonyl)propanoate [3.1.2a].
  • Step 2 Synthesis of 3-((S)-3-(4-(cyclopropylethynyl)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoic acid [3.1.2b].
  • 3.1.2a (0.33 g, 0.79 mmol, 1.0 equiv) dissolved in THF (6 mL), MeOH (2 mL).
  • LiOH.H 2 0 (0.099 g, 2.36 mmol, 3.0 equiv) in water (1 mL) was added to the reaction mixture and the resulting mixture was stirred at room temperature for 3 hours.
  • Step 1 DBU, dppb, PdCI 2 (PPh 3 ) 2 , DMSO, 100°C.
  • Step 2 LiOH.H 2 0, THF, MeOH, Water, room temperature.
  • Step 3 NH 2 OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, room temperature.
  • Step 4 35.5% aq. HCI, EtOH, room temperature.
  • Step 1 Synthesis of ethyl (R)-3-((S)-3-(4-(but-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoate [3.1.3a]
  • Step 4 Synthesis of (R)-3-((S)-3-(4-(but-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy -2-methyl-2-(methylsulfonyl)propanamide [3.1.3]. 3.1.3c (0.1 1 g, 0.23 mmol, 1.0 equiv) was dissolved in ethanol (5.0 ml_), 35.5 % aqueous HCI (1 ml.) was added and the reaction mixture was stirred at rt for 2 hours. The reaction mixture was quenched with water, neutralized by sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated.
  • Step A But-3-yn-2-ol, n-BuLi (23 % in hexane), C0 2 , THF, -40 °C.
  • Step 1 DBU, dppb, PdCI 2 (PPh 3 ) 2 , DMSO, 90 °C.
  • Step 2 LiOH.H 2 0, THF, MeOH, Water, room temperature.
  • Step 3 NH 2 OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, room temperature.
  • Step 4 35.5% aq. HCI, EtOH, room temperature.
  • Step A Synthesis of 4-hydroxypent-2-ynoic acid.
  • But-3-yn-2-ol 0.5 g, 7.13 mmol, 1.0 equiv
  • THF 15 ml_
  • n-BuLi 23% in hexane
  • the C0 2 gas was purged into reaction mixture for 40 minutes.
  • the reaction mixture was diluted with water and extracted with EtOAc.
  • the aqueous layer was acidified by 35.5% aq. HCI to pH 3 to 4 and extracted with EtOAc.
  • Step 2 Synthesis of 3-((5S)-3-(4-(3-hydroxybut-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)- 2-methyl-2-(methylsulfonyl)propanoic acid [3.1.4b].
  • 3.1.4a (0.13 g, 0.31 mmol, 1.0 equiv) was dissolved in THF (4 ml_), MeOH (1.5 ml_).
  • LiOH.H 2 0 (0.039 g, 0.92 mmol, 3.0 equiv) in water (1.5 ml_) was added and the resulting mixture was stirred at room temperature for 3 hours.
  • reaction mixture was diluted with water, acidified by 1 N HCI aqueous solution to pH 4 to 5 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 3.1.4b (0.10 g, 82.6 % yield).
  • Step 4 Synthesis of (2R)-N-hydroxy-3-((5S)-3-(4-(3-hydroxybut-1-yn-1-yl)phenyl)-2-oxo oxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide [3.1.4].
  • 3.1.4c (0.10 g, 0.20 mmol, 1.0 equiv) was dissolved in ethanol (3 ml_), 35.5% aq. HCI (0.1 ml_) was added to the solution and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with EtOAc.
  • Step A 3-methoxyprop-1-yne, n-BuLi (2.5M in hexane), C0 2 , THF, -40°C.
  • Step V. DBU, dppb, PdCI 2 (PPh 3 ) 2 , DMSO, 90°C.
  • Step 2 LiOH.H 2 0, THF, MeOH, Water, room temperature.
  • Step 3 NH 2 OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, room temperature.
  • Step 4 35.5% aq. HCI, EtOH, room temperature.
  • Step 1 Synthesis of ethyl 3-((S)-3-(4-(3-methoxyprop-1-yn-1-yl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanoate [3.1.5a].

Abstract

L'invention concerne de manière générale le traitement d'infections bactériennes à l'aide de composés organiques de formule I. Dans certains aspects, l'invention concerne le traitement d'infections provoquées par des bactéries Gram négatif. (I) dans laquelle X, Y, R1, R2, R3, R4 et R5 sont tels que définis dans la description.
PCT/US2014/063325 2013-11-01 2014-10-31 Composés d'acide oxazolidinone-hydroxamique pour le traitement d'infections bactériennes WO2015066413A1 (fr)

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WO2017037221A1 (fr) 2015-09-03 2017-03-09 Actelion Pharmaceuticals Ltd Composés antibactériens 1,2-dihydro-3h-pyrrolo[1,2-c]imidazol-3-one substitués
JP2018526354A (ja) * 2015-08-11 2018-09-13 イドーシア ファーマシューティカルズ リミテッドＩｄｏｒｓｉａ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ 置換１，２−ジヒドロ−３Ｈ−ピロロ［１，２−ｃ］イミダゾール−３−オン抗菌剤
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