WO2015066413A1 - Oxazolidinone hydroxamic acid compounds for the treatment of bacterial infections - Google Patents

Oxazolidinone hydroxamic acid compounds for the treatment of bacterial infections Download PDF

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Publication number
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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French (fr)
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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

This invention pertains generally to treating bacterial infections using organic compounds of Formula I. In certain aspects, the invention pertains to treating infections caused by Gram-negative bacteria. (I) wherein X, Y, R1, R2, R3, R4 and R5 and defined herein.

Description

OXAZOLIDINONE HYDROXAMIC ACID COMPOUNDS FOR THE TREATMENT OF
BACTERIAL INFECTIONS
FIELD OF THE INVENTION
This invention pertains generally to compounds and compositions for treating bacterial infections. In certain aspects, 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.
BACKGROUND OF THE INVENTION
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. Among Gram-positive organisms, the most important resistant pathogens are methicillin-(oxacillin-) resistant Staphylococcus aureus, β-lactam-resistant and multidrug-resistant pneumococci, and vancomycin-resistant enterococci. Important causes of Gram-negative resistance include extended-spectrum β-lactamases (ESBLs) in Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis, high-level third-generation cephalosporin (Amp C) β-lactamase resistance among Enterobacter species and Citrobacter freundii, and multidrug-resistance genes observed in Pseudomonas, Acinetobacter, and Stenotrophomonas.
The problem of antibacterial resistance is compounded by the existence of bacterial strains resistant to multiple antibacterials. For example, Pseudomonas aeruginosa isolates resistant to fluoroquinolones are virtually all resistant to additional antibacterial medicines. This makes it increasingly difficult to select a suitable antibiotic for a given infection:
frequently an ineffective antibiotic is administered first, which delays effective treatment and increases mortality. Thus there is therefore a need for new antibactenals, particularly antibactenals that are not cross-resistant with widely-used antibiotics. In particular, there is a need for new Gram-negative antibactenals. Gram-negative bacteria are in general more resistant to a large number of antibactenals and chemotherapeutic agents than are Gram-positive bacteria.
Summary of the Invention
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.
In one aspect, the invention provides compounds of Formula (I):
Figure imgf000003_0001
(I) or a pharmaceutically acceptable salt thereof, wherein:
X is N or C, wherein when X is N, R4 is absent;
Y is N or C, wherein when Y is N, R5 is absent;
R1, R2, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, -CH3, and -Cihaloalkyl;
R3 is L-R;
L is a divalent bond, or -CH2-;
R is selected from group consisting of
halogen,
-C C4alkyl optionally substituted with one or more groups selected from halogen, d- C4alkoxy, -CN and -OH;
-CN,
-CrC4alkoxy optionally substituted with one or more groups selected from halogen, C C4alkoxy, -CN and -OH;
-S-Ci-C4 alkyl wherein the alkyl is optionally substituted with one or more groups selected from halogen, CrC4alkoxy, -CN and -OH;
-C2-C6alkenyl optionally substituted with one or more groups selected from halogen, - CN, -OH and C C4alkoxy;
-C2-C6alkynyl optionally substituted with one or more groups selected from halogen, C C4alkoxy, -CN and -OH;
-C3-C7cycloalkyl optionally substituted with one or more groups selected from halogen, C Calkyl, -Ci-C alkylCrCalkoxy, C C alkoxy, CrC haloalkyl, nitrile, -S(0)2C C4alkyl and -OH;
-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more groups selected from halogen, C Calkoxy, CrC haloalkoxy, CrC haloalkyl and C C alkyl;
-CrC4alkyl-C6-Cioaryl, wherein the aryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, C C haloalkoxy, CrC haloalkyl and C C alkyl;
-CrCalkyl-C3-C7cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more groups selected from halogen, Ci-Calkoxy, C C haloalkoxy, CrC haloalkyl and C C4 alkyl;
-C5-C6cycloalkenyl optionally substituted with one or more groups selected from halogen, C Calkoxy, CrC haloalkoxy, CrC haloalkyl and C C alkyl;
4 to 7 membered 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)2CrCalkyl and -OH, and said heterocyclyl may contain one unsaturated bond;
-CrCalkyl-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 groups selected from halogen, C Calkoxy, Ci-C haloalkoxy, CrC haloalkyl, Ci-C alkyl, nitrile, - S(0)2C C4alkyl and -OH;
-C3-C5cycloalkyl-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 groups selected from halogen, C C alkoxy, C C haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, -S(0)2C C4alkyl and -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 groups selected from halogen, C Calkoxy, Ci-C haloalkoxy, Ci-C haloalkyl, Ci-C alkyl, nitrile, -S(0)2Ci-Calkyl and -OH;
-CrCalkyl-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 groups selected from halogen, C Calkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, - S(0)2C C4alkyl and -OH; and -C3-C5cycloalkyl-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 groups selected from halogen, CrC4alkoxy, CrC4haloalkoxy, CrC4haloalkyl, C C4 alkyl, nitrile, - S(0)2C C4alkyl and -OH; or
Figure imgf000005_0001
L is ;
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;
-C2-C6alkenyl optionally substituted with one or more groups selected from halogen, - CN, -OH and C C4alkoxy;
-C2-C alkynyl optionally substituted with one or more groups selected from halogen, C C4alkoxy, -CN and -OH;
-C3-C7cycloalkyl 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)2C C4alkyl, -OH, and C1-C3 alkyl substituted with a group selected from CN, OH, -S02R', - 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;
-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl and C C alkyl;
-CrC alkyl-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, C C haloalkoxy, CrC haloalkyl and C C alkyl;
4 to 7 membered 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)2C C alkyl and -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 groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, - S(0)2C C4alkyl and -OH;
-C3-C5cycloalkyl-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 groups selected from halogen, CrC4alkoxy, CrC4haloalkoxy, CrC4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl and -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 groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, -S(0)2CrC alkyl and -OH;
-CrC alkyl-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 groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, - S(0)2C C4alkyl and -OH; and
-C3-C5cycloalkyl-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 groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, - S(0)2C C4alkyl and -OH; or
R2 and R3 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 C4 alkyl.
Various embodiments of these compounds are described herein.
In one aspect, 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.
In another aspect, 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.
In another aspect, 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. In certain embodiments, the subject is a mammal and in some other embodiments, the subject is a human.
In another aspect, the invention provides a method of administering an inhibitory amount of a compound of formula I to fermentative or non-fermentative Gram-negative bacteria. In certain embodiment of the 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.
In another embodiment, 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,
Morganella, Cedecea, Yersina and Edwardsiella species and Escherichia coli.
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.
Pharmaceutical formulations according to the present invention are provided which include any of the compounds described above and a pharmaceutically acceptable carrier.
Other aspects of the invention are discussed infra.
DETAILED DESCRIPTION OF THE INVENTION
For purposes of interpreting this specification, the following definitions will apply unless specified otherwise and whenever appropriate, terms used in the singular will also include the plural and vice versa.
Definitions
Terms used in the specification have the following meanings:
"LpxC" is an abbreviation that stands for UDP-3-0-(R-3-hydroxydecan- oyl)-N- acetylglucosamine deacetylase.
As used herein, the term "subject" refers to an animal. In certain aspects, 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. In certain
embodiments, the subject is a human.
As used herein, 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.
As used herein, the term "treating" or "treatment" of any disease or disorder 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). In another embodiment "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "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. In yet another embodiment, "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.
As used herein, the term "a," "an," "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.
All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.
The term "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.
"CrC4-Alkyl", as used herein, denotes straight chain or branched alkyl having 1-4 carbon atoms. If a different number of carbon atoms is specified, such as C6 or C3, then the definition is to be amended accordingly, such as "CrC4-Alkyl" will represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
"CrC4-Alkoxy", as used herein, 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 "CrC4-Alkoxy" will represent methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
"CrC -Haloalkyl", as used herein, 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 C6 or C3, then the definition is to be amended accordingly, such as "Ci-C4-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: CF3CF2-, (CF3)2CH-, CH3-CF2-, CF3CF2-, CF3, CF2H-, CF3CF2CHCF3 or CF3CF2CF2CF2-.
"C3-C7-cycloalkyl" as used herein 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 C3-C6, then the definition is to be amended accordingly.
"4- to 8-Membered heterocyclyl", "5- to 6- membered heterocyclyl", "3- to 10- membered heterocyclyl", "3- to 14-membered heterocyclyl", "4- to 14-membered
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. The term "heterocyclyl" includes single ring groups, fused ring groups and bridged groups. Examples of such heterocyclyl 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. Typically, 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.
The term "hydroxy" or "hydroxyl" includes groups with an -OH.
The term "a," "an," "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. Various embodiments of the invention are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments.
In one aspect, 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:
1. A compound of the formula (I):
Figure imgf000010_0001
(I) or a pharmaceutically acceptable salt thereof, wherein:
X is N or C, wherein when X is N, R4 is absent;
Y is N or C, wherein when Y is N, R5 is absent;
R1, R2, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, -CH3, and -Cihaloalkyl;
R3 is L-R;
L is a divalent bond, or -CH2-;
R is selected from group consisting of
halogen,
-CrC4alkyl optionally substituted with one or more groups selected from halogen, d- C4alkoxy, -CN and -OH;
-CN,
-CrC4alkoxy optionally substituted with one or more groups selected from halogen, C C4alkoxy, -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-C6alkenyl optionally substituted with one or more groups selected from halogen, - CN, -OH and C C4alkoxy;
-C2-Cealkynyl optionally substituted with one or more groups selected from halogen, C C4alkoxy, -CN and -OH; -C3-C7cycloalkyl optionally substituted with one or more groups selected from halogen, CrC4alkyl, -Ci-C4alkylCrC4alkoxy, CrC4alkoxy, CrC4haloalkyl, nitrile, -S(0)2C C4alkyl and -OH;
-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more groups selected from halogen, C Calkoxy, CrC haloalkoxy, CrC haloalkyl and C C alkyl;
-CrCalkyl-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, C C haloalkoxy, CrC haloalkyl and C C alkyl;
-CrC4alkyl-C3-C7cycloalkyl, wherein the 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;
4 to 7 membered 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)2CrCalkyl and -OH, and said heterocyclyl may contain one unsaturated bond;
-CrCalkyl-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 groups selected from halogen, C C4alkoxy, CrC4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, - S(0)2C C4alkyl and -OH;
-C3-C5cycloalkyl-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 groups selected from halogen, C C alkoxy, C C haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, -S(0)2CrC4alkyl and -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 groups selected from halogen, C C4alkoxy, CrC4haloalkoxy, CrC4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl and -OH;
-CrCalkyl-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 groups selected from halogen, C Calkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, - S(0)2CrC4alkyl and -OH; and
-C3-C5cycloalkyl-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 groups selected from halogen, C Calkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, - S(0)2C C4alkyl and -OH; or
Figure imgf000012_0001
L is ;
R is selected from group consisting of
-CrC6alkyl 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;
-C2-Cealkenyl optionally substituted with one or more groups selected from halogen, - CN, -OH and C C4alkoxy;
-C2-C4alkynyl optionally substituted with one or more groups selected from halogen, C C4alkoxy, -CN and -OH;
-C3-C7cycloalkyl 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)2C C alkyl, -OH, and C C3 alkyl substituted with a group selected from CN, OH, -S02R', - 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;
-Ce-Cioaryl, wherein the aryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl and C C alkyl;
-CrC alkyl-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, C C haloalkoxy, CrC haloalkyl and C C alkyl;
4 to 7 membered 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 C4alkoxy, CrC4haloalkoxy, CrC4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl and -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 groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, - S(0)2CrC4alkyl and -OH;
-C3-C5cycloalkyl-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 groups selected from halogen, C C alkoxy, C C haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, -S(0)2C C4alkyl and -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 groups selected from halogen, CrC4alkoxy, CrC4haloalkoxy, CrC4haloalkyl, C C4 alkyl, nitrile, -S(0)2CrC alkyl and -OH;
-CrC alkyl-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 groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, - S(0)2C C4alkyl and -OH; and
-C3-C5cycloalkyl-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 groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, - S(0)2C C4alkyl and -OH; or
R2 and R3 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 C4 alkyl.
An 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. In some substituted embodiments, the alkyl, alkenyl, alkynyl, cycloalkyi, aryl, heteroaryl, heterocyclyl, or cycloalkenyl is substituted with one, two or three of the designated groups, unless otherwise specified.
2. The compound of embodiment 1 , wherein X is N and Y is C, and R4 is absent.
3. The compound of embodiment 1 , wherein X is C and Y is N, and R5 is absent.
4. The compound of embodiment 1 , wherein X is C and Y is C.
5. The compound of any of the preceding embodiments, wherein L is
6. The compound of any of embodiments 1 -4, wherein L is a bond.
Figure imgf000013_0001
7. The compound of any of embodiments 1 -4, wherein L is
8. The compound of any of the preceding embodiments, wherein R is -C3- C7cycloalkyl 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)2CrC alkyl.
9. The compound of any of embodiments 1 -7, wherein R is phenyl optionally substituted with one or more groups selected from halogen, d-C4alkoxy, CrC4haloalkoxy, CrC4haloalkyl and C1-C4 alkyl.
In some such embodiments, phenyl is unsubstituted or substituted with up to three groups selected from F, CI, Br, CrC4alkoxy, CrC4haloalkoxy, CrC haloalkyl and C C alkyl.
10. The compound of any of the preceding embodiments, wherein Z is H.
11. The compound of embodiment 1 , wherein
X is N or C, wherein when X is N, R4 is absent;
Y is N or C, wherein when Y is N, R5 is absent;
R1, R2, R4 or R5 are independently selected from the group consisting of hydrogen, halogen, -CH3, and -Cihaloalkyl;
R3 is L-R;
L is a divalent bond, or -CH2-;
R is selected from group consisting of
halogen,
-CrC alkyl optionally substituted with halogen, C C alkoxy, -CN or -OH,
-CN,
-CrC alkoxy optionally substituted with halogen or C C alkoxy,
-C2-C6alkenyl optionally substituted with halogen, -CN, -OH or C C alkoxy,
-C2-C alkynyl optionally substituted with halogen, C C alkoxy, -CN or -OH,
-C3-C7cycloalkyl optionally substituted with halogen, Ci-C alkyl, -CrC alkylCr
C4alkoxy, C C4alkoxy, C C4haloalkyl, nitrile, -S(0)2C C4alkyl or -OH,
-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, C
C alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl,
-CrC alkyl-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl or Ci-C alkyl,
4 to 7 membered 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 C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl or -OH,
-Ci-C4alkyl-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)2C C alkyl or -OH,
-C3-C5cycloalkyl-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, Ci-C alkoxy, C C haloalkoxy, CrC haloalkyl, Ci-C alkyl, nitrile, -S(0)2Cr C4alkyl 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-C4alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2CrC4alkyl or -OH,
-CrC4alkyl-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 alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, -S(0)2CrC alkyl or -OH, and
-C3-C5cycloalkyl-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, C C4alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl or -OH; or '
L is ;
R is selected from group consisting of
-CrC4alkyl optionally substituted with halogen, Ci-C4alkoxy, -CN or -OH,
-C2-C6alkenyl optionally substituted with halogen, -CN, -OH or C C alkoxy,
-C2-C alkynyl optionally substituted with halogen, C C alkoxy, -CN or -OH,
-C3-C7cycloalkyl optionally substituted with halogen, CrC4alkyl, -C C4alkylCr
C4alkoxy, C C4alkoxy, C C4haloalkyl, nitrile, -S(0)2C C4alkyl or -OH,
-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, C
C alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl,
-CrC alkyl-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl or Ci-C alkyl,
4 to 7 membered 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, CrC4haloalkoxy, Ci-C4haloalkyl, d-C4 alkyl, nitrile, -S(0)2Ci-C4alkyl 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)2C C alkyl or -OH,
-C3-C5cycloalkyl-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, Ci-C alkoxy, C C haloalkoxy, CrC haloalkyl, Ci-C alkyl, nitrile, -S(0)2Cr C4alkyl 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, Ci-C alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl or -OH, -CrC4alkyl-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- C4alkoxy, CrC4haloalkoxy, CrC4haloalkyl, C C alkyl, nitrile, -S(0)2CrC alkyl or -OH, and
-C3-C5cycloalkyl-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, C C4alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl or -OH; or
R2 and R3 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.
In additional embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is represented by formula II:
Figure imgf000016_0001
II
wherein the substituents are as defined in any of the embodiments above.
In other embodiments of the invention, 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, R4 is absent;
Y is N or C, wherein when Y is N, R5 is absent;
R1, R2, R4 or R5 are independently selected from the group consisting of hydrogen, halogen, -CH3, and Cihaloalkyl;
R3 is L-R;
L is a divalent bond, or -CH2-;
R is selected from group consisting of
halogen,
-CrC alkyl optionally substituted with halogen, C C alkoxy, -CN or -OH,
-CN,
-C C alkoxy optionally substituted with halogen or C C alkoxy,
-C2-C6alkenyl optionally substituted with halogen, -CN, -OH or C C alkoxy, -C2-C4alkynyl optionally substituted with halogen, CrC4alkoxy, -CN or -OH,
-C3-C7cycloalkyl optionally substituted with halogen, d-C4alkyl, -CrC alkylCr C4alkoxy, C C4alkoxy, C C4haloalkyl, nitrile, -S(0)2C C4alkyl or -OH,
-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl,
-CrC alkyl-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, Ci-C haloalkyl or Ci-C alkyl,
4 to 7 membered 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 C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl or -OH,
-Ci-C4alkyl-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)2CrC alkyl or -OH,
-C3-C5cycloalkyl-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, Ci-C alkoxy, C C haloalkoxy, CrC haloalkyl, Ci-C alkyl, nitrile, -S(0)2Cr C4alkyl 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, Ci-C alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl or -OH,
-CrC alkyl-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- C4alkoxy, Ci-C4haloalkoxy, CrC4haloalkyl, Ci-C4 alkyl, nitrile, -S(0)2Ci-C4alkyl or -OH, and
-C3-C5cycloalkyl-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, C C4alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl or -OH; or '
L is ;
R is selected from group consisting of
-CrC alkyl optionally substituted with halogen, C C alkoxy, -CN or -OH,
-C2-C6alkenyl optionally substituted with halogen, -CN, -OH or C C alkoxy,
-C2-C alkynyl optionally substituted with halogen, C C alkoxy, -CN or -OH,
-C3-C7cycloalkyl optionally substituted with halogen, CrC4alkyl, -Ci-C4alkylCr C4alkoxy, C C4alkoxy, C C4haloalkyl, nitrile, -S(0)2C C4alkyl or -OH, -C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, C C4alkoxy, CrC4haloalkoxy, CrC4haloalkyl or C1-C4 alkyl,
-CrC4alkyl-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, CrC4alkoxy, CrC haloalkoxy, Ci-C haloalkyl or Ci-C alkyl,
4 to 7 membered 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 C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl or -OH,
-Ci-C4alkyl-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)2CrC alkyl or -OH,
-C3-C5cycloalkyl-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, Ci-C alkoxy, C C haloalkoxy, CrC haloalkyl, Ci-C alkyl, nitrile, -S(0)2Cr C4alkyl 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, Ci-C alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl or -OH,
-CrC alkyl-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 alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, -S(0)2CrC alkyl or -OH, and
-C3-C5cycloalkyl-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, C C4alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl or -OH; or
R2 and R3 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.
In other embodiments of the invention, 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, R4 is absent;
Y is N or C, wherein when Y is N, R5 is absent;
R1, R2, R4 or R5 are independently selected from the group consisting of hydrogen, halogen, -CH3, and Cihaloalkyl;
R3 is L-R; L is a divalent bond, or -CH2-;
R is selected from group consisting of
halogen,
-CrC4alkyl optionally substituted with halogen, CrC4alkoxy, -CN or -OH,
-CN,
-C C4alkoxy optionally substituted with halogen or CrC4alkoxy,
-C2-C6alkenyl optionally substituted with halogen, -CN, -OH or C C alkoxy,
-C2-C4alkynyl optionally substituted with halogen, Ci-C4alkoxy, -CN or -OH,
-C3-C7cycloalkyl optionally substituted with halogen, Ci-C alkyl, -d-C alkylCr
C4alkoxy, C C4alkoxy, C C4haloalkyl, nitrile, -S(0)2C C4alkyl or -OH,
-Ce-Cioaryl, wherein the aryl is optionally substituted with one or more halogen, Cr
C alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl,
-CrC alkyl-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl or Ci-C alkyl,
4 to 7 membered 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 C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl 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)2CrC alkyl or -OH,
-C3-C5cycloalkyl-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, Ci-C alkoxy, Ci-C haloalkoxy, Ci-C haloalkyl, Ci-C alkyl, nitrile, -S(0)2Ci- C4alkyl 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, C C alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl or -OH,
-CrC alkyl-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 alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, -S(0)2C C alkyl or -OH, and
-C3-C5cycloalkyl-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, C C4alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl or -OH; or
R2 and R3 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-C4alkoxy, CrC4haloalkoxy, CrC4haloalkyl or C C4 alkyl.
In other embodiments of the invention, the compound or a pharmaceutically acceptable salt is any of the preceding embodiments where the compound is represented by formula III:
Figure imgf000020_0001
III
wherein
X is N or C, wherein when X is N, R4 is absent;
Y is N or C, wherein when Y is N, R5 is absent;
R1, R2, R4 or R5 are independently selected from the group consisting of hydrogen, halogen, -CH3, and Cihaloalkyl;
R is selected from group consisting of
-CrC alkyl optionally substituted with halogen, C C alkoxy, -CN or -OH,
-C2-C6alkenyl optionally substituted with halogen, -CN, -OH or C C alkoxy,
-C2-C alkynyl optionally substituted with halogen, C C alkoxy, -CN or -OH,
-C3-C7cycloalkyl optionally substituted with halogen, Ci-C alkyl, -CrC alkylCr
C4alkoxy, C C4alkoxy, C C4haloalkyl, nitrile, -S(0)2C C4alkyl or -OH,
-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, C
C alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl,
-CrC alkyl-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl or Ci-C alkyl,
4 to 7 membered heterocyclyl containing 1 to 3 heteroatom selected from N, S, and
O, wherein said heterocyclyl is optionally substituted with one or more halogen, CrC4alkoxy,
C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl 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)2C C alkyl or -OH,
-C3-C5cycloalkyl-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 C4alkoxy, C C4haloalkoxy, CrC4haloalkyl, C C4 alkyl, nitrile, -S(0)2Cr C4alkyl 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-C4alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl or -OH,
-CrC alkyl-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 alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, -S(0)2CrC alkyl or -OH, and
-C3-C5cycloalkyl-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, C C4alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl or -OH; or
R2 and R3 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.
In additional embodiments of the invention, the compound or a pharmaceutically acceptable salt represented by formula III as described above, wherein:
X is C,
Y is N or C, wherein when Y is N, R5 is absent;
R1, R2, R4 or R5 are independently selected from the group consisting of hydrogen, halogen, -CH3, and Cihaloalkyl;
R is selected from group consisting of
-CrC alkyl optionally substituted with halogen, C C alkoxy, -CN or -OH,
-C2-Cealkene optionally substituted with halogen, Ci-C4alkoxy, -CN or -OH,
-C3-C7cycloalkyl optionally substituted with halogen, Ci-C alkyl, -CrC alkylCr C4alkoxy, C C4alkoxy, C C4haloalkyl, nitrile, -S(0)2C C4alkyl or -OH,
-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl,
-CrC alkyl-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, Ci-C haloalkyl or Ci-C alkyl,
4 to 7 membered heterocyclyl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, CrC4alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl 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)2C C alkyl or -OH, -C3-C5cycloalkyl-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-C4alkoxy, CrC4haloalkoxy, CrC4haloalkyl, C C4 alkyl, nitrile, -S(0)2Cr C4alkyl 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, C C alkoxy, CrC haloalkoxy, Ci-C haloalkyl or C C alkyl, and
-Ci-C4alkyl-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 alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl.
In additional embodiments of the invention, the compound or a pharmaceutically acceptable salt is represented by formula III as described above, wherein:
X is C,
Y is C,
R1, R2, R4 or R5 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,
-C3-C7cycloalkyl optionally substituted with halogen, Ci-C alkyl, -CrC alkylCr C4alkoxy, C C4alkoxy, C C4haloalkyl, nitrile, -S(0)2C C4alkyl or -OH,
-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl,
-CrC4alkyl-C6-Cioaryl, wherein the aryl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, Ci-C haloalkyl or Ci-C alkyl,
4 to 7 membered 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 C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl 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)2CrC alkyl or -OH,
-C3-C5cycloalkyl-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, Ci-C alkoxy, C C haloalkoxy, CrC haloalkyl, Ci-C alkyl, nitrile, -S(0)2Cr C4alkyl 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-C4alkoxy, CrC4haloalkoxy, CrC4haloalkyl or CrC4 alkyl, and
-CrC alkyl-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 alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl.
In another embodiment of the invention, the compound or a pharmaceutically acceptable salt represented by formula III (above), wherein
X is C,
Y is C,
R1, R2, R4 or R5 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.
In additional embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is any of the preceding embodiments represented by formula III above, wherein:
X is C,
Y is C,
R1, R2, R4 or R5 are independently selected from the group consisting of hydrogen and halogen;
R is -C3-C7cycloalkyl optionally substituted with halogen, C C alkyl, -CrC alkylCr C4alkoxy, C C4alkoxy, C C4haloalkyl, nitrile, -S(0)2C C4alkyl or -OH.
In an embodiment of the invention, the compound or a pharmaceutically acceptable salt represented by formula III (above), wherein:
X is C,
Y is C,
R1, R2, R4 or R5 are independently selected from the group consisting of hydrogen and fluorine;
R is -C3-C7cycloalkyl optionally substituted with halogen, C C alkyl, -CrC alkylCr C4alkoxy, Ci-C4alkoxy, C C4haloalkyl, nitrile, -S(0)2C C4alkyl or -OH.
In additional embodiments of the invention, 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,
R1, R2, R4 or R5 are independently selected from the group consisting of hydrogen and halogen;
R is selected from group consisting of
4 to 7 membered heterocyclyl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, C C4alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2CrC4alkyl or -OH,
-Ci-C4alkyl-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)2CrC alkyl or -OH,
-C3-C5cycloalkyl-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, Ci-C alkoxy, C C haloalkoxy, CrC haloalkyl, Ci-C alkyl, nitrile, -S(0)2Cr C4alkyl or -OH.
In additional embodiments of the invention, 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,
R1, R2, R4 or R5 are independently selected from the group consisting of hydrogen, halogen, -CH3, and Cihaloalkyl;
R is selected from group consisting of
Figure imgf000024_0001
Figure imgf000024_0002
Figure imgf000025_0001
and
Figure imgf000025_0002
In further embodiments of the invention, the compound or a pharmaceutically acceptable salt of any of the preceding embodiments is represented by formula IV:
Figure imgf000025_0003
IV
wherein,
Y is N or C, wherein when Y is N, R5 is absent;
R1, R2, R4 or R5 are independently selected from the group consisting of hydrogen, halogen, -CH3, and Cihaloalkyl;
L is a divalent bond;
R is selected from group consisting of
Figure imgf000025_0004
Figure imgf000025_0005
In additional embodiments of the invention, the compound or a pharmaceutically acceptable salt of any of the preceding embodiments is represented by formula I, II or IV, wherein:
X is C; Y is C;
R1, R2, R4 or R5 are independently selected from the group consisting of hydrogen, halogen, -CH3 and Cihaloalkyl;
R3 is L-R;
L is a divalent bond, or -CH2-;
R is halogen,
-CrC4alkyl optionally substituted with halogen, CrC4alkoxy, -CN or -OH,
-CN,
-CrC4alkoxy optionally substituted with halogen or CrC4alkoxy, or
R2 and R3 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.
In specific embodiments of the invention, the compound is selected from:
1.1. (R)-3-((S)-3-(4-bromophenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2- (methylsulfonyl)propanamide
1.2. (R)-3-((S)-3-(4-bromo-2-methylphenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)propanamide
1.3. (R)-3-((S)-3-(4-bromo-2-fluorophenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2-methyl- 2-(methylsulfonyl)propanamide
1.4. (R)-3-((S)-3-(4-bromo-2,6-difluorophenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)propanamide
2.1. (R)-3-((S)-3-([1 ,1 '-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2- (methylsulfonyl)propanamide
2.2. (R)-3-((S)-3-(4-(3-fluoropyridin-4-yl)phenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)propanamide
2.3. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-3-(naphthalen-2-yl)-2- oxooxazolidin-5-yl)propanamide
2.4. (R)-3-((S)-3-(benzo[d]thiazol-6-yl)-2-oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2- (methylsulfonyl)propanamide
2.5. (R)-N-hydroxy-2-methyl-3-((S)-3-(1-methyl-1 H-indazol-5-yl)-2-oxooxazolidin-5- yl)-2-(methylsulfonyl)propanamide
2.6. (R)-3-((S)-3-(benzo[b]thiophen-6-yl)-2-oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2- (methylsulfonyl)propanamide
2.7. (2R)-N-hydroxy-3-((5S)-3-(4'-(2-hydroxypropyl)-[1 ,1 '-biphenyl]-4-yl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide 2.8. (R)-N-hydroxy-3-((S)-3-(4'-((R)-2-hydroxypropyl)-[1 , 1 '-biphenyl]-4-yl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.1. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(prop-1-yn-1- yl)phenyl)oxazolidin-5-yl)propanamide
3.1.2. (R)-3-((S)-3-(4-(cyclopropylethynyl)phenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)propanamide
3.1.3. (R)-3-((S)-3-(4-(but-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)propanamide
3.1.4. (2R)-N-hydroxy-3-((5S)-3-(4-(3-hydroxybut-1 -yn-1 -yl)phenyl)-2-oxooxazolidin- 5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.5. (R)-N-hydroxy-3-((S)-3-(4-(3-methoxyprop-1 -yn-1 -yl)phenyl)-2-oxooxazolidin-5- yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.6. (R)-N-hydroxy-3-((S)-3-(4-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.17. (2R)-N-hydroxy-3-((5S)-3-(4-((2-(methoxymethyl)cyclopropyl)ethynyl)phenyl)- 2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.8. (R)-N-hydroxy-3-((S)-3-(4-(3-methoxy-3-methylbut-1-yn-1-yl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.9. N-hydroxy-3-((5S)-3-(4-(3-methoxybut-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)- 2-methyl-2-(methylsulfonyl)propanamide
3.1.10. (R)-N-hydroxy-3-((S)-3-(4-(4-hydroxybut-1 -yn-1 -yl)phenyl)-2-oxooxazolidin-5- yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.1 1. (R)-N-hydroxy-3-((S)-3-(4-(4-methoxybut-1-yn-1-yl)phenyl)-2-oxooxazolidin-5- yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.12. (2R)-3-((5S)-3-(4-((2-(cyanomethyl)cyclopropyl)ethynyl)phenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.1.13. (2R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((5S)-3-(4-((2- (morpholinomethyl)cyclopropyl)ethynyl)phenyl)-2-oxooxazolidin-5-yl)propanamide
3.1.14. (R)-3-((S)-3-(4-(4-cyanobut-1 -yn-1 -yl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.1.15. N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-3-(4-(4-morpholinobut-1 -yn-1 - yl)phenyl)-2-oxooxazolidin-5-yl)propanamide
3.1.16. (2R)-N-hydroxy-3-((5S)-3-(4-((2-(hydroxymethyl)cyclopropyl)ethynyl)phenyl)- 2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.17. (2R)-N-hydroxy-3-((5S)-3-(4-(4-methoxypent-1 -yn-1 -yl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide 3.1.18. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-((tetrahydro-2H- pyran-4-yl)ethynyl)phenyl)oxazolidin-5-yl)propanamide
3.1.19. (R)-3-((S)-3-(4-((3-ethoxycyclobutyl)ethynyl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.1.20. (R)-3-((S)-3-(4-(4-fluorobut-1 -yn-1 -yl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.1.21. (R)-3-((S)-3-(4-((3-(cyanomethyl)cyclobutyl)ethynyl)phenyl)-2-oxooxazolidin- 5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.1.22. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(3-(tetrahydro- 2H-pyran-4-yl)prop-1-yn-1-yl)phenyl)oxazolidin-5-yl)propanamide
3.1.23. (R)-3-((S)-3-(4-(4,4-difluorobut-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.1.24. (R)-N-hydroxy-3-((S)-3-(4-((3-hydroxy-3-methylcyclobutyl)ethynyl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.25. (R)-N-hydroxy-3-((S)-3-(4-((3-hydroxy-3-methylcyclobutyl)ethynyl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.26. (R)-3-((S)-3-(4-(5-fluoropent-1 -yn-1 -yl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.1.27. (R)-N-hydroxy-3-((S)-3-(4-(6-methoxyhex-1-yn-1-yl)phenyl)-2-oxooxazolidin- 5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.28. (R)-N-hydroxy-3-((S)-3-(4-(6-hydroxyhex-1-yn-1-yl)phenyl)-2-oxooxazolidin-5- yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.29. (R)-3-((S)-3-(4-(5,5-difluoropent-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.1.30. (R)-N-hydroxy-3-((S)-3-(4-(5-methoxypent-1 -yn-1 -yl)phenyl)-2-oxooxazolidin- 5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.31. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-3-(4-((3- ((methylsulfonyl)methyl)cyclobutyl)ethynyl)phenyl)-2-oxooxazolidin-5-yl)propanamide
3.1.32. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(4,4,4- trifluorobut-1-yn-1-yl)phenyl)oxazolidin-5-yl)propanamide
3.1.33. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-3-(4-((3- ((methylsulfonyl)methyl)cyclobutyl)ethynyl)phenyl)-2-oxooxazolidin-5-yl)propanamide
3.1.34. (R)-3-((S)-3-(4-(5-(2H-1 ,2,3-triazol-2-yl)pent-1-yn-1-yl)phenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.1.35. (2R)-3-((5S)-3-(4-((2,2-difluorocyclopropyl)ethynyl)phenyl)-2-oxooxazolidin-5- yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide 3.1.36. (R)-N-hydroxy-3-((S)-3-(4-(((1 r,3S)-3-(2-hydroxypropan-2- yl)cyclobutyl)ethynyl)phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanam
3.1.37. (R)-N-hydroxy-3-((S)-3-(4-(5-hydroxypenta-1 ,3-diyn-1 -yl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.38. (R)-N-hydroxy-3-((S)-3-(4-(5-methoxypenta-1 ,3-diyn-1-yl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.39. (2R)-N-hydroxy-3-((5S)-3-(4-(6-hydroxyhept-1 -yn-1 -yl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.40. (R)-N-hydroxy-3-((S)-3-(4-(6-hydroxy-6-methylhept-1 -yn-1 -yl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.41. (2R)-N-hydroxy-3-((5S)-3-(4-(5-hydroxyhexa-1 ,3-diyn-1-yl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.42. (R)-3-((S)-3-(4-((3-(2-acetamidopropan-2-yl)cyclobutyl)ethynyl)phenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.1.43. (R)-3-((S)-3-(4-((3-(2-acetamidopropan-2-yl)cyclobutyl)ethynyl)phenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.1.44. (2R)-N-hydroxy-3-((5S)-3-(4-(4-hydroxypent-1 -yn-1 -yl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.45. (R)-N-hydroxy-3-((S)-3-(4-(((1s,3R)-3-hydroxycyclobutyl)ethynyl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.46. (R)-N-hydroxy-3-((S)-3-(4-(((1 r,3S)-3-hydroxycyclobutyl)ethynyl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.47. (R)-N-hydroxy-3-((S)-3-(4-(((1s,3R)-3-methoxycyclobutyl)ethynyl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.48. (R)-N-hydroxy-3-((S)-3-(4-(((1 r,3S)-3-methoxycyclobutyl)ethynyl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.49. (R)-N-hydroxy-2-methyl-3-((S)-3-(4-((1-methyl-1 H-pyrazol-4- yl)ethynyl)phenyl)-2-oxooxazolidin-5-yl)-2-(methylsulfonyl)propanamide
3.1.50. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(pent-1 -yn-1 - yl)phenyl)oxazolidin-5-yl)propanamide
3.1.51. (2R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((5S)-2-oxo-3-(4-(3- (tetrahydrofuran-3-yl)prop-1-yn-1-yl)phenyl)oxazolidin-5-yl)propanamide
3.1.52. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(pyridin-4- ylethynyl)phenyl)oxazolidin-5-yl)propanamide
3.1.53. (R)-N-hydroxy-2-methyl-3-((S)-3-(4-(3-methylbut-1-yn-1-yl)phenyl)-2- oxooxazolidin-5-yl)-2-(methylsulfonyl)propanamide 3.1.54. (R)-3-((S)-3-(4-(((1s,3R,4S)-3,4-dimethoxycyclopentyl)ethynyl)phenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.1.55. (R)-N-hydroxy-2-methyl-3-((S)-3-(4-((6-methylpyridin-3-yl)ethynyl)phenyl)-2- oxooxazolidin-5-yl)-2-(methylsulfonyl)propanamide
3.1.56. (2R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((5S)-2-oxo-3-(4- ((tetrahydrofuran-3-yl)ethynyl)phenyl)oxazolidin-5-yl)propanamide
3.1.57. (R)-N-hydroxy-3-((S)-3-(4-((3-(methoxymethyl)cyclobutyl)ethynyl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.58. (R)-N-hydroxy-3-((S)-3-(4-((3-(methoxymethyl)cyclobutyl)ethynyl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
3.1.59. (R)-3-((S)-3-(4-((3-fluorocyclobutyl)ethynyl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.1.60. (R)-3-((S)-3-(4-((3-fluorocyclobutyl)ethynyl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide 3.2.1. (R)-N-hydroxy-2-methyl-3-((S)-3-(2- methyl-4-(prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)-2-(methylsulfonyl)propanamide
3.3.1. (R)-3-((S)-3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.3.3. (R)-3-((S)-3-(2-fluoro-4-(((1 r,3S)-3-methoxycyclobutyl)ethynyl)phenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.4.1. (R)-3-((S)-3-(3-fluoro-4-(prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.5.1. (R)-N-hydroxy-2-methyl-3-((S)-3-(3-methyl-4-(prop-1-yn-1-yl)phenyl)-2- oxooxazolidin-5-yl)-2-(methylsulfonyl)propanamide
3.6.1. (R)-3-((S)-3-(3-chloro-4-(prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.7. (R)-3-((S)-3-(2,3-difluoro-4-(prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.8. (R)-3-((S)-3-(3,5-difluoro-4-(prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.9. (R)-3-((S)-3-(4-(but-1-yn-1-yl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)propanamide
3.10. (R)-3-((S)-3-(3-fluoro-4-(((1 r,3S)-3-methoxycyclobutyl)ethynyl)phenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.1 1. (R)-3-((S)-3-(4-(cyclopropylethynyl)-2-fluorophenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
3.12. (R)-3-((S)-3-(4-(cyclopropylethynyl)-3-fluorophenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide 4.1. (R)-3-((S)-3-(4-(but-2-yn-1-yloxy)phenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)propanamide
4.2. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(2,2,2- trifluoroethoxy)phenyl)oxazolidin-5-yl)propanamide
5.1.1. (R)-3-((S)-3-(4-cyclopropylphenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2- (methylsulfonyl)propanamide
5.3. (R)-N-hydroxy-3-((S)-3-(4-(methoxymethyl)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanamide
5.4. (R)-3-((S)-3-(4-(cyanomethyl)phenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2-methyl- 2-(methylsulfonyl)propanamide
5.5. (R)-N-hydroxy-3-((S)-3-(4-(2-methoxyethyl)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanamide
5.6. (2R)-N-hydroxy-3-((5S)-3-(4-(2-(2-methoxyethyl)cyclopropyl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
5.7. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4- propylphenyl)oxazolidin-5-yl)propanamide
5.8. (R)-3-((S)-3-(4-(2-(3-ethoxycyclobutyl)ethyl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
5.9. (R)-3-((S)-3-(4-((E)-but-2-en-2-yl)phenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)propanamide
5.10. (R)-3-((S)-3-(4-(2-(3-ethoxycyclobutyl)ethyl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
5.1 1. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-((E)-prop-1-en-1- yl)phenyl)oxazolidin-5-yl)propanamide
5.12. (R)-N-hydroxy-3-((S)-3-(4-(3-(3-methoxyprop-1 -yn-1 -yl)cyclobutyl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
5.13. (R)-3-((S)-3-(4-(2-cyclopropylethyl)phenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)propanamide
5.14. (R)-3-((S)-3-(4-(3-fluoropropyl)phenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)propanamide
5.15. (R)-3-((S)-3-(4-(2,2-difluoropropyl)phenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)propanamide
5.16. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-((2,2,2- trifluoroethyl)thio)phenyl)oxazolidin-5-yl)propanamide
5.17. (R)-3-((S)-3-(4-(3,3-difluoropropyl)phenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)propanamide 5.18. (R)-3-((S)-3-(4-(ethylthio)phenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2- (methylsulfonyl)propanamide
5.19. (R)-3-((S)-3-(4-(3,3-difluorocyclobutyl)phenyl)-2-oxooxazolidin-5-yl)-N-hydroxy- 2-methyl-2-(methylsulfonyl)propanamide
5.20. (R)-3-((S)-3-(4-(1 ,1-difluoropropyl)phenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)propanamide
5.21. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(pent-3-yn-1 - yl)phenyl)oxazolidin-5-yl)propanamide
5.22. (2R)-N-hydroxy-2-methyl-3-((5S)-3-(4-(2-methylcyclopropyl)phenyl)-2- oxooxazolidin-5-yl)-2-(methylsulfonyl)propanamide
5.23. (2R)-3-((5S)-3-(4-(4-fluorocyclopent-1 -en-1 -yl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
5.24. (R)-3-((S)-3-(4-((Z)-1-fluoroprop-1-en-1-yl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
5.25. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-3-(4'-(2-morpholinoethyl)- [1 , 1 '-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)propanamide
5.26. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-3-(4'-(2-morpholinoethoxy)- [1 , 1 '-biphenyl]-4-yl)-2-oxooxazolidin-5-yl)propanamide
5.27. (R)-N-hydroxy-3-((S)-3-(4'-(2-hydroxyethyl)-[1 , 1 '-biphenyl]-4-yl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide
5.28. (R)-3-((S)-3-(4-(3,6-dihydro-2H-pyran-4-yl)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide
5.29. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(tetrahydro-2H- pyran-4-yl)phenyl)oxazolidin-5-yl)propanamide
6.1. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(5-(prop-1-yn-1- yl)pyridin-2-yl)oxazolidin-5-yl)propanamide
6.2. (R)-3-((S)-3-(6-(cyclopropylethynyl)pyridin-3-yl)-2-oxooxazolidin-5-yl)-N-hydroxy- 2-methyl-2-(methylsulfonyl)propanamide
6.3. (R)-3-((S)-3-(5-(cyclopentylethynyl)pyridin-2-yl)-2-oxooxazolidin-5-yl)-N-hydroxy- 2-methyl-2-(methylsulfonyl)propanamide
6.4. (R)-3-((S)-3-(5-(cyclobutylethynyl)pyridin-2-yl)-2-oxooxazolidin-5-yl)-N-hydroxy- 2-methyl-2-(methylsulfonyl)propanamide
6.5. (R)-3-((S)-3-(5-(but-1-yn-1-yl)pyridin-2-yl)-2-oxooxazolidin-5-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)propanamide
6.6. (R)-N-hydroxy-2-methyl-3-((S)-3-(5-(3-methylbut-1-yn-1-yl)pyridin-2-yl)-2- oxooxazolidin-5-yl)-2-(methylsulfonyl)propanamide 6.7. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(5-pentylpyridin-2- yl)oxazolidin-5-yl)propanamide
6.8. (R)-3-((S)-3-(5-bromopyridin-2-yl)-2-oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2- (methylsulfonyl)propanamide
6.9. (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(5-phenylpyridin-2- yl)oxazolidin-5-yl)propanamide
6.10. (R)-3-((S)-3-(5-(cyclopropylethynyl)pyridin-2-yl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide; and
6.1 1. (R)-3-((S)-3-(5-(4-chlorophenyl)pyridin-2-yl)-2-oxooxazolidin-5-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)propanamide;
and the pharmaceutically acceptable salts of any of these species.
In another aspect, 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. In some embodiments, 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.
In another aspect, 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. Typically, 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.
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:
391779-82; Bennett et al. (2003) J. Immunol. 170:71 1-8). 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).
In one embodiment, the combination therapies of the invention include an immunomodulator that is an inhibitor or antagonist of an inhibitory molecule of an immune checkpoint molecule. In another embodiment the immunomodulator binds to a protein that naturally inhibits the immuno-inhibitory checkpoint molecule. When used in combination with antibacterial compounds, these immunomodulators can enhance the antimicrobial response, and thus enhance efficacy relative to treatment with the antibacterial compound alone.
The term "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.
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
beta. Inhibition of an inhibitory molecule can be performed by inhibition at the DNA, RNA or protein level. In some embodiments, an inhibitory nucleic acid (e.g., a dsRNA, siRNA or shRNA), can be used to inhibit expression of an inhibitory molecule. In other embodiments, 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.
By "in combination with," it is not intended to imply that the therapy or the therapeutic agents must be administered at the same time and/or formulated for delivery together, although these methods of delivery are within the scope described herein. The
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.
In certain embodiments, 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.
In some embodiments, the immunomodulator is an anti-PD-1 antibody chosen from MDX-1 106, Merck 3475 or CT- 01 1 .
In some embodiments, 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).
In some embodiments, the immunomodulator is a PD-1 inhibitor such as AMP-224.
In some embodiments, the the immunomodulator is a PD-LI inhibitor such as anti- PD-LI antibody.
In some embodiments, 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
WO2007/005874. Antibody YW243.55.S70 is an anti-PD-LI described in WO 2010/077634.
In some embodiments, 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
WO2006/121 168.
In some embodiments, the immunomodulator is an anti-PD-1 antibody
Pembrolizumab. Pembrolizumab (also referred to as Lambrolizumab, MK-3475, MK03475, SCH-900475 or KEYTRUDA®; Merck) 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,
WO2009/1 14335, and WO2013/079174. In some embodiments, 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 .
Other 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. In some embodiments, the anti-PD- L1 antibody is MSB0010718C. MSB0010718C (also referred to as A09-246-2; Merck Serono) is a monoclonal antibody that binds to PD-L1 .
In some embodiments, 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.
In some embodiments, 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 .
In some embodiments, 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
In certain embodiments, the combination therapies disclosed herein include a modulator of a costimulatory molecule or an inhibitory molecule, e.g., a co-inhibitory ligand or receptor.
In one embodiment, 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.
In another embodiment, 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.
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. Patent No.: 8,591 ,886, European Patent No.: EP 1866339, PCT Publication No.: WO 201 1/028683, PCT Publication No. :WO 2013/039954, PCT Publication No.: WO2005/007190, PCT Publication No.: WO
2007/133822, PCT Publication No.: WO2005/055808, PCT Publication No.: WO 99/40196, PCT Publication No.: WO 2001/03720, PCT Publication No.: WO99/20758, PCT Publication No.: WO2006/083289, PCT Publication No.: WO 2005/1 15451 , U.S. Patent No.: 7,618,632, and PCT Publication No.: WO 201 1/051726.
In one embodiment, 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. For example, the anti-PD-1 antibody molecule can be administered in combination with an anti-CTLA-4 antibody, e.g., ipilimumab, for example. Exemplary 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).
In one embodiment, an anti-PD-1 antibody molecule is administered after treatment with a compound of the invention as described herein.
In another embodiment, 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. In another embodiment, the anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-TIM-3 antibody or antigen-binding fragment thereof. In yet other embodiments, 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. In one embodiment, 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. In certain
embodiments, the combination of antibodies recited herein is used to treat 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).
Exemplary 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
(CC4047); and cytokines, e.g., IL-21 or IRX-2 (mixture of human cytokines including interleukin 1 , interleukin 2, and interferon γ, CAS 951209-71-5, available from IRX
Therapeutics).
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.
Examples of embodiments of the methods of using the antibacterial compounds of the invention in combination with an immunomodulator include these:
1. 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.
2. The method of embodiment 1 , wherein the immunomodulator is an activator of a costimulatory molecule or an inhibitor of an immune checkpoint molecule.
3. The method of either of embodiments 1 and 2, wherein 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.
4. The method of any of embodiments 1-3 above, wherein the 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.
5. The method of any of any of embodiments 1-3, wherein the 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.
6. The method of any of embodiments 1-5, wherein the inhibitor of the immune checkpoint molecule is a soluble ligand or an antibody or antigen-binding fragment thereof, that binds to the immune checkpoint molecule.
7. The method of any of embodiments 1-6, wherein the antibody or antigen-binding fragment thereof is from an lgG1 or lgG4 (e.g., human lgG1 or lgG4).
8. The method of any of embodiments 1-9, wherein the antibody or antigen-binding fragment thereof is altered, e.g., mutated, to increase or decrease one or more of: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function.
9. The method of any of embodiments 1-8, wherein 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.
10. The method of any of embodiments 1-9, wherein the immunomodulator is an anti-PD-1 antibody chosen from Nivolumab, Pembrolizumab or Pidilizumab. 11. The method of any of embodiments 1-10, wherein the immunomodulator is an anti-PD-L1 antibody chosen from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-
0010718C, or MDX-1 105.
12. The method of any of embodiments 1-10, wherein the immunomodulator is an anti-LAG-3 antibody molecule.
13. The method of embodiment 12, wherein the anti-LAG-3 antibody molecule is BMS-986016.
14. The method of any of embodiments 1-10, wherein the immunomodulator is an anti-PD-1 antibody molecule administered by injection (e.g., subcutaneously or
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.
15. The method of embodiment 14, wherein the anti-PD-1 antibody molecule is administered at a dose from about 10 to 20 mg/kg every other week.
16. The method of embodiment 15, wherein the anti-PD-1 antibody molecule, e.g., Nivolumab, is administered intravenously at a dose from about 1 mg/kg to 3 mg/kg, e.g., about 1 mg/kg, 2 mg/kg or 3 mg/kg, every two weeks.
17. The method of claim 15, wherein the anti-PD-1 antibody molecule, e.g., Nivolumab, is administered intravenously at a dose of about 2 mg/kg at 3-week intervals.
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.
Compounds of the present invention and intermediates can also be converted into each other according to methods generally known to those skilled in the art.
Within the scope of this text, only a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention is designated a "protecting group", unless the context indicates otherwise. 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. Meienhofer), Academic Press, London and New York 1981 , in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jeschkeit, "Aminosauren, Peptide, Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic of protecting groups is that they can be removed readily (i.e. without the occurrence of undesired secondary reactions) for example by solvolysis, reduction, photolysis or alternatively under physiological conditions (e.g. by enzymatic cleavage).
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. For example, 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. 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.
Mixtures of isomers obtainable according to the invention can be separated in a manner known to those skilled in the art into the individual isomers; 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.
The following applies in general to all processes mentioned herein before and hereinafter.
All the above-mentioned process steps can be carried out under reaction conditions that are known to those skilled in the art, 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 nitrogen atmosphere.
At all stages of the reactions, 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".
The 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, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, methycyclohexane, or mixtures of those solvents, for example aqueous solutions, unless otherwise indicated in the description of the processes. Such solvent mixtures may also be used in working up, for example by chromatography or partitioning.
The compounds of the present invention, 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.
All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21 ).
The term "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)-.
Depending on the choice of the starting materials and procedures, 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 mixtures of isomers can be separated on the basis of the
physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
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. In particular, 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
chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their
crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such 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. The term "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.
As used herein, the terms "salt" or "salts" refers to an acid addition or base addition salt of a compound of the present invention. "Salts" include in particular "pharmaceutically acceptable salts". The term "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. In many cases, 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 phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate and trifluoroacetate salts.
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. In certain embodiments, 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. Generally, 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. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
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. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18F 31P, 32P, 35S, 36CI, 125l respectively. The invention includes various isotopically labeled compounds of the present invention, for example those into which radioactive isotopes, such as 3H and 14C, or those into which non-radioactive isotopes, such as 2H and 13C are present. Such isotopically labelled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), 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. In particular, an 18F 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.
Further, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the present invention. The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If 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).
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D20, de-acetone, d6-DMSO.
Compounds of the present invention that contain groups capable of acting as donors and/or acceptors for hydrogen bonds 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.
All methods described herein can be performed in any suitable order unless otherwise indicated or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided herein is intended merely to better illuminate the invention and not as a limitation on the scope of the claimed invention.
Substitution with heavier isotopes such as deuterium, i.e. 2H, 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. For example, deuterium substitution at non-exchangeable hydrocarbon bonds (e.g., C-H) may retard epimerization and/or metabolic oxidation in vivo.
Isotopically-labeled compounds of the invention, i.e. 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.
In another aspect, 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.
In still another aspect, 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.
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.
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). For these conditions, 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.
For sepsis, septic shock, systemic inflammation, localized inflammation, chronic obstructive pulmonary disease (COPD) and acute exacerbations of chronic bronchitis (AECB), 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.
In treatment of serious or chronic respiratory tract infections, 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. In particular, 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.
By the term "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.
When used for treating Gram-negative bacteria, 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:
(1 ) Macrolides or ketolides such as erythromycin, azithromycin, clarithromycin, and telithromycin;
(2) 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 ;
(3) Monobactams such as aztreonam;
(4) Quinolones such as nalidixic acid, oxolinic acid, norfloxacin, pefloxacin, enoxacin, ofloxacin, levofloxacin, ciprofloxacin, temafloxacin, lomefloxacin, fleroxacin, grepafloxacin, sparfloxacin, trovafloxacin, clinafloxacin, gatifloxacin, moxifloxacin, sitafloxacin,
ganefloxacin, gemifloxacin and pazufloxacin;
(5) Antibacterial sulfonamides and antibacterial sulphanilamides, including para- aminobenzoic acid, sulfadiazine, sulfisoxazole, sulfamethoxazole and sulfathalidine;
(6) Aminoglycosides such as streptomycin, neomycin, kanamycin, paromycin, gentamicin, tobramycin, amikacin, netilmicin, spectinomycin, sisomicin, dibekalin and isepamicin;
(7) Tetracyclines such as tetracycline, chlortetracycline, demeclocycline, minocycline, oxytetracycline, methacycline, doxycycline, tegacycline;
(8) Rifamycins such as rifampicin (also called rifampin), rifapentine, rifabutin, bezoxazinorifamycin and rifaximin;
(9) Lincosamides such as lincomycin and clindamycin;
(10) Glycopeptides such as vancomycin and teicoplanin;
(1 1 ) Streptogramins such as quinupristin and daflopristin;
(12) Oxazolidinones such as linezolid;
(13) Polymyxin, colistin and colymycin;
(14) Trimethoprim and bacitracin.
(15) Efflux pump inhibitors. 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. When simultaneous administration of a compound of the invention with a second agent is desired and the route of administration is the same, then 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.
When used for treating serious or chronic respiratory tract infections, the compounds of the invention may be used alone or in combination with a second antibacterial agent administered via inhalation. In the case of inhalation, a preferred second antibacterial agent is selected from a group consisting of tobramycin, gentamicin, aztreonam, ciprofloxacin, polymyxin, colistin, colymycin, azithromycin and clarithromycin.
While the compounds of the invention are often less susceptible to beta-lactamases that confer resistance to other monobactams in drug-resistant bacteria, their activity may be enhanced in some resistant strains by use in combination with a beta-lactamase inhibitor (BLI). Suitable BLI's include clavulanic acid, sulbactam, tazobactam, avibactam, and various BLIs disclosed in WO2014/152996, WO2013/149136, and US2013/02813459. Accordingly, the invention also provides 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.
The language "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. In an example, an effective amount of the LpxC inhibitor is the amount sufficient to treat bacterial infection in a subject. In another example, 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.
The language "pharmaceutical composition" includes preparations suitable for administration to mammals, e.g., humans. When the compounds of the present invention are administered as pharmaceuticals to mammals, e.g., humans, they can be given per se or as a 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.
The phrase "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. Some examples of 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's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.
Wetting agents, emulsifiers and lubricants, 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.
Examples of pharmaceutically acceptable antioxidants 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.
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. In general, 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.
In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), 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 monostearate; absorbents, such as kaolin and bentonite clay; lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical 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, such as dragees, capsules, pills and granules, 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. They 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. Examples of 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. In addition to the active ingredient, 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.
Besides inert diluents, the oral compositions can also include 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.
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.
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.
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. Such 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, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
Pharmaceutical 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.
Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention 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. 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.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of
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.
In some cases, 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
poly(orthoesters) and poly(anhydrides). 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.
The phrases "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.
The phrases "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" as used herein mean 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.
Regardless of the route of administration selected, 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. For example, 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.
In general, 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. Generally, 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.
If desired, 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.
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.
General Synthetic Schemes
One method for synthesizing compounds with formula (I) was described in Scheme A. The synthesis started with protecting 4-bromoanaline A-1 as benzyl carbmate A-2.
Deprotonation of compound A-2 followed by reacting with (R)-glycidyl butyrate yielded the oxazolidinone alcohol A-3, which was then converted to iodide A-4. Compound A-4 was coupled with ethyl 2-(methylsulfonyl)propanoate under basic condition to provide compound A-5. Various fragment R3 could be coupled with aryl bromide A-5 to give ester A-6. Ester A-6 was converted to hydroxamic acid I via saponification of the ethyl ester, amidation of the free acid with 0-(tetrahydro-2Hpyran-2-yl)hydroxylamine (THPONH2) and THP deprotection under acid condition.
Scheme A
Figure imgf000057_0001
Figure imgf000057_0002
Figure imgf000057_0003
The intermediate A-4 could also be synthesis by general method described in
Scheme B. Reaction between amine A-1 and epichlorohydrin under heating condition provided epoxide opening product B-1. Cyclization of aminoalcohol B-1 by treating with CDI provide oxazolidinone B-2. The chloride B-2 was then displaced with iodide to provide compound A-4.
Scheme B
Figure imgf000058_0001
Figure imgf000058_0002
B-2
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.
Scheme C
Figure imgf000058_0003
Figure imgf000058_0004
Compounds of the invention are prepared from commonly available compounds using procedures known to those skilled in the art, including any one or more of the following conditions without limitation:
Within the scope of this text, only a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention is designated a "protecting group," unless the context indicates otherwise. 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
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. Meienhofer), Academic Press, London and New York 1981 , in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D.
Jakubke and H. Jeschkeit, "Aminosauren, Peptide, Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic of protecting groups is that they can be removed readily (i.e. , without the occurrence of undesired secondary reactions) for example by solvolysis, reduction, photolysis or alternatively under physiological conditions (e.g., by enzymatic cleavage).
Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known per se. For example, 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. 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.
Mixtures of isomers obtainable according to the invention 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 nitrogen atmosphere.
At all stages of the reactions, 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.
The 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, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, or mixtures of those solvents, for example aqueous solutions, unless otherwise indicated in the description of the processes. Such solvent mixtures may also be used in working up, for example by chromatography or partitioning.
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.
In accordance with the foregoing the invention provides in a yet further aspect:
• 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.
The terms "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. Alternatively, to decrease the number of dosage forms administered to a patient, the compound of the invention and any additional agent may be formulated together in any combination. For example, 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.
Alternatively, a 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.
The invention is further illustrated by the following examples, which should not be construed as further limiting. The assays used throughout the Examples are accepted in the art as being predictive of efficacy for treating subjects.
GENERAL SYNTHESIS METHODS
All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21 ). Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples.
LIST OF ABBREVIATIONS
Ac acetyl
ACN Acetonitrile
AcOEt / EtOAc Ethyl acetate
AcOH acetic acid
aq aqueous
Ar aryl
Bn benzyl
Bu butyl (nBu = n-butyl, tBu = tert-butyl)
CDI Carbonyldiimidazole
CH3CN Acetonitrile
DBU 1 ,8-Diazabicyclo[5.4.0]-undec-7-ene
Boc20 di-tert-butyl dicarbonate
DCE 1 ,2-Dichloroethane
DCM Dichloromethane
DiBAI-H Diisobutylaluminum Hydride DIPEA N-Ethyldiisopropylamine
DMAP Dimethylaminopyridine
DMF N,N'-Dimethylformamide
DMSO Dimethylsulfoxide
El Electrospray ionisation
Et20 Diethylether
Et3N Triethylamine
Ether Diethylether
EtOAc Ethylacetate
EtOH Ethanol
FC Flash Chromatography
h hour(s)
HATU 0-(7-Azabenzotriazole-1-yl)-N,N,N'N'- tetramethyluronium hexafluorophosphate
HBTU 0-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
HCI Hydrochloric acid
HMPA Hexamethylphosphoramide
HOBt 1-Hydroxybenzotriazole
HPLC High Performance Liquid Chromatography
H20 Water
L liter(s)
LC-MS Liquid Chromatography Mass Spectrometry
LiHMDS Lithium bis(trimethylsilyl)amide
MgS04 Magnesium Sulfate
Me methyl
Mel lodomethane
MeOH Methanol
mg milligram
min minute(s)
mL milliliter
MS Mass Spectrometry
NaHC03 Sodium Bicarbonate
Na2S04 Sodium Sulfate
NH2OH hydroxylamine
Pd/C palladium on charcoal
Pd(OH)2 palladium hydroxide PG protecting group
Ph phenyl
Ph3P triphenyl phosphine
Prep Preparative
Rf ratio of fronts
RP reverse phase
Rt Retention time
rt Room temperature
Si02 Silica gel
SOCI2 Thionyl Chloride
TBAF Tetrabutylammonium fluoride
TEA Triethylamine
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TLC Thin Layer Chromatography
1-1. Synthesis of compound 1.1
Figure imgf000064_0001
Reagents: Step 1 : CBZ-CI, NaHC03, 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: NH2OTHP, EDC.HCI, HOBt, TEA, dichloromethane, room temperature. Step 7: 35.5% aq. HCI, EtOH, room temperature. Step 1. Synthesis of benzyl (4-bromophenyl) carbamate [1.1a] 4- Bromoaniline (5.0 g, 29.1 mmol, 1.0 equiv) was dissolved in acetone: water (2:1 , 45 ml_) mixture. The solution was cooled to 5 °C and NaHC03 (5.13 g, 61.1 mmol, 2.1 equiv), CBZ-CI (4.96 g, 29.1 mmol, 1.0 equiv) were added. The reaction mixture was stirred at room temperature for 3 hours, then quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to obtain a crude residue. The residue was purified by silica gel column chromatography (8-10 % EtOAc/Hexane) to afford product 1.1a (8.0 g, 90 % yield). LCMS (m/z): 306.3 [M+H]. 1H NMR (400 MHz, CDCI3) δ 7.45 - 7.38 (m, 7H), 7.31 (d, J = 8.6 Hz, 2H), 6.70 (s, 1 H), 5.21 (d, J = 8.7 Hz, 2H).
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. (R)-oxiran-2-ylmethyl butyrate (2.82 g, 19.6 mmol, 1.0 equiv) was added, the reaction mixture was stirred at -75 °C for 1 hour, allowed to attain room temperature, and stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (50-60% EtOAc/Hexane) to afford product 1.1 b (3.5 g, 65.6 % yield). LCMS (m/z): 274.1 [M+H]. 1H NMR(400 MHz, DMSO d- 6) δ 7.64 - 7.49 (m, 4H), 5.23 (t, J = 5.7 Hz, 1 H), 4.71 (td, J = 9.4, 3.7 Hz, 1 H), 4.08 (t, J = 9.0 Hz, 1 H), 3.82 (dd, J = 8.8, 6.2 Hz, 1 H), 3.68 (ddd, J = 12.3, 5.5, 3.4 Hz, 1 H), 3.56 (ddd, J = 12.3, 5.8, 4.1 Hz, 1 H).
Step 3. Synthesis of (R)-3-(4-bromophenyl)-5-(iodomethyl) oxazolidin-2-one [1.1c]
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. The residue was purified by silica gel column chromatography (20-30% EtOAc/Hexane) to afford product 1.1c (1.5 g, 53.4 % yield). LCMS (m/z): 382.1 [M+H]. 1H NMR (400 MHz, DMSO d-6) δ 7.69 - 7.48 (m, 4H), 4.75 (td, J = 10.8, 5.1 Hz, 1 H), 4.27 - 4.13 (m, 1 H), 3.72 - 3.53 (m, 3H).
Step 4. Synthesis of ethyl 3-((S)-3-(4-bromophenyl)-2-oxooxazolidin-5-yl)-2-methyl-2- (methylsulfonyl) propanoate [1.1 d]
Ethyl 2-(methylsulfonyl) propanoate (0.95 g, 5.2 mmol, 2.0 equiv) dissolved in N,N- dimethylformamide (6 mL) and cooled to 0-5 °C. NaH (60 %) (0.157 g, 3.9 mmol, 1.5 equiv) was added in portion wise and the reaction mixture was stirred at room temperature for 1.5 hours. A solution of 1.1c (1.0 g, 26.2 mmol, 1.0 equiv) in N,N-dimethylformamide (4 ml_) was added drop wise at 5 °C. The reaction mixture was stirred at 5 °C for 30 minutes. The reaction mixture was allowed to stir at room temperature for 2 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. The residue was purified by silica gel column chromatography (20-25 % EtOAc/Hexane) to afford product 1.1d (0.165 g, 14.5 % yield). In some cases, 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. LCMS (m/z): 436.3 [M+H]. 1H NMR (400 MHz, DMSO d-6) δ 7.64 - 7.56 (m, 2H), 7.54 - 7.48 (m, 2H), 4.96 - 4.75 (m, 1 H), 4.31 - 4.16 (m, 2H), 3.85 - 3.73 (m, 1 H), 3.22 - 3.10 (m, 4H), 2.68 (dd, J = 14.9, 2.5 Hz, 1 H), 2.36 (dd, J = 14.7, 8.9 Hz, 1 H), 1.61 (d, J = 27.1 Hz, 3H), 1.26 (dd, J = 8.5, 5.7 Hz, 3H). Step 5. Synthesis of 3-((S)-3-(4-bromophenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methyl sulfonyl) propanoic acid [1.1e]
1.1d (0.15 g, 0.34 mmol, 1.0 equiv) was dissolved in THF (2.0 ml_), MeOH (1.0 ml_). LiOH (0.025 g, 1.04 mmol, 3.0 equiv) in water (1 ml_) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness and the residue was diluted with water, acidified by 1.0 N HCI aqueous solution to the pH 4 to 5 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford compound 1.1e (0.1 1 g, 78.3 % yield). The crude material was used in the next step with no further purification. LCMS (m/z): 408.2 [M+H]. 1H NMR (400 MHz, DMSO d-6) δ 7.57 (d, J = 8.9 Hz, 2H), 7.49 (d, J = 9.1 Hz, 2H), 4.78 (d, J = 7.9 Hz, 1 H), 4.19 (d, J = 8.9 Hz, 1 H), 3.79 (t, J = 8.1 Hz, 1 H), 3.13 (s, 3H), 2.70 - 2.57 (m, 1 H), 2.30 (dd, J = 14.3, 9.0 Hz, 1 H), 1.59 (s, 3H).
Step 6. Synthesis of 3-((S)-3-(4-bromophenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methyl sulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [1.1f]
1.1e (0.1 1 g, 0.27 mmol, 1.0 equiv) was dissolved in dichloromethane (4 ml_). Et3N (0.137 g, 1.35 mmol, 5.0 equiv), EDC.HCI (0.078 g, 0.41 mmol, 1.5 equiv), HOBT (0.066 g, 0.49 mmol, 1.8 equiv) and 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.064 g, 0.54 mmol, 2.0 equiv) were added to the solution. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (70-75% EtOAc/Hexane) to afford product 1.1f which was used as such for next step (0.075 g, 54.7 % yield). LCMS (m/z): 522.4 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.58 (t, J = 6.0 Hz, 2H), 7.51 (dd, J = 8.0, 6.7 Hz, 2H), 4.67 (d, J = 8.1 Hz, 1 H), 4.17 (t, J = 8.8 Hz, 1 H), 4.04 (s, 1 H), 3.78 (t, J = 8.2 Hz, 1 H), 3.07 (t, J = 8.2 Hz, 3H), 2.78 (d, J = 12.2 Hz, 1 H), 2.23 (dd, J = 13.4, 8.2 Hz, 1 H), 1.59 - 1.41 (m, 6H).
Step 7. Synthesis of (R)-3-((S)-3-(4-bromophenyl)-2-oxooxazolidin-5-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl) propanamide [1.1]
1.1f (0.07 g, 0.14 mmol, 1.0 equiv) was dissolved in ethanol (2.0 ml_), 35.5% aqueous HCI (0.5 ml_) was added and reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and residue was triturated with n-pentane. The solvent was decanted and the crude product was further purified by preparative HPLC purification to afford the product 1.1 as desired diasteromer (0.023 g, 39.5 % yield). LCMS (m/z): 423.2 [M+H]. 1H NMR (400 MHz, CD3CN) δ 9.56 (s, 1 H), 7.53 (dd, J = 24.8, 9.1 Hz, 4H), 4.76 - 4.62 (m, 1 H), 4.16 (t, J = 8.7 Hz, 1 H), 3.76 (t, J = 8.3 Hz, 1 H), 3.00 (d, J = 23.6 Hz, 3H), 2.83 - 2.70 (m, 1 H), 2.33 (dd, J = 14.4, 9.0 Hz, 1 H), 2.18 (s, 3H), 1.66 (d, J = 21.6 Hz, 3H). -2. Synthesis of compound 1.2
Figure imgf000067_0001
Reagents: Step 1 : CBZ-CI, NaHC03, 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%), Ν,Ν-dimethylformamide, 0°C to room temperature. Step 5: LiOH, THF, MeOH, Water, room temperature. Step 6: NH2OTHP, 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]
4- Bromo-2-methylaniline (3.0 g, 16.1 mmol, 1.0 equiv) was dissolved in acetone: water (2:1 , 27 mL) and the solution was cooled to 0°C. NaHC03 (2.84 g, 33.8 mmol, 2.1 equiv), CBZ-CI (2.75 g, 16.1 mmol, 1.0 equiv) were added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to obtain a crude residue. The residue was purified by silica gel column chromatography (5-8 % EtOAc in Hexane) to afford product 1.2a (4.8 g, 92.9 % yield). LCMS (m/z): 320.2 [M-H]. 1H NMR (400 MHz, DMSO) δ 9.08 (s, 1 H), 7.82 -
7.06 (m, 8H), 5.14 (s, 2H), 2.27 (d, J = 54.4 Hz, 3H).
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. (R)-oxiran-2-ylmethyl butyrate (0.91 g, 6.3 mmol, 1.01 equiv) was added, the reaction mixture was stirred at -78° for 15 minutes and allowed to attain room temperature for 24 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (10-35 % EtOAc in Hexane) to afford product 1.2b (1.30 g, 73.0 % yield). LCMS (m/z): 286.2 [M-H]. 1H NMR (400 MHz, DMSO) δ 7.64 - 7.40 (m, 2H), 7.29 (d, J = 8.4 Hz, 1 H), 5.26 (t, J = 5.7 Hz, 1 H), 4.71 (td, J = 9.3, 3.8 Hz, 1 H), 4.03 - 3.89 (m, 1 H), 3.77 - 3.63 (m, 2H), 3.61 - 3.48 (m, 1 H), 2.22 (s, 3H).
Step 3. Synthesis of (R)-3-(4-bromo-2-methylphenyl)-5-(iodomethyl)oxazolidin-2-one
[1.2c]. Triphenylphosphine (1.54 g, 5.9 mmol, 1.3 equiv) and imidazole (0.40 g, 5.9 mmol, 1.3 equiv) were dissolved in dichloromethane (15 mL). Iodine (1.49 g, 5.9 mmol, 1.3 equiv) was added and the reaction mixture was stirred at room temperature for 15 min. 1.2b (1.3 g, 4.5 mmol, 1.0 equiv) was dissolved in dichloromethane (10 mL) and added dropwise. The reaction mixture was stirred at room temperature for 10 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. The residue was purified by silica gel column chromatography (10-25 % EtOAc in Hexane) to afford product 1.2c (1.28 g, 74.4 % yield). LCMS (m/z): 396.1 [M-H]. 1H NMR (400 MHz, DMSO) δ 7.65 - 7.43 (m, 2H), 7.33 (d, J = 8.4 Hz, 1 H), 4.76 (td, J = 10.8, 5.1 Hz, 1 H), 4.16 - 3.95 (m, 1 H), 3.72 - 3.51 (m, 3H), 2.26 (s, 3H).
Step 4. Synthesis of ethyl (R)-3-((S)-3-(4-bromo-2-methylphenyl)-2-oxooxazolidin-5-yl)- 2-methyl-2-(methylsulfonyl)propanoate [1.2d]. Ethyl 2-(methylsulfonyl)propanoate (1.91 g, 10.6 mmol, 4.0 equiv) was dissolved in N,N-dimethylformamide (14 mL) and cooled the reaction mixture to 0-5°C. NaH (60 %) (0.13 g, 5.3 mmol, 2.0 equiv) was added and the reaction mixture was stirred at the same temperature for 1 hour. A solution of 1.2c (1.05 g,
2.7 mmol, 1.0 equiv) in N,N-dimethylformamide (4 mL) was added drop wise at 0-5°C and the reaction mixture was allowed to stir at room temperature for 24 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 crude residue. The residue was purified by silica gel column chromatography (10-30 % EtOAc in Hexane) to afford product 1.2d as mixture of diastereomers. The product was further purified by preparative HPLC to afford 1.2d as the desired diastereomer (0.64 g, 53.4 % yield). LCMS (m/z): 448.3 [M-H]. 1H NMR (400 MHz, DMSO) δ 7.62 - 7.42 (m, 2H), 7.33 (d, J = 8.5 Hz, 1 H), 5.01 - 4.75 (m, 1 H), 4.39 - 4.19 (m, 2H), 4.1 1 (ddd, J = 26.7, 6.7, 4.2 Hz, 1 H), 3.69 (dd, J = 27.8, 19.3 Hz, 1 H), 3.28 - 3.06 (m, 3H), 2.68 (d, J = 14.8 Hz, 1 H), 2.39 (dd, J = 14.6, 8.9 Hz, 1 H), 2.30 - 2.13 (s, 3H), 1.74 - 1.51 (m, 3H), 1.27 - 1.22 (m, 3H).
Step 5. Synthesis of (R)-3-((S)-3-(4-bromo-2-methylphenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoic acid [1.2e]. 1.2d (0.2 g, 0.44 mmol, 1.0 equiv) was dissolved in THF (4 mL) and MeOH (2 ml_). LiOH (0.037 g, 0.89 mmol, 2.0 equiv) in water (1 mL) was added and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness, the residue was diluted with water, acidified by 1 N HCI aqueous solution to the pH 4 to 5 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 1.2e (0.175 mg, 93.3 % yield). The crude material was used in the next step with no further purification. LCMS (m/z): 422.1 [M+H]. 1H NMR (400 MHz, DMSO) δ 14.12 (s, 1 H), 7.62 - 7.42 (m, 2H), 7.34 (d, J = 8.5 Hz, 1 H), 4.84 (d, J = 5.8 Hz, 1 H), 4.04 (dd, J = 10.7, 6.1 Hz, 1 H), 3.72 (t, J = 8.1 Hz, 1 H), 3.16 (s, 3H), 2.64 (d, J = 14.7 Hz, 1 H), 2.36 (dd, J = 14.6, 8.7 Hz, 1 H), 2.22 (s, 3H), 1.62 (s, 3H).
Step 6. Synthesis of (2R)-3-((S)-3-(4-bromo-2-methylphenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [1.2f]
1.2e (0.20 g, 0.44 mmol, 1.0 equiv) was dissolved in THF (6 mL). Et3N (0.26 g, 2.2 mmol, 5.0 equiv), EDC.HCI (0.16 g, 0.8 mmol, 1.8 equiv), HOBT (0.09 g, 0.7 mmol, 1.5 equiv) and 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.1 1 g, 0.9 mmol, 2.0 equiv) were added to the solution. The reaction mixture was stirred at room temerature for 24 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. The residue was purified by silica gel column chromatography (10-40 % EtOAc in Hexane) to afford product 1.2f which was used as such for next step (0.15 g, 71.4 % yield). LCMS (m/z): 538.3 [M+18].
Step 7. Synthesis of (R)-3-((S)-3-(4-bromo-2-methylphenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide [1.2]
1.2f (0.15 g, 0.28 mmol, 1.0 equiv) was dissolved in methanol (2.0 mL). Methanolic HCI solution (8% w/w, 2.0. mL) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness and the crude product was purified by preparative HPLC to afford product 1.2 as desired diastereomer (0.08 g, 56.1 % yield). LCMS (m/z): 452.3 [M+18]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 9.29 (s, 1 H), 7.62 - 7.44 (m, 2H), 7.33 (d, J = 8.5 Hz, 1 H), 4.68 (d, J = 6.2 Hz, 1 H), 3.99 (t, J = 8.5 Hz, 1 H), 3.69 (t, J = 8.2 Hz, 1 H), 3.09 (s, 3H), 2.77 (d, J = 16.3 Hz, 1 H), 2.35 - 2.15 (m, 4H), 1.61 (s, 3H). -3. Synthesis of compound 1.3
Figure imgf000070_0001
Reagents: Step 1 : CBZ-CI, NaHC03, 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.H20, THF, MeOH, Water, room temperature. Step 6: NH2OTHP, EDC.HCI, HOBt, NMM, THF, room temperature. Step 7: 35.5% aq. HCI, EtOH, room temperature.
Step 1. Synthesis of benzyl (4-bromo-2-fluorophenyl)carbamate [1.3a]
4-bromo-2-fluoroaniline (5.0 g, 26.3 mmol, 1.0 equiv) was dissolved in acetone: water (2:1 , 100 mL) mixture. The solution was cooled to 5 °C and NaHC03 (4.42 g, 52.6 mmol, 2.0 equiv) , CBZ-CI (6.73 g, 39.5 mmol, 1.0 equiv) were added. The reaction mixture was stirred at room temperature for 4 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 afford product 1.3a (7.80 g, 91.8% yield). LCMS (m/z): 321.9 [M-H]. 1H NMR (400 MHz, DMSO) δ 9.63 (s, 1 H), 7.66 (t, J = 8.5 Hz, 1 H), 7.57 (dd, J = 10.4, 2.2 Hz, 1 H), 7.37 (ddt, J = 9.7, 7.9, 6.6 Hz, 6H), 5.16 (s, 2H).
Step 2. Synthesis of (R)-3-(4-bromo-2-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2- one [1.3b]
1. 3a (3.0 g, 9.3 mmol, 1.0 equiv) was dissolved in THF (50 mL) and cooled to -75 °C. n-BuLi (23 % in hexane) (1.19 g, 18.6 mmol, 2.0 equiv) was gradually added and the reaction mixture was stirred at -75 °C for 1 hour. (R)-oxiran-2-ylmethyl butyrate (1.61 g, 11.15 mmol, 1.2 equiv) was added, the reaction mixture was stirred at -75 °C for 1 hour, allowed to attain room temperature and stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (50-60 % EtOAc in Hexane) to afford product 1.3b (1.6 g, 59.7% yield). LCMS (m/z): 290.2 [M+] 1H NMR (400 MHz, DMSO) δ 7.70 (dd, J = 10.7, 2.0 Hz, 0.5H), 7.58 - 7.46 (m, 1.5H), 7.39 - 7.23 (m, 1 H), 5.31 (d, J = 53.6 Hz, 1 H), 4.73 (ddd, J = 13.0, 6.4, 4.0 Hz, 1 H), 4.09 - 3.97 (m, 1 H), 3.80 (t, J = 7.4 Hz, 1 H), 3.73 - 3.64 (m, 1 H), 3.63 - 3.53 (m, 1 H).
Step 3. Synthesis of (R)-3-(4-bromo-2-fluorophenyl)-5-(iodomethyl)oxazolidin-2-one
[1.3c]. Triphenylphosphine (1.88 g, 7.2 mmol, 1.3 equiv) and imidazole (0.49 g, 7.2 mmol, 1.3 equiv) were dissolved in THF (25 ml_). Iodine (1.83 g, 7.2 mmol, 1.3 equiv) was added and the reaction mixture was stirred at room temperature for 10 minutes. A solution of 1.3b (1.60 g, 5.5 mmol, 1.0 equiv) in THF (5 ml_) was added dropwise. The reaction mixture was stirred at room temperature for 5 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. The residue was purified by silica gel chromatography (15-20% EtOAc in Hexane) to afford product 1.3c (1.4 g, 63.6 % yield). LCMS (m/z): 401.99 [M+2], 1H NMR (400 MHz, DMSO) δ 7.72 (dd, J = 10.7, 2.0 Hz, 0.5H), 7.61 - 7.47 (m, 1.5H), 7.39 - 7.24 (m, 1 H), 4.78 (td, J = 9.8, 4.9 Hz, 1 H), 4.15 (td, J = 8.8, 1.6 Hz, 1 H), 3.71 - 3.52 (m, 3H).
Step 4. Synthesis of (R)-ethyl 3-((S)-3-(4-bromo-2-fluorophenyl)-2-oxooxazolidin-5-yl)- 2-methyl-2-(methylsulfonyl)propanoate [1.3d]. Ethyl 2-(methylsulfonyl)propanoate (2.53 g, 14.0 mmol, 4.0 equiv) dissolved in N,N-dimethylformamide (25 ml_) and cooled to 0-5 °C. NaH (60%) (0.17 g, 7.0 mmol, 2.0 equiv) was added in portion wise and the reaction mixture was stirred at room temperature for 2 hours. A solution of 1.3c (1.4 g, 3.51 mmol, 1.0 equiv) in N,N-dimethylformamide (5 ml_) was added drop wise. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (50-60 % EtOAc in Hexane) to afford 1.3d as mixture of diastereomers. The product was further purified by preparative HPLC to afford product 1.3d as desired diastereomer (0.35 g, 22.2% yield). LCMS (m/z): 471.3 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.78 - 7.68 (m, 1 H), 7.60 - 7.47 (m, 2H), 4.94 - 4.76 (m, 1 H), 4.25 (q, J = 7.1 Hz, 2H), 4.1 1 (t, J = 8.4 Hz, 1 H), 3.80 (t, J = 8.2 Hz, 1 H), 3.17 (s, 3H), 2.75 - 2.64 (m, 1 H), 2.37 (dd, J = 14.8, 8.7 Hz, 1 H), 1.64 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H).
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. The reaction mixture was concentrated to dryness and the residue was diluted with water, acidified by 1 N HCI aqueous solution to the pH 4 to 5 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford compound 1.3e (0.1 1 g, 90.2% yield). The crude material was used in the next step with no further purification. LCMS (m/z): 426.2 [M+2]. 1H NMR (400 MHz, DMSO) δ 7.71 (dd, J = 10.6, 1.9 Hz, 1 H), 7.52 (dt, J = 8.8, 7.7 Hz, 2H), 4.85 (d, J = 5.8 Hz, 1 H), 4.13 (t, J = 8.4 Hz, 1 H), 3.80 (t, J = 8.1 Hz, 1 H), 3.14 (d, J = 1 1.6 Hz, 3H), 2.65 (d, J = 17.3 Hz, 1 H), 2.34 (dd, J = 14.7, 8.6 Hz, 1 H), 1.62 (d, J = 8.3 Hz, 3H).
Step 6. Synthesis of (R)-3-((S)-3-(4-bromo-2-fluorophenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [1.3f]
1.3e (0.1 1 g, 0.26 mmol, 1.0 equiv) was dissolved in THF (13 ml_). N-methyl morpholine (0.13 g, 1.3 mmol, 5.0 equiv), HOBT (0.042 g, 0.31 mmol, 1.2 equiv) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (0.061 g, 0.52 mmol, 2.0 equiv) were added. The reaction mixture was stirred at room temperature for 10 minutes and EDC.HCI (0.074 g, 0.39 mmol, 1.5 equiv) was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated up to dryness. The residue was purified by silica gel column chromatography (2-3 % MeOH in dichloromethane) to afford product 1.3f which was used as such for next step (0.09 g, 66.2% yield). LCMS (m/z): 540.4 [M+18]. 1H NMR (400 MHz, DMSO) δ 1 1.48 (s, 1 H), 7.71 (d, J = 10.7 Hz, 1 H), 7.52 (dd, J = 15.4, 6.0 Hz, 2H), 4.73 (s, 1 H), 4.07 (d, J = 8.3 Hz, 1 H), 3.80 - 3.72 (m, 2H), 3.10 (t, J = 1 1.3 Hz, 3H), 2.79 (d, J = 13.8 Hz, 1 H), 2.24 (s, 1 H), 1.48 (d, J = 27.7 Hz, 6H).
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. The crude product was purified by preparative HPLC to afford 1.3 as desired diastereomer (0.042 g, 55.2% yield). LCMS (m/z): 458.3 [M+18]. 1H NMR (400 MHz, CD3CN) δ 9.66 (s, 1 H), 7.61 - 7.37 (m, 3H), 7.25 (s, 1 H), 4.75 (dt, J = 8.2, 5.7 Hz, 1 H), 4.1 1 (t, J = 8.6 Hz, 1 H), 3.77 (t, J = 8.2 Hz, 1 H), 2.99 (d, J = 32.5 Hz, 3H), 2.75 (dd, J = 14.4, 2.5 Hz, 1 H), 2.36 (dd, J = 14.4, 8.9 Hz, 1 H), 1.69 (s, 3H).
I-4. Synthesis of compound 1.4
Figure imgf000073_0001
Figure imgf000073_0002
Reagents: Step 1 : CBZ-CI, NaHC03, 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%), Ν,Ν-dimethylformamide, 0°C to room temperature. Step 5: LiOH.H20, THF, MeOH, Water, rt. Step 6: NH2OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, rt. Step 7: 35.5% aq. HCI, EtOH, room temperature. Step 1. Synthesis of benzyl (4-bromo-2,6-difluorophenyl)carbamate [1.4a]
4-bromo-2,6-difluoroaniline (1.0 g, 4.81 mmol, 1.0 equiv) was dissolved in acetone: water (2:1 , 9 mL) and cooled to 0°C. NaHC03 (0.89 g, 10.58 mmol, 2.2 equiv), CBZ-CI (1.07 g, 6.25 mmol, 1.3 equiv) were added and the reaction mixture was stirred at room temperature for 7 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 afford the residue. The residue was purified by silica gel chromatography (2-5 % EtOAc in Hexane) to afford product 1.4a (1.23 g, 75% yield). 1H NMR (400 MHz, DMSO) δ 9.40 (s, 1 H), 7.57 (d, J = 7.2 Hz, 2H), 7.50 - 7.26 (m, 5H), 5.14 (s, 2H).
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. (R)-oxiran-2-ylmethyl butyrate (0.62 g, 4.32 mmol, 1.2 equiv) in THF (5 mL) was added drop wise and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (55-60 % EtOAc in Hexane) to afford product 1.4b (0.72 g, 65% yield). LCMS (m/z): 308.1 [M-H]. 1H NMR (400 MHz, DMSO) δ 7.73 - 7.22 (m, 2H), 5.28 (t, J = 5.7 Hz, 1 H), 4.81 (dd, J = 8.9, 6.3 Hz, 1 H), 3.99 - 3.88 (m, 1 H), 3.75 - 3.65 (m, 2H), 3.60 - 3.52 (m, 1 H). Step 3. Synthesis of (R)-3-(4-bromo-2,6-difluorophenyl)-5-(iodomethyl)oxazolidin-2- one [1.4c]. 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. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by silica gel column chromatography (10-15 % EtOAc in Hexane) to afford product 1.4c (0.70 g, 72% yield). 1H NMR (400 MHz, DMSO) δ 7.91 - 7.18 (m, 2H), 4.85 (dt, J = 10.8, 4.7 Hz, 1 H), 4.18 - 3.96 (m, 1 H), 3.69 - 3.54 (m, 2H), 3.47 - 3.25 (m, 1 H).
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. A solution of 1.4c (0.70 g, 1.67 mmol, 1.0 equiv) in DMF (6 mL) was added drop wise at 0-5°C. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to obtain a crude residue. The residue was purified by silica gel column chromatography (28-32 % EtOAc in Hexane) to afford product 1.4d (0.39 g, 50% yield). LCMS (m/z): 472.1 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.70 - 7.29 (m, 2H), 5.06 - 4.89 (m, 1 H), 4.34 - 4.17 (m, 2H), 4.15 - 4.00 (m, 1 H), 3.78 - 3.60 (m, 1 H), 3.20 - 3.08 (m, 3H), 2.70 (d, J = 2.8 Hz, 1 H), 2.39 - 2.27 (m, 1 H), 1.71 - 1.53 (m, 3H), 1.28 - 1.21 (m, 3H).
Step 5. Synthesis of 3-((S)-3-(4-bromo-2,6-difluorophenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoic acid [1.4e]. 1.4d (0.39 g, 0.84 mmol, 1.0 equiv) was dissolved in THF (7 mL), MeOH (1.8 mL). LiOH.H20 (0.1 12 g, 2.57 mmol, 3.0 equiv) in water (1.8 mL) was added and the resulting mixture was stirred at room temperature for 2 hours. The 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. 1H NMR (400 MHz, DMSO) δ 14.24 - 13.75 (m, 1 H), 7.70 - 7.28 (m, 2H), 5.10 - 4.88 (m, 1 H), 4.13 - 4.04 (m, 1 H), 3.76 - 3.62 (m, 1 H), 3.19 - 3.09 (m, 3H), 2.77 - 2.58 (m, 1 H), 2.30 (dd, J = 14.8, 8.5 Hz, 1 H), 1.60 (dd, J = 18.5, 15.0 Hz, 3H). Step 6. Synthesis of 3-((S)-3-(4-bromo-2,6-difluorophenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [1.4f]
1.4e (0.16 g, 0.36 mmol, 1.0 equiv) was dissolved in THF (10 ml_). N-methyl morpholine (0.183 g, 1.81 mmol, 5.0 equiv), HOBT (0.058 g, 0.43 mmol, 1.2 equiv) and EDC.HCI (0.104 g, 0.54 mmol, 1.5 equiv) were added to the solution and the reaction mixture was stirred at rt for 5 minutes. 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.085 g, 0.72 mmol, 2.0 equiv) was added and the reaction mixture was stirred at room temperature for 24 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 crude residue. The residue was purified by silica gel chromatography (2% MeOH in dichloromethane) to afford product 1.4f which was used as such for next step (0.16 g, 81.6% yield). LCMS (m/z): 560.4 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.66 (d, J = 8.2 Hz, 1 H), 7.27 (d, J = 8.4 Hz, 1 H), 4.95 (d, J = 10.2 Hz, 1 H), 4.79 (s, 1 H), 4.03 (d, J = 6.1 Hz, 2H), 3.78 - 3.65 (m, 2H), 3.46 (d, J = 31.5 Hz, 2H), 3.08 (d, J = 10.1 Hz, 3H), 2.79 (d, J = 14.1 Hz, 1 H), 2.20 (dd, J = 14.7, 8.7 Hz, 1 H), 1.87 - 1.70 (m, 3H), 1.52 (s, 6H).
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. The organic layer was washed with brine, dried over sodium sulfate and concentrated to obtain a residue. The residue was purified by preparative HPLC to afford 1.4 as desired diastereomer (0.1 g, 74 % yield). LCMS (m/z): 476.3 [M+18]. 1H NMR (400 MHz, DMSO) δ 11.07 (s, 1 H), 9.28 (s, 1 H), 7.70 (d, J = 7.5 Hz, 2H), 4.76 (tt, J = 8.2, 3.9 Hz, 1 H), 4.04 (t, J = 8.5 Hz, 1 H), 3.68 (t, J = 8.3 Hz, 1 H), 3.09 (s, 3H), 2.94 - 2.69 (m, 1 H), 2.20 (dd, J = 14.5, 8.7 Hz, 1 H), 1.60 (s, 3H). -1 Synthesis of compound 2.1
Figure imgf000075_0001
Reagents: Step 1 : CH3COOK, PdCI2(dppf),1 ,4-dioxane, 1 10°C. Step 2: LiOH.H20, THF, MeOH, Water, room temperature. Step 3: NH2OTHP, 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) were dissolved in 1 ,4-dioxane (5 ml_) and degassed for 10 minutes. PdCI2(dppf) (0.042 g, 0.06 mmol, 0.1 eq) was added and the resulting reaction mixture was stirred at 1 10°C for 2 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. The residue was purified by silica gel chromatography (5-10% EtOAc in Hexane) to afford product 2.1a (0.23 g, 91.6% yield). LCMS (m/z): 449.4 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.73 (d, J = 8.9 Hz, 2H), 7.70 - 7.61 (m, 4H), 7.47 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1 H), 4.82 (dd, J = 14.9, 7.1 Hz, 1 H), 4.27 (q, J = 6.9 Hz, 3H), 3.92 - 3.83 (m, 1 H), 3.18 (s, 3H), 2.71 (dt, J = 10.0, 5.0 Hz, 1 H), 2.44 - 2.33 (m, 1 H), 1.66 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).
Step 2. Synthesis of (R)-3-((S)-3-(biphenyl-4-yl)-2-oxooxazolidin-5-yl)-2-methyl-2- (methylsulfonyl)propanoic acid [2.1 b]. 2.1a (0.23 g, 0.5 mmol, 1.0 equiv) was dissolved in THF (4 ml_), MeOH (1 mL) and water (1 ml_). LiOH.H20 (0.067 g, 1.6 mmol, 3.0 equiv) was added and the resulting mixture was stirred at rt for 3 hours. The reaction mixture was concentrated to dryness, the residue was diluted with water, acidified by 1 N aqueous HCI to the pH 4 to 5, the precipitated solid was filtered and dried to afford product 2.1 b (0.19 g, 88.8 % yield). LCMS (m/z): 404.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 14.14 (s, 1 H), 7.72 (d, J = 8.6 Hz, 2H), 7.65 (dd, J = 17.4, 8.1 Hz, 3H), 7.46 (t, J = 7.4 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1 H), 4.82 (d, J = 7.5 Hz, 1 H), 4.28 (t, J = 8.7 Hz, 1 H), 3.87 (t, J = 8.2 Hz, 1 H), 3.16 (s, 3H), 2.67 (d, J = 14.3 Hz, 1 H), 2.34 (dd, J = 14.3, 8.8 Hz, 1 H), 1.64 (d, J = 10.2 Hz, 3H).
Step 3. Synthesis of (2R)-3-((S)-3-(biphenyl-4-yl)-2-oxooxazolidin-5-yl)-2-methyl-2- (methyl sulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)propanamide [2.1c]. 2.1 b (0.19 g, 0.5 mmol, 1.0 equiv) was dissolved in dichloromethane (10 mL), Et3N (0.24 g, 2.4 mmol, 5.0 equiv) was added dropwise and stirred for 10 minutes. EDC.HCI (0.14 g, 0.7 mmol, 1.5 equiv), HOBT (0.12 g, 0.8 mmol, 1.8 equiv), 0-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.1 1 g, 0.9 mmol, 2.0 equiv) were added and the reaction mixture was stirred at rt for 24 hours. The reaction mixture was concentrated to afford a residue. The residue was purified by silica gel chromatography (0.5-2 % MeOH in dichloromethane) to afford product 2.1c which was used as such for next step (0.165 g, 69.6 % yield). LCMS (m/z): 520.2 [M+23]. 1H NMR (400 MHz, DMSO) δ 7.78 - 7.59 (m, 6H), 7.47 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1 H), 4.99 (d, J = 9.5 Hz, 1 H), 4.69 (s, 1 H), 4.24 (t, J = 8.4 Hz, 1 H), 4.05 (d, J = 6.9 Hz, 1 H), 3.52 (s, 1 H), 3.48 - 3.41 (m, 2H), 3.10 (d, J = 9.3 Hz, 3H), 2.82 (d, J = 16.6 Hz, 1 H), 2.25 (dd, J = 14.7, 9.1 Hz, 1 H), 1.83 (d, J = 9.1 Hz, 5H), 1.52 (dd, J = 28.4, 6.9 Hz, 6H). Step 4. Synthesis of (R)-3-((S)-3-(biphenyl-4-yl)-2-oxooxazolidin-5-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)propanamide [2.1]. 2.1c (0.165 g, 0.3 mmol, 1.0 equiv) was dissolved in ethanol (5 ml_). 35.5% aq. HCI (1 ml_) was added and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to dryness to afford a residue. The residue was co-distilled with diethyl ether and purified by preparative HPLC purification to afford product 2.1 (0.07 g, 50.7 % yield). LCMS (m/z): 419.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 9.33 (s, 1 H), 7.73 (d, J = 8.9 Hz, 2H), 7.70 - 7.59 (m, 4H), 7.47 (t, J = 7.6 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1 H), 4.66 (dd, J = 13.7, 7.8 Hz, 1 H), 4.24 (t, J = 8.8 Hz, 1 H), 3.90 - 3.78 (m, 1 H), 3.10 (s, 3H), 2.85 - 2.76 (m, 1 H), 2.23 (dd, J = 14.5, 8.9 Hz, 1 H), 1.62 (s, 3H).
Figure imgf000077_0001
Reagents: Step 1 : K2C03, PdCI2(dppf), N, N-dimethylformamide, 80°C. Step 2: LiOH.H20, THF, MeOH, Water, room temperature. Step 3: NH2OTHP, 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]. 1.1d (0.2 g, 0.46 mmol, 1.0 eq) and K2CC>3 (0.19 g, 1.4 mmol, 3.0 equiv) were dissolved in N, N-dimethylformamide (5 ml_). 3- fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) pyridine (0.17 g, 0.78 mmol, 1.7 equiv) was added and the reaction mixture was degassed for 10 minutes. PdCI2(dppf)2 (0.023 g, 0.032 mmol, 0.07 equiv) was added and the reaction mixture was stirred at 80°C under microwave irradiation for 4 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (80-90 % EtOAc in Hexane) to afford product 2.2a which was used as such for next step (0.15 g, 72 % yield). LCMS (m/z): 451.3 [M+H].
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.H20 (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. The reaction mixture was concentrated to dryness and the residue was diluted in water, acidified by 1 N HCI aqueous solution to the pH 4 to 5 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 2.2b (0.1g, 71 % yield). LCMS (m/z): 423.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 14.45 - 13.91 (m, 1 H), 8.79 - 8.25 (m, 2H), 8.08 - 7.44 (m, 4H), 6.94 - 6.51 (m, 1 H), 4.83 (s, 1 H), 4.29 (t, J = 8.7 Hz, 1 H), 4.01 - 3.80 (m, 1 H), 3.14 (dd, J = 19.6, 1 1.8 Hz, 3H), 2.67 (d, J = 14.8 Hz, 1 H), 2.37 (d, J = 8.7 Hz, 1 H), 1.75 - 1.34 (m, 3H).
Step 3. Synthesis of 3-((S)-3-(4-(3-fluoropyridin-4-yl)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [2.2c]
2.2b (0.1 g, 0.23 mmol, 1.0 equiv) was dissolved in THF (10 ml_). Et3N (0.1 1 g, 1.18 mmol, 5.0 equiv), HOBT (0.057 g, 0.42 mmol, 1.8 equiv) and EDC.HCI (0.067 g, 0.35 mmol, 1.5 equiv) were added. 0-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.055 g, 0.47 mmol, 2.0 equiv) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 2.2c which was used as such for next step (0.1 g, 81 % yield). LCMS (m/z): 522.4 [M+H].
Step 4. Synthesis of (R)-3-((S)-3-(4-(3-fluoropyridin-4-yl)phenyl)-2-oxooxazolidin-5-yl)- N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide [2.2]. 2.2c (0.1 g, 0.191 mmol, 1.0 equiv) was dissolved in ethanol (5 mL). 35.5% aq. HCI (0.5 mL) was added and reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford crude product. The crude product was purified by preparative HPLC to afford 2.2 as desired diastereomer (0.01 g, 12 % yield). LCMS (m/z): 438.5 [M+H]. 1H NMR (400 MHz, CD3CN) δ 9.75 - 9.46 (m, 1 H), 8.56 (s, 1 H), 8.48 (d, J = 4.8 Hz, 1 H), 7.71 (d, J = 9.1 Hz, 4H), 7.62 - 7.51 (m, 1 H), 4.73 (d, J = 5.9 Hz, 1 H), 4.25 (t, J = 8.7 Hz, 1 H), 3.89 - 3.81 (m, 1 H), 3.04 (s, 3H), 2.79 (d, J = 14.1 Hz, 1 H), 2.36 (dd, J = 13.6, 8.1 Hz, 1 H), 1.71 (s, 3H).
11 -3. Synthesis of compound 2.3
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_). NaHC03 (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. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated to afford a crude residue. The residue was purified by silica gel column chromatography (0-40 % EtOAc in Hexane) to afford product 2.3a (3.7 g, 76.4 % yield). LCMS (m/z): 278.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 10.02 (s, 1 H), 8.09 (s, 1 H), 7.88 - 7.74 (m, 3H), 7.51 - 7.30 (m, 8H), 5.20 (s, 2H).
Step 2. Synthesis of (R)-5-(hydroxymethyl)-3-(naphthalen-2-yl)oxazolidin-2-one [2.3b]
2.3a (1 g, 3.6 mmol, 1.0 equiv) was dissolved in THF (8 ml.) and cooled to -78 °C. n-BuLi (1.5M in hexane) (0.46 g ,7.22 mmol, 2.0 equiv) was added and the reaction mixture was stirred at -78 °C for 1 hour. (R)-oxiran-2-ylmethyl butyrate (0.62 g, 4.3 mmol, 1.2 equiv) was added and the reaction mixture was allowed to attain room temperature for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (0- 60 % EtOAc in Hexane) to afford product 2.3b (0.4 g, 40.7 % yield). LCMS (m/z): 274.9 [M+H]. 1H NMR (400 MHz, DMSO) δ 8.04 (dd, J = 9.0, 2.3 Hz, 1 H), 7.95 (d, J = 9.1 Hz, 1 H), 7.87 (dd, J = 10.7, 5.5 Hz, 3H), 7.55 - 7.41 (m, 2H), 5.26 (t, J = 5.7 Hz, 1 H), 4.77 (dt, J = 9.7, 3.8 Hz, 1 H), 4.28 - 4.17 (m, 1 H), 3.98 (dd, J = 8.8, 6.3 Hz, 1 H), 3.72 (ddd, J = 12.3, 5.5, 3.5 Hz, 1 H), 3.67 - 3.54 (m, 1 H).
Step 3. Synthesis of (R)-5-(iodomethyl)-3-(naphthalen-2-yl)oxazolidin-2-one [2.3c].
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). LCMS (m/z): 354.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 8.06 - 7.84 (m, 5H), 7.58 - 7.41 (m, 2H), 4.81 (td, J = 10.8, 5.4 Hz, 1 H), 4.41 - 4.25 (m, 1 H), 3.82 (dd, J = 9.3, 6.0 Hz, 1 H), 3.64 (qd, J = 10.7, 5.0 Hz, 2H). Step 4. Synthesis of ethyl 2-methyl-2-(methylsulfonyl)-3-((S)-3-(naphthalen-2-yl)-2-oxo oxazolidin-5-yl)propanoate [2.3d]. Ethyl 2-(methylsulfonyl)propanoate (0.61 g, 3.4 mmol, 3.0 equiv) was dissolved in N,N-dimethylformamide (6 mL) and cooled the reaction mixture to 0-5 °C. NaH(60 %) (0.07 g, 2.8 mmol, 2.5 equiv) was added and the reaction mixture was stirred at room temperature for 1 hour. 2.3c (0.4 g, 1.1 mmol, 1.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 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 afford a residue. The residue was purified by silica gel column chromatography (0-60 % EtOAc in Hexane) to afford 2.3d (0.18 g, 39.2 % yield). LCMS (m/z): 406.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.96 (s, 2H), 7.88 (dd, J = 15.2, 10.5 Hz, 3H), 7.49 (dt, J = 14.9, 6.8 Hz, 2H), 4.85 (d, J = 7.8 Hz, 1 H), 4.40 - 4.18 (m, 3H), 4.08 - 3.92 (m, 1 H), 3.18 (s, 3H), 2.77 - 2.67 (m, 1 H), 2.41 (dd, J = 14.9, 8.9 Hz, 1 H), 1.68 (s, 3H), 1.25 (dd, J = 7.9, 3.2 Hz, 3H).
Step 5. Synthesis of 2-methyl-2-(methylsulfonyl)-3-((S)-3-(naphthalen-2-yl)-2-oxo oxazolidin-5-yl)propanoic acid [2.3e]. 2.3d (0.18 mg, 0.4 mmol, 1.0 equiv) was dissolved in MeOH (2 mL) and water (1 ml_). LiOH.H20 (0.037 g, 0.8 mmol, 2.0 equiv) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness, the residue was diluted with water, acidified by 1 N HCI aqueous solution to the pH 4 to 5 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford compound 2.3e (0.15 g, 90.1 % yield). The crude product was used in the next step with no further purification. LCMS (m/z):
378.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 14.22 - 13.76 (m, 1 H), 7.96 (s, 2H), 7.88 (dd, J = 16.6, 9.4 Hz, 2H), 7.68 - 7.57 (m, 1 H), 7.56 - 7.49 (m, 1 H), 7.49 - 7.40 (m, 1 H), 4.86 (s, 1 H), 4.36 (t, J = 8.8 Hz, 1 H), 4.03 (dd, J = 14.3, 7.1 Hz, 1 H), 3.16 (d, J = 9.7 Hz, 3H), 2.69 (d, J = 13.4 Hz, 1 H), 2.37 (dd, J = 14.7, 8.9 Hz, 1 H), 1.65 (d, J = 6.3 Hz, 3H).
Step 6. Synthesis of 2-methyl-2-(methylsulfonyl)-3-((S)-3-(naphthalen-2-yl)-2-oxo oxazolidin-5-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [2.3f]. 2.3e (0.15 g, 0.4 mmol, 1.0 equiv), Et3N (0.20 g, 2.0 mmol, 5.0 equiv), EDC.HCI (0.1 1 g, 0.6 mmol, 1.5 equiv), HOBT (0.09 g, 0.7 mmol, 1.8 equiv) and 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.09 g, 0.8 mmol, 2.0 equiv) were dissolved in dichloromethane. The reaction mixture was stirred at rt for 24 hours. The reaction mixture was concentrated to afford a residue. The residue was purified by silica gel column chromatography (0-5 % MeOH in dichloromethane) to afford product 2.3f which was used as such for next step (0.15 g, 79.7 % yield). LCMS (m/z):
494.4 [M+18]. 1H NMR (400 MHz, DMSO) δ 8.17 (d, J = 8.4 Hz, 1 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.97 (d, J = 2.0 Hz, 1 H), 7.92 - 7.82 (m, 2H), 7.78 - 7.72 (m, 1 H), 7.60 - 7.50 (m, 2H), 4.73 (s, 1 H), 4.33 (d, J = 8.6 Hz, 1 H), 3.92 (d, J = 8.8 Hz, 1 H), 3.77 - 3.73 (m, 3H), 3.45 - 3.43 (m, 2H), 3.16 - 3.07 (m, 3H), 2.83 (m, 1 H), 2.29 (m, 1 H), 1.67 - 1.60 (m, 9H).
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). LCMS (m/z): 400 [M+18]. 1H NMR (400 MHz, DMSO) δ 9.36 (s, 1 H), 8.20 - 7.78 (m, 5H), 7.49 (d, J = 27.3 Hz, 2H), 4.71 (m, 1 H), 4.32 (m, 1 H), 3.93 (m,1 H), 3.10 (s, 3H), 2.83 (d, J = 14.1 Hz, 1 H), 2.34 - 2.20 (m, 1 H), 1.63 (s, 3H), 1.24 (s, 3H). -4. Synthesis of compound 2.4
Figure imgf000081_0001
Reagents: Step 1 : Cul, Cs2C03, trans-cyclohexane-1 ,2-diamine, 1 ,4-dioxane, 125 °C. Step 2: LiOH.H20, THF, MeOH, Water, room temperature. Step 3: NH2OTHP, 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). Cul (0.25 g, 1.3 mmol, 1.2 equiv), trans-cyclohexane-1 ,2-diamine (0.17 g, 1.5 mmol, 1.4 equiv), Cs2C03 (0.52 g, 1.6 mmol, 1.5 equiv) were added and the reaction mixture was stirred at 125 °C for 5 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 afford a residue. The residue was purified by silica gel column chromatography (20-30 % EtOAc in Hexane) to afford product 2.4a (0.32 g, 48.5 % yield). LCMS (m/z): 413.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 9.33 (s, 1 H), 8.28 (d, J = 2.1 Hz, 1 H), 8.1 1 (dd, J = 8.9, 3.0 Hz, 1 H), 7.93 - 7.78 (m, 1 H), 4.84 (d, J = 7.5 Hz, 1 H), 4.38 - 4.17 (m, 3H), 3.91 (dd, J = 17.1 , 8.3 Hz, 1 H), 3.18 (s, 3H), 2.75 - 2.64 (m, 1 H), 2.40 (dd, J = 14.8, 8.9 Hz, 1 H), 1.70 - 1.57 (m, 3H), 1.30 - 1.25 (m, 3H).
Step 2. Synthesis of 3-((S)-3-(benzo[d]thiazol-6-yl)-2-oxooxazolidin-5-yl)-2-methyl-2- (methylsulfonyl)propanoic acid [2.4b]. 2.4a (0.35 g, 0.84 mmol, 1.0 equiv) was dissolved in THF (5 mL), MeOH (2 mL). LiOH.H20 (0.071 g, 1.69 mmol, 2.0 equiv) in water (2mL) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness; 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 2.4b (0.19 g, 60 % yield). LCMS (m/z): 385.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 14.27 - 14.02 (m, 1 H), 9.33 (s, 1 H), 8.28 (d, J = 2.2 Hz, 1 H), 8.1 1 (d, J = 8.9 Hz, 1 H), 7.88 - 7.77 (m, 1 H), 4.85 (d, J = 5.5 Hz, 1 H), 4.32 (t, J = 8.6 Hz, 1 H), 3.98 - 3.85 (m, 1 H), 3.17 (s, 3H), 2.66 (d, J = 14.6 Hz, 1 H), 2.36 (dd, J = 14.8, 8.9 Hz, 1 H), 1.71 - 1.54 (m, 3H).
Step 3. Synthesis of 3-((S)-3-(benzo[d]thiazol-6-yl)-2-oxooxazolidin-5-yl)-2-methyl-2- (methyl sulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [2.4c]. 2.4b (0.19 g, 0.49 mmol, 1.0 equiv), N-methyl morpholine (0.25 g, 2.4 mmol, 5.0 equiv), EDC.HCI (0.14 g, 0.74 mmol, 1.5 equiv), HOBT (0.080 g, 0.6 mmol, 1.2 equiv) and 0-(tetrahydro-2H-pyran-2- yl)hydroxylamine (0.1 1 g, 0.98 mmol, 2.0 equiv) were added in THF (6 ml_). The reaction mixture was stirred at room temperature for 20 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 afford a residue. The residue was purified by silica gel column chromatography (3-5 % MeOH in dichloromethane) to afford product 2.4c which was used for next step (0.16 g, 67 % yield). LCMS (m/z): 484.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 9.29 (s, 1 H), 8.24 (d, J = 9.8 Hz, 1 H), 8.09 (d, J = 9.1 Hz, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 4.70 (s, 1 H), 4.26 (t, J = 8.7 Hz, 1 H), 4.02 (s, 1 H), 3.88 (t, J = 8.1 Hz, 1 H), 3.49 (s, 1 H), 3.10 - 3.01 (m, 3H), 2.79 (d, J = 14.3 Hz, 1 H), 2.32 - 2.21 (m, 1 H), 1.72 - 1.47 (m, 9H). Step 4. Synthesis of (R)-3-((S)-3-(benzo[d]thiazol-6-yl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide [2.4]. 2.4c (0.16 g, 0.33 mmol, 1.0 equiv) was dissolved in methanol (2 ml_) and dichloromethane (4 ml_). HCI (in IPA) (1 ml_) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to afford a crude product. The crude product was purified by preparative HPLC purification to afford 2.4 as desired diastereomer (0.042 g, 32 % yield). LCMS (m/z): 399.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 9.29 (s, 1 H), 8.24 (d, J = 2.2 Hz, 1 H), 8.09 (d, J = 9.0 Hz, 1 H), 7.79 (dd, J = 9.0, 2.2 Hz, 1 H), 4.67 (d, J = 7.6 Hz, 1 H), 4.25 (t, J = 8.7 Hz, 1 H), 3.93 - 3.84 (m, 1 H), 3.07 (s, 3H), 2.79 (d, J = 14.6 Hz, 1 H), 2.23 (dd, J = 14.5, 9.0 Hz, 1 H), 1.63 (d, J = 19.8 Hz, 3H).
II-5. Synthesis of compound 2.5
Figure imgf000083_0001
Reagents: Step 1 : CBZ-CI, NaHC03, 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.H20, THF, MeOH, Water, room temperature. Step 6: NH2OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, room temperature. Step 7: 35.5% aq. HCI, EtOH, room temperature.
Step 1. Synthesis of benzyl (1-methyl-1 H-indazol-5-yl)carbamate [2.5a]
1-methyl-1 H-indazol-5-amine (2.0 g, 13.6 mmol, 1.0 equiv) was dissolved in acetone: water (2:1 , 15 ml_), NaHC03 (2.39 g, 28.5 mmol, 2.1 equiv) was added and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0 °C, CBZ-CI (3.01 g, 17.7 mmol, 1.3 equiv) was added and the reaction mixture was stirred at room temperature for 2 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 afford a crude residue. The crude product was triturated with n- pentane, decanted the solvent and dried to afford product 2.5a (3.18 g, 83.2 % yield). LCMS (m/z): 282.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 9.78 (s, 1 H), 7.97 (d, J = 0.6 Hz, 1 H), 7.91 (s, 1 H), 7.56 (d, J = 9.0 Hz, 1 H), 7.52 - 7.31 (m, 6H), 5.17 (s, 2H), 4.01 (s, 3H).
Step 2. Synthesis of (R)-5-(hydroxymethyl)-3-(1-methyl-1 H-indazol-5-yl)oxazolidin-2- one [2.5b]. 2.5a (3 g, 10.66 mmol, 1.0 equiv) was dissolved in THF (16 ml_) and cooled to - 70 °C. n-BuLi (2.5M in hexane) (1.36 g, 21.32 mmol, 2.0 equiv) was gradually added and the reaction mixture was stirred at -70 °C for 1 hour. (R)-oxiran-2-ylmethyl butyrate (1.46 g, 12.79 mmol, 1.2 equiv) was added drop wise and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (0-2 % MeOH in dichloromethane) to afford product 2.5b (2.1 g, 79.6 % yield). LCMS (m/z): 248.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 8.05 (dd, J = 8.2, 0.8 Hz, 1 H), 7.83 - 7.77 (m, 2H), 7.71 - 7.65 (m, 1 H), 5.21 (d, J = 29.6 Hz, 1 H), 4.76 - 4.67 (m, 1 H), 4.15 (t, J = 8.9 Hz, 1 H), 4.05 (d, J = 3.2 Hz, 3H), 3.90 (dt, J = 12.0, 6.0 Hz, 1 H), 3.70 (dd, J = 12.2, 3.1 Hz, 1 H), 3.59 (dd, J = 12.2, 3.9 Hz, 1 H).
Step 3. Synthesis of (R)-5-(iodomethyl)-3-(1-methyl-1 H-indazol-5-yl)oxazolidin-2-one
[2.5c]. 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. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by silica gel column chromatography (0-5 % MeOH in dichloromethane) to afford product 2.5c (2.1 g, 72.7 % yield). LCMS (m/z): 358.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 8.05 (dd, J = 8.2, 0.8 Hz, 1 H), 7.83 - 7.77 (m, 2H), 7.71 - 7.65 (m, 1 H), 4.75 (td, J = 10.7, 5.2 Hz, 1 H), 4.27 (t, J = 9.0 Hz, 1 H), 4.1 1 - 4.01 (m, 3H), 3.73 (dd, J = 9.1 , 6.0 Hz, 1 H), 3.62 (qd, J = 10.7, 4.9 Hz, 2H).
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. A solution of 2.5c (2 g, 5.6 mmol, 1.0 equiv) in DMF (4 mL) was added drop wise at 0-5 °C and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The residue was purified by silica gel column chromatography (0-20 % EtOAc in Hexane) to afford product 2.5d which was used for next step (1.8 g, 78.5 % yield). LCMS (m/z): 410.4 [M+H]. Step 5. Synthesis of 2-methyl-3-((S)-3-(1-methyl-1 H-indazol-5-yl)-2-oxooxazolidin-5-yl)- 2-(methylsulfonyl)propanoic acid [2.5e]. 2.5d (1.8 g, 4.39 mmol, 1.0 equiv) was dissolved in THF (5 mL), MeOH (2.5 mL). LiOH.H20 (0.55 g, 13.2 mmol, 3.0 equiv) in water (2.5 mL) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, acidified by 1 N HCI aqueous solution to the pH 3 to 4 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford 2.5e (0.95 g, 56.7 % yield). The crude product was used in the next step with no further purification. LCMS (m/z): 382.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 14.07 (s, 1 H), 8.08 (d, J = 24.4 Hz, 1 H), 7.82 - 7.64 (m, 3H), 4.96 - 4.76 (m, 1 H), 4.27 (dd, J = 10.5, 6.8 Hz, 1 H), 4.07 (d, J = 20.5 Hz, 3H), 3.98 - 3.84 (m, 1 H), 3.15 (d, J = 11.4 Hz, 3H), 2.66 (dd, J = 14.6, 2.6 Hz, 1 H), 2.39 - 2.28 (m, 1 H), 1.69 - 1.49 (m, 3H).
Step 6. Synthesis of 2-methyl-3-((S)-3-(1-methyl-1 H-indazol-5-yl)-2-oxooxazolidin-5-yl)- 2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [2.5f]. 2.5e (0.8 g, 2.09 mmol, 1.0 equiv) was dissolved in THF (12 mL), N-methyl morpholine (1.06 g, 10.48 mmol, 5.0 equiv) was added and the reaction mixture was stirred at rt for 5 minutes. EDC.HCI (0.6 g, 3.14 mmol, 1.5 equiv), HOBT (0.34 g, 2.52 mmol, 1.2 equiv), 0-(tetrahydro- 2H-pyran-2-yl)hydroxylamine (0.49 g, 4.19 mmol, 2.0 equiv) were added and the reaction mixture was stirred at rt for 14 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The residue was purified by silica gel column chromatography (0-5 % MeOH in dichloromethane) to afford product 2.5f which was used for next step immediately (0.41 g, 40.7 % yield). LCMS (m/z): 397.3 [M+18]. 1H NMR (400 MHz, DMSO) δ 1 1.57 - 1 1.47 (m, 1 H), 8.05 (s, 1 H), 7.79 - 7.65 (m, 3H), 5.06 - 4.94 (m, 1 H), 4.69 (d, J = 7.6 Hz, 1 H), 4.23 (t, J = 8.8 Hz, 1 H), 3.86 (t, J = 7.5 Hz, 1 H), 3.49 (dd, J = 24.5, 12.9 Hz, 2H), 3.09 (t, J = 7.6 Hz, 3H), 2.81 (m, 1 H), 2.30 - 2.20 (m, 1 H), 1.60 (m, 9H). Step 7. Synthesis of (R)-N-hydroxy-2-methyl-3-((S)-3-(1-methyl-1 H-indazol-5-yl)-2- oxooxazolidin-5-yl)-2-(methylsulfonyl)propanamide [2.5]. 2.5f (0.41 g, 0.85 mmol, 1.0 equiv) was dissolved in ethanol (7 mL). 35.5% aq. HCI (0.82 mL) was added and reaction mixture was stirred at rt for 1 hour. The reaction mixture was diluted with water, neutralized by saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude product. The crude product was purified by preparative HPLC purification to afford 2.5 as desired diastereomer (0.065 g, 19.2 % yield). LCMS (m/z): 397.4 [M+H]. 1H NMR (400 MHz, DMSO) 5 11.09 (s, 1 H), 9.31 (s, 1 H), 8.05 (s, 1 H), 7.72 (ddd, J = 17.6, 1 1.6, 5.2 Hz, 3H), 4.66 (d, J = 6.1 Hz, 1 H), 4.23 (t, J = 8.6 Hz, 1 H), 4.07 (d, J = 20.2 Hz, 3H), 3.91 - 3.82 (m, 1 H), 3.10 (s, 3H), 2.79 (d, J = 14.6 Hz, 1 H), 2.24 (dd, J = 14.4, 8.8 Hz, 1 H), 1.62 (s, 3H).
11 -6. Synthesis of compound 2.6
Figure imgf000086_0001
Reagents: Step 1 : Cul, Cs2C03, trans-cyclohexane-1 ,2-diamine, 1 ,4-dioxane, 125 °C. Step 2: LiOH.H20, THF, MeOH, Water, room temperature. Step 3: NH2OTHP, 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_). Cul (0.20 g, 1.1 mmol, 1.2 equiv), trans-cyclohexane-1 ,2-diamine (0.14 g, 1.2 mmol, 1.4 equiv) and Cs2C03 (0.44 g, 1.3 mmol, 1.5 equiv) were added and the reaction mixture was stirred at 125 °C for 4 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 afford a residue. The residue was purified by silica gel column chromatography (20-30 % EtOAc in Hexane) to afford product 2.6a which was used for next step (0.35 g, 79 % yield). LCMS (m/z): 412.3 [M+H].
Step 2. Synthesis of (R)-3-((S)-3-(benzo[b]thiophen-6-yl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoic acid [2.6b]. 2.6a (0.35 g, 0.8 mmol, 1.0 equiv) was dissolved in THF (4 ml_), MeOH (1 ml_). LiOH.H20 (0.1 1 g, 2.5 mmol, 3.0 equiv) in water (1 ml_) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, acidified by 1 N HCI aqueous solution to the pH 3 to 4 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford the product 2.6b which was used for next step (0.29 g, 89.2 % yield). LCMS (m/z): 384.4 [M+H].
Step 3. Synthesis of (R)-3-((S)-3-(benzo[b]thiophen-6-yl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [2.6c]
2.6b (0.23 g, 0.6 mmol, 1.0 equiv) was dissolved in THF (5 ml_). N-methyl morpholine (0.30 g, 3.0 mmol, 5.0 equiv), EDC.HCI (0.17 g, 0.9 mmol, 1.5 equiv), HOBT (0.15 g, 1.1 mmol, 1.8 equiv), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.14 g, 1.2 mmol, 2.0 equiv) were added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (1-2 % MeOH in dichloromethane) to afford product 2.6c which was used for next step (0.2 g, 54.8 % yield). LCMS (m/z): 481.6 [M+H]. 1H NMR (400 MHz, DMSO) δ 8.14 - 8.08 (m, 1 H), 7.89 (d, J = 8.8 Hz, 1 H), 7.72 - 7.66 (m, 2H), 7.43 (d, J = 5.4 Hz, 1 H), 4.72 (d, J = 7.8 Hz, 1 H), 4.26 (t, J = 8.7 Hz, 1 H), 3.93 - 3.83 (m, 2H), 3.76 (d, J = 15.4 Hz, 1 H), 3.50 (dd, J = 23.6, 12.0 Hz, 3H), 3.08 (dd, J = 9.5, 7.5 Hz, 3H), 2.81 (d, J = 16.5 Hz, 1 H), 2.32 - 2.23 (m, 1 H), 1.64 (s, 3H), 1.52 (m, 6H).
Step 4. Synthesis of (R)-3-((S)-3-(benzo[b]thiophen-6-yl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide [2.6]. 2.6c (0.2 g, 0.4 mmol, 1.0 equiv) was dissolved in ethanol (5 ml_). 35.5% aq. HCI (0.2 ml_) was added to the solution and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude product. The crude product was purified by preparative HPLC purification to afford 2.6 as desired diastereomer (0.083 g, 50.3 % yield). LCMS (m/z): 399.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.1 1 (s, 1 H), 9.33 (s, 1 H), 8.1 1 (s, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.76 - 7.63 (m, 2H), 7.43 (d, J = 5.4 Hz, 1 H), 4.80 - 4.58 (m, 1 H), 4.26 (t, J = 8.7 Hz, 1 H), 3.94 - 3.81 (m, 1 H), 3.18 - 3.04 (m, 3H), 2.80 (dd, J = 14.4, 2.7 Hz, 1 H), 2.24 (dd, J = 14.4, 8.8 Hz, 1 H), 1.62 (s, 3H).
II-7. Synthesis of 2.7 and 2.8 Compounds 2.7 and 2.8 were synthesized by the process of example 2.1. Compound 2.7: LCMS (m/z): 477.4 [M+H]. Compound 2.8: LCMS (m/z): 477.3 [M+H]. 1H NMR (400 MHz, DMSO-c 6) δ 1 1.08 (s, 1 H), 9.30 (br s, 1 H), 7.69 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 7.7 Hz, 2H), 7.27 (d, J = 7.8 Hz, 2H), 4.65 (q, J = 9.1 , 8.6 Hz, 1 H), 4.22 (t, J = 8.7 Hz, 1 H), 3.84 (q, J = 9.2, 7.9 Hz, 2H), 3.09 (s, 3H), 2.80 (d, J = 15.0 Hz, 1 H), 2.70 (dt, J = 15.1 , 7.9 Hz, 1 H), 2.60 (dd, J = 13.3, 6.0 Hz, 1 H), 2.22 (dd, J = 14.7, 9.1 Hz, 1 H), 1.61 (s, 3H), 1 .06 (d, J = 5.9 Hz, 3H).
Figure imgf000087_0001
Reagents: Step 1 : DBU, dppb, PdCI2 (PPh3)2, DMSO, 100°C. Step 2: LiOH.H20, THF, MeOH, Water, room temperature. Step 3: N-methyl morpholine, NH2OTHP, 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]. 1.1 d (4.0 g, 9.22 mmol, 1.0 equiv) (mixture of diastereomer), but-2-ynoic acid (1.16 g, 13.83 mmol, 1.5 equiv), PdCI2(PPh3)2 (0.072 g, 0.10 mmol, 0.01 equiv), 1 ,4-bis (diphenylphosphino) butane (0.09 g, 0.20 mmol, 0.02 equiv) and DBU (2.80 g, 18.43 mmol, 2.0 equiv) were added in DMSO (40 mL) in sealed tube. The reaction mixture was stirred at 100°C for 5 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 crude residue. The residue was purified by silica gel chromatography. 40-50 % EtOAc in Hexane was used as gradient to afford 3.1.1a (2.71 g, 74.8 % yield). LCMS (m/z): 394.4 [M+H], 1H NMR (400 MHz, DMSO) δ 7.51 (d, J = 8.8 Hz, 2H), 7.41 (dd, J = 8.7, 3.3 Hz, 2H), 4.79 (dd, J = 14.5, 7.8 Hz, 1 H), 4.34 - 4.13 (m, 3H), 3.90 - 3.73 (m, 1 H), 3.23 - 3.08 (m, 3H), 2.86 - 2.64 (m, 1 H), 2.31 (ddd, J = 17.1 , 14.5, 6.0 Hz, 1 H), 2.01 (d, J = 15.4 Hz, 3H), 1.61 (d, J = 27.7 Hz, 3H), 1.25 (q, J = 6.9 Hz, 3H).
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.H20 (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. The 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. LCMS (m/z): 366.4 [M+H], 1H NMR (400 MHz, DMSO) δ 7.50 (d, J = 8.9 Hz, 2H), 7.43 - 7.37 (m, 2H), 4.84 - 4.73 (m, 1 H), 4.20 (t, J = 8.7 Hz, 1 H), 3.84 - 3.76 (m, 1 H), 3.13 (s, 3H), 2.63 (d, J = 14.8 Hz, 1 H), 2.30 (dd, J = 14.9, 8.9 Hz, 1 H), 2.01 (s, 3H), 1.60 (s, 3H).
Step 3. Synthesis of 2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(prop-1-ynyl)phenyl) oxazolidin-5-yl)-N-(tetrahydro-2H-pyran-2-yloxy)propanamide [3.1.1 g]
3.1.1b (2.3 g, 6.30 mmol, 1.0 equiv) was dissolved in to THF (50 mL), N-methyl morpholine (3.18 g, 31.51 mmol, 5.0 equiv), EDC.HCI (1.12 g, 9.45 mmol, 1.5 equiv), HOBT (1.02 g, 7.56 mmol, 1.2 equiv) and 0-(tetrahydro-2H-pyran-2-yl) hydroxylamine (1.47 g, 12.61 mmol, 2.0 equiv) were added and the reaction mixture was stirred at room temperature for 24 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 crude residue. The residue was purified by silica gel column chromatography. 2-3 % MeOH in dichloromethane was used as gradient for elution to afford product 3.1.1c and carry forwarded for next step. (2.5 g, 85.5 % yield). LCMS (m/z): 482.6 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.58 - 7.48 (m, 2H), 7.41 (d, J = 8.7 Hz, 2H), 4.67 (d, J = 8.3 Hz, 1 H), 4.18 (t, J = 8.7 Hz, 1 H), 4.13 - 3.96 (m, 1 H), 3.84 - 3.71 (m, 2H), 3.51 (s, 1 H), 3.46 - 3.37 (m, 1 H), 3.15 - 2.96 (m, 3H), 2.78 (d, J = 13.3 Hz, 1 H), 2.23 (dd, J = 14.5, 9.0 Hz, 1 H), 2.10 - 1.95 (m, 3H), 1.64 - 1.51 (m, 6H).
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. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to afford crude product 3.1.1. The crude product was purified by preparative HPLC purification to afford 3.1.1 as desired diastereomer (0.70 g, 34.0 % yield). LCMS (m/z): 379.3 [M-H]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.32 (s, 1 H), 7.51 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 4.63 (dd, J = 14.0, 7.7 Hz, 1 H), 4.18 (t, J = 8.8 Hz, 1 H), 3.83 - 3.74 (m, 1 H), 3.08 (s, 3H), 2.82 - 2.72 (m, 1 H), 2.21 (dd, J = 14.5, 8.9 Hz, 1 H), 2.03 (s, 3H), 1.60 (s, 3H).
Figure imgf000089_0001
Reagents: Step 1 : DBU, dppb, PdCI2(PPh3)2, DMSO, 90°C. Step 2: LiOH.H20, THF, MeOH, Water, room temperature. Step 3: NH2OTHP, 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]. 1.1d (0.50 g, 1.15 mmol, 1.0 equiv), 3-cyclopropylpropiolic acid (0.13 g, 1.15 mmol, 1.0 equiv), PdCI2(PPh3)2 (0.008 g, 0.012 mmol, 0.01 equiv), 1 ,4-bis(diphenylphosphino)butane (0.01 1 g, 0.026 mmol, 0.02 equiv) and DBU(0.35 g, 2.30 mmol, 2.0 equiv) were added in DMSO (5 mL) in sealed tube. The reaction mixture was stirred at 90°C for 4 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 crude residue. The residue was purified by silica gel column chromatography (20-30 % EtOAc in Hexane) to afford product 3.1.2a (0.33 g, 68.3 % yield). LCMS (m/z): 437.3 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.50 (d, J = 8.9 Hz, 2H), 7.44 - 7.32 (m, 2H), 4.97 - 4.71 (m, 1 H), 3.80 (dd, J = 15.3, 7.6 Hz, 3H), 3.15 (d, J = 6.5 Hz, 3H), 2.74 - 2.63 (m, 1 H), 2.35 (dd, J = 14.8, 8.9 Hz, 1 H), 1.64 (s, 3H), 1.26 (dd, J = 9.0, 5.1 Hz, 3H), 0.96 - 0.81 (m, 2H), 0.78 - 0.66 (m, 2H).
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.H20 (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. The reaction mixture was concentrated to dryness, diluted with water, acidified by 1.ON HCI aqueous solution to pH 4 to 5 and extracted with EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated to obtain product 3.1.2b (0.25 g, 81.4 % yield). LCMS (m/z): 392.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 14.18 - 14.04 (m, 1 H), 7.56 - 7.47 (m, 1 H), 7.43 - 7.35 (m, 1 H), 4.79 (d, J = 7.5 Hz, 1 H), 4.21 (t, J = 8.7 Hz, 1 H), 3.84 - 3.77 (m, 1 H), 3.19 - 3.13 (m, 2H), 2.70 - 2.62 (m, 1 H), 2.36 - 2.29 (m, 1 H), 1.62 (d, J = 10.1 Hz, 2H), 1.18 (t, J = 7.1 Hz, 1 H), 0.88 (dt, J = 6.3, 4.0 Hz, 1 H), 0.72 (dt, J = 6.7, 3.9 Hz, 1 H).
Step 3. Synthesis of 3-((S)-3-(4-(cyclopropylethynyl)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [3.1.2c]
3.1.2b (0.13 g, 0.34 mmol, 1.0 equiv) was dissolved in dichloromethane (7 mL). Et3N (0.32 g, 3.20 mmol, 5.0 equiv) was added to obtain clear solution. EDC.HCI (0.19 g, 0.96 mmol, 1.5 equiv), HOBT (0.16 g, 1.15 mmol, 1.8 equiv) and 0-(tetrahydro-2H-pyran-2- yl)hydroxylamine (0.15 g, 1.28 mmol, 2.0 equiv) were added to the reaction mixture and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to afford the residue. The residue was purified by silica gel column chromatography (2-4 % MeOH in dichloromethane) to afford product 3.1.2c which was used as such for next step (0.25 g, 79.6 % yield). LCMS (m/z): 489.3 [M-H]. 1H NMR (400 MHz, DMSO) 5 1 1.51 (s, 1 H), 7.62 - 7.46 (m, 2H), 7.38 (d, J = 8.8 Hz, 2H), 4.67 (d, J = 8.0 Hz, 1 H), 4.03 (dd, J = 14.2, 7.1 Hz, 1 H), 3.84 - 3.66 (m, 2H), 3.54 - 3.42 (m, 2H), 3.07 (t, J = 8.4 Hz, 3H), 2.76 (t, J = 1 1.3 Hz, 1 H), 2.28 - 2.19 (m, 1 H), 1.81 (t, J = 13.5 Hz, 3H), 1.77 - 1.62 (m, 6H), 0.92 - 0.79 (m, 2H), 0.76 - 0.60 (m, 2H).
Step 4. Synthesis of (R)-3-((S)-3-(4-(cyclopropylethynyl)phenyl)-2-oxooxazolidin-5-yl)- N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide [3.1.2]. 3.1.2c (0.25 g, 0.51 mmol, 1.0 equiv) was dissolved in ethanol (5 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 dryness to afford the residue. The residue was diluted with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford crude product. The crude product was purified by preparative HPLC to afford 3.1.2 as the desired diastereomer (0.020 g, 9.7 % yield). LCMS (m/z): 407.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 9.31 (s, 1 H), 7.50 (d, J = 8.9 Hz, 2H), 7.39 (d, J = 8.9 Hz, 2H), 4.64 (d, J = 8.3 Hz, 1 H), 4.17 (t, J = 8.8 Hz, 1 H), 3.83 - 3.73 (m, 1 H), 3.08 (s, 3H), 2.77 (d, J = 12.0 Hz, 1 H), 2.21 (dd, J = 14.4, 8.8 Hz, 1 H), 1.60 (s, 3H), 1.53 (td, J = 8.2, 4.1 Hz, 1 H), 0.92 - 0.84 (m, 2H), 0.77 - 0.69 (m, 2H).
Figure imgf000091_0001
Reagents: Step 1 : DBU, dppb, PdCI2(PPh3)2, DMSO, 100°C. Step 2: LiOH.H20, THF, MeOH, Water, room temperature. Step 3: NH2OTHP, 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]
1.1d (desired diastereomer) (0.2 g, 0.46 mmol, 1.0 equiv), pent-2-ynoic acid (0.068 g, 0.69 mmol, 1.5 equiv), PdCI2(PPh3)2 (0.005 g, 0.007 mmol, 0.012 equiv), 1 ,4-bis (diphenylphosphino)butane (0.005 g, 0.013 mmol, 0.023 equiv) and DBU (0.142 g, 0.93 mmol, 2.0 equiv) was added in DMSO (7 ml_) in sealed tube. The reaction mixture was stirred at 100°C for 4 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. The residue was purified by silica gel column chromatography (30-40 % EtOAc in Hexane) to afford product 3.1.3a (0.15 g, 80 % yield). LCMS (m/z): 408.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.52 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 4.79 (dd, J = 14.3, 7.8 Hz, 1 H), 4.24 (dt, J = 18.1 , 7.8 Hz, 3H), 3.88 - 3.76 (m, 1 H), 3.16 (s, 3H), 2.76 - 2.63 (m, 1 H), 2.47 - 2.31 (m, 3H), 1.64 (s, 3H), 1.21 - 1.13 (m, 3H).
Step 2. Synthesis of (R)-3-((S)-3-(4-(but-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoic acid [3.1.3b]. 3.1.3a (0.15 g, 0.37 mmol, 1.0 equiv) was dissolved in THF (2.0 ml_), MeOH (1.0 ml_). LiOH.H20 (0.046 g, 1.1 mmol, 3.0 equiv) in water (1 ml_) was added. The resulting mixture was stirred at rt for 2 hours. The reaction mixture was concentrated to dryness and the residue was diluted with water, acidified by 1 N HCI aqueous solution to the pH 4 to 5 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford compound 3.1.3b (0.1 10 mg, 78.5 % yield). The crude material was used in the next step with no further purification. LCMS (m/z): 380.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 14.10 (s, 1 H), 7.51 (d, J = 8.9 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 4.79 (d, J = 7.5 Hz, 1 H), 4.22 (t, J = 8.8 Hz, 1 H), 3.81 (dd, J = 10.5, 6.1 Hz, 1 H), 3.16 (d, J = 5.2 Hz, 3H), 2.64 (dd, J = 14.8, 2.7 Hz, 1 H), 2.42 (q, J = 7.5 Hz, 2H), 2.32 (dd, J = 14.7, 8.8 Hz, 1 H), 1.61 (s, 3H), 1.16 (t, J = 7.5 Hz, 3H). Step 3. Synthesis of (2R)-3-((S)-3-(4-(but-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [3.1.3c]
3.1.3b (0.1 1 g, 0.29 mmol, 1.0 equiv) was dissolved in THF (5 ml_). N-methyl morpholine (0.15 g, 1.45 mmol, 5.0 equiv), HOBT (0.05 g, 0.35 mmol, 1.2 equiv) and O- (tetrahydro-2H-pyran-2-yl) hydroxylamine (0.07 g, 0.58 mmol, 2.0 equiv) were added and stirred for 5 minutes. EDC.HCI (0.05 g, 0.44 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (1-2 % MeOH in dichloromethane) to afford product 3.1.3c which was carry forwarded for next step. (0.1 1 g, 79.1 % yield). LCMS (m/z): 477.4 [M-H]. 1H NMR (400 MHz, DMSO) δ 7.51 (dd, J = 8.6, 2.9 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 4.67 (d, J = 7.8 Hz, 1 H), 4.19 (q, J = 8.9 Hz, 1 H), 4.12 - 4.01 (m, 1 H), 3.83 - 3.75 (m, 2H), 3.52 - 3.39 (m, 2H), 3.18 - 3.04 (m, 3H), 2.78 (d, J = 14.1 Hz, 1 H), 2.42 (q, J = 7.5 Hz, 2H), 2.23 (dd, J = 13.8, 9.8 Hz, 1 H), 1.45 (m, 6H), 1.16 (t, J = 7.5 Hz, 3H).
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. The crude product was purified by preparative HPLC to afford 3.1.3 as desired diastereomer (0.065 g, 72 % yield). LCMS (m/z): 395.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.32 (d, J = 1.5 Hz, 1 H), 7.51 (d, J = 8.8 Hz, 2H), 7.42 (t, J = 8.8 Hz, 2H), 4.63 (d, J = 6.5 Hz, 1 H), 4.18 (t, J = 8.8 Hz, 1 H), 3.84 - 3.71 (m, 1 H), 3.08 (s, 3H), 2.77 (d, J = 1 1.8 Hz, 1 H), 2.42 (q, J = 7.5 Hz, 2H), 2.21 (dd, J = 14.4, 8.9 Hz, 1 H), 1.60 (s, 3H), 1.16 (t, J = 7.5 Hz, 3H).
Figure imgf000093_0001
Reagents: Step A: But-3-yn-2-ol, n-BuLi (23 % in hexane), C02, THF, -40 °C. Step 1 : DBU, dppb, PdCI2(PPh3)2, DMSO, 90 °C. Step 2: LiOH.H20, THF, MeOH, Water, room temperature. Step 3: NH2OTHP, 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) was dissolved in THF (15 ml_) and the reaction mixture was cooled at -40 °C. n-BuLi (23% in hexane) (0.91 g, 14.27 mmol, 2.0 equiv) was added dropwise and the mixture was stirred at -40 °C for 1 hour. The C02 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. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product (0.5 g, 61.4% yield). The crude material was used in the next step without further purification. 1H NMR (400 MHz, DMSO) δ 5.69 (s, 1 H), 4.52 (q, J = 6.5 Hz, 1 H), 1.33 (d, J = 6.7 Hz, 3H). Step 1. Synthesis of ethyl 3-((5S)-3-(4-(3-hydroxybut-1-yn-1-yl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanoate [3.1.4a]
1.1d (0.73 g, 1.68 mmol, 1.0 equiv), 4-hydroxypent-2-ynoic acid (0.38 g, 3.37 mmol, 2.0 equiv), PdCI2(PPh3)2 (0.012 g, 0.017 mmol, 0.01 equiv), 1 ,4-bis(diphenylphosphino) butane (0.016 g, 0.039 mmol, 0.02 equiv) and DBU(0.51 g, 3.36 mmol, 2.0 equiv) were dissolved in DMSO (23 ml_) in sealed tube. The reaction mixture was stirred at 90 °C for 8 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The residue was purified by silica gel column chromatography (40-60 % EtOAc in Hexane) to afford product 3.1.4a (0.36 g, 50.6 % yield). LCMS (m/z): 424.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.55 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 4.79 (d, J = 7.4 Hz, 1 H), 4.58 (q, J = 6.5 Hz, 1 H), 4.32 - 4.17 (m, 3H), 3.88 - 3.76 (m, 1 H), 3.15 (d, J = 13.9 Hz, 3H), 2.68 (d, J = 12.7 Hz, 1 H), 2.36 (dd, J = 14.8, 8.9 Hz, 1 H), 1.61 (d, J = 27.7 Hz, 3H), 1.38 (d, J = 6.6 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H).
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.H20 (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. The 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). 1H NMR (400 MHz, DMSO) δ 14.09 - 13.98 (m, 1 H), 7.54 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.9 Hz, 2H), 5.46 (s, 3H), 4.83 - 4.76 (m, 1 H), 4.62 - 4.55 (m, 1 H), 4.23 (s, 1 H), 3.82 (s, 1 H), 3.15 (s, 3H), 2.68 - 2.65 (m, 1 H), 2.33 (m, 1 H), 1.61 (s, 3H), 1.38 (d, J = 6.6 Hz, 3H). Step 3. Synthesis of 3-((5S)-3-(4-(3-hydroxybut-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)- 2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [3.1.4c]
3.1.4b (0.08 g, 0.20 mmol, 1.0 equiv) was dissolved in THF (8 ml_). N-methyl morpholine (0.10 g, 1.01 mmol, 5.0 equiv), HOBT (0.033 g, 0.24 mmol, 1.2 equiv), O- (tetrahydro -2H-pyran-2-yl) hydroxylamine (0.048 g, 0.41 mmol, 2.0 equiv) were added and the reaction mixture was stirred at room temperature for 10 minutes. EDC.HCI (0.058 g, 0.30 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to afford a residue. The residue was purified by silica gel column chromatography (2-3 % MeOH in dichloromethane) to afford product 3.1.4c which was used as such for next step (0.10 g, 80% yield). LCMS (m/z): 512.6 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.55 (dd, J = 8.3, 5.9 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 4.67 (m, 1 H), 4.19 (m, 1 H), 3.76 (dd, J = 7.3, 4.1 Hz, 2H), 3.60 (m, 1 H), 3.51 (m, 1 H), 3.47 - 3.43 (m, 2H), 3.14 - 3.02 (m, 3H), 2.78 (m, 1 H), 2.27 (m, 1 H), 1.62 (s, 3H), 1.44 (m, 6H), 1.38 (d, J = 6.6 Hz, 3H).
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. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford the crude product. The crude product was purified by preparative HPLC purification to afford product 3.1.4 (0.02 g, 24.1 % yield). LCMS (m/z): 408.9 [M-H]. 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1 H), 9.32 (s, 1 H), 7.54 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 5.46 (d, J = 5.4 Hz, 1 H), 4.71 - 4.54 (m, 1 H), 4.19 (t, J = 8.8 Hz, 1 H), 3.86 - 3.72 (m, 1 H), 3.08 (s, 3H), 2.78 (d, J = 14.5 Hz, 1 H), 2.21 (dd, J = 14.4, 8.9 Hz, 1 H), 1.60 (s, 3H), 1.38 (d, J = 6.6 Hz, 3H).
Figure imgf000095_0001
Reagents: Step A: 3-methoxyprop-1-yne, n-BuLi (2.5M in hexane), C02, THF, -40°C. Step V. DBU, dppb, PdCI2(PPh3)2, DMSO, 90°C. Step 2: LiOH.H20, THF, MeOH, Water, room temperature. Step 3: NH2OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, room temperature. Step 4: 35.5% aq. HCI, EtOH, room temperature.
Step A. Synthesis of 4-methoxybut-2-ynoic acid.
3-methoxyprop-1-yne (1.0 g, 14.2 mmol, 1.0 equiv) was dissolved in THF (25 mL) and the solution was cooled at -40°C. n-BuLi (2.5M in hexane) (1.80 g, 28.5 mmol, 2.0 equiv) was added drop wise and the reaction mixture was stirred at -40°C for 1 hour. The C02 gas was purged into the reaction mixture for 30 minutes. The reaction mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified with 35.5% aq. HCI solution to pH 3 to 4 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product (1.10 g, 67.6% yield). 1H NMR (400 MHz, DMSO) δ 13.74 (s, 1 H), 4.29 (s, 2H), 3.29 (s, 3H).
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]. 1.1 d (0.26 g, 0.59 mmol, 1.0 equiv), 4-methoxybut-2-ynoic acid (0.082 g, 0.72 mmol, 1.2 equiv), PdCI2(PPh3)2 (0.004 g, 0.006 mmol, 0.01 equiv), 1 ,4-bis(diphenylphosphino)butane (0.006 g, 0.014 mmol, 0.023 equiv) and DBU (0.18 g, 1.20 mmol, 2.0 equiv) were dissolved in DMSO (15.0 mL) in sealed tube and the reaction mixture was stirred at 90°C for 24 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 afford a residue. The residue was purified by silica gel column chromatography (50 % EtOAc in Hexane) to afford product 3.1.5a (0.19 g, 75 % yield). LCMS (m/z): 424.5 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.67 - 7.42 (m, 4H), 4.80 (dd, J = 15.5, 9.4 Hz, 1 H), 4.35 (d, J = 20.0 Hz, 2H), 4.28 - 4.20 (m, 2H), 3.88 - 3.77 (m, 1 H), 3.33 (s, 2H), 3.23 - 3.10 (m, 3H), 2.79 - 2.65 (m, 1 H), 2.37 (dd, J = 14.9, 8.9 Hz, 1 H), 1.68 - 1.53 (m, 3H), 1.28 - 1.23 (m, 3H).
Step 2. Synthesis of 3-((S)-3-(4-(3-methoxyprop-1-yn-1-yl)phenyl)-2-oxooxazolidin-5- yl)-2-methyl-2-(methylsulfonyl)propanoic acid [3.1.5b]
3.1.5a (0.19 g, 0.45 mmol, 1.0 equiv) was dissolved in THF (1.5 ml_), MeOH (0.9 ml_). LiOH.H20 (0.057 g, 1.35 mmol, 3.0 equiv) in water (0.9 mL) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness; 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 a crude product. The crude product was triturated with n-pentane, the solvent was decanted and dried to afford product 3.1.5b (0.17 g, 93.2 % yield). LCMS (m/z): 396.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 14.18 - 13.86 (m, 1 H), 7.56 (dd, J = 9.6, 2.7 Hz, 2H), 7.49 (d, J = 8.9 Hz, 2H), 4.81 (d, J = 5.3 Hz, 1 H), 4.30 (d, J = 17.8 Hz, 2H), 4.22 (t, J = 8.8 Hz, 1 H), 3.86 - 3.80 (m, 1 H), 3.33 (s, 3H), 3.14 (s, 3H), 2.67 - 2.60 (m, 1 H), 2.32 - 2.26 (m, 1 H), 1.59 (s, 3H).
Step 3. Synthesis of 3-((S)-3-(4-(3-methoxyprop-1-yn-1-yl)phenyl)-2-oxooxazolidin-5- yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [3.1.5c] 3.1.5b (0.14 g, 0.36 mmol, 1.0 equiv) was dissolved in THF (12 mL). N-methyl morpholine (0.18 g, 1.77 mmol, 5.0 equiv), HOBT (0.057 g, 0.42 mmol, 1.2 equiv), O- (tetrahydro -2H-pyran-2-yl)hydroxylamine (0.084 g, 0.71 mmol, 2.0 equiv) were added and the reaction mixture was stirred at room temperature for 5 minutes. EDC.HCI (0.10 g, 0.53 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 24 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 afford a crude residue. The residue was purified by silica gel column chromatography (2 % MeOH in dichloromethane) to afford product 3.1.5c which was used for next step (0.14 g, 82 % yield). LCMS (m/z): 493.5 [M-H]. AA27-sttep-3 1H NMR (400 MHz, DMSO) δ 7.66 - 7.46 (m, 4H), 4.67 (m, 1 H), 4.57 (d, J = 4.9 Hz, 10H), 4.21 (m, 1 H), 4.05 (m, 1 H), 3.77 (m, 2H), 3.51 (m, 1 H), 3.46 - 3.39 (m, 2H), 3.33 (s, 3H), 3.15 - 3.02 (m, 3H), 2.85 - 2.70 (m, 1 H), 2.24 (m, 1 H), 1.62 (m, 3H), 1.50 - 1.40 (m, 6H).
Step 4. Synthesis of (R)-N-hydroxy-3-((S)-3-(4-(3-methoxyprop-1-yn-1-yl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide [3.1.5]
3.1.5c (0.14 g, 0.29 mmol, 1.0 equiv) was dissolved in ethanol (5 mL), 35.5% aq. HCI (1 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude product. The crude product was purified by preparative HPLC purification to afford 3.1.5 as desired diastereomer (0.033 g, 27.7 % yield). LCMS (m/z): 41 1.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 9.31 (s, 1 H), 7.56 (d, J = 8.9 Hz, 2H), 7.50 (d, J = 8.9 Hz, 2H), 4.71 - 4.59 (m, 1 H), 4.32 (s, 2H), 4.20 (t, J = 8.8 Hz, 1 H), 3.84 - 3.76 (m, 1 H), 3.33 (s, 3H), 3.08 (s, 3H), 2.84 - 2.73 (m, 1 H), 2.22 (dd, J = 14.4, 8.9 Hz, 1 H), 1.60 (s, 3H).
Figure imgf000097_0001
Reagents: Step A: 2-methylbut-3-yn-2-ol, n-BuLi (2.5M in hexane), C02, THF, -40 °C. Step V. DBU, dppb, PdCI2(PPh3)2, DMSO, 90 °C. Step 2: LiOH.H20, THF, MeOH, Water, room temperature. Step 3: NH2OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, room temperature. Step 4: 35.5% aq. HCI, EtOH, 0 °C to room temperature.
Step A. Synthesis of 4-hydroxy-4-methylpent-2-ynoic acid.
2-methylbut-3-yn-2-ol (1.0 g, 1 1.89 mmol, 1.0 equiv) was dissolved in THF (40 mL) and the reaction mixture was cooled at -40°C. n-BuLi (2.5M in hexane) (1.52 g, 23.7 mmol, 2.0 equiv) was added drop wise and the reaction mixture was stirred at -40°C for 1 hour. The C02 gas was purged into reaction mixture for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution, acidified by 35.5% aq. HCI solution to pH 3 to 4 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product (0.75 g, 49.2 % yield). The crude material was used in the next step with no further purification. LCMS (m/z): 127.1 [M-H]. 1H NMR (400 MHz, DMSO) δ 13.59 (s, 1 H), 5.73 (s, 1 H), 1.40 (s, 6H).
Step 1. Synthesis of ethyl 3-((S)-3-(4-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)-2-oxo oxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanoate [3.1.6a]. 1.1 d (0.5 g, 1.15 mmol, 1.0 equiv), 4-hydroxy-4-methylpent-2-ynoic acid (0.18 g, 1.38 mmol, 1.2 equiv), PdCI2(PPh3)2 (0.008 g, 0.01 1 mmol, 0.01 equiv), 1 ,4-bis(diphenylphosphino) butane (0.01 1 g, 0.026 mmol, 0.02 equiv) and DBU(0.35 g, 2.3 mmol, 2.0 equiv) were dissolved in DMSO (10 ml_) in sealed tube. The reaction mixture was stirred at 90 °C for 5 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The residue was purified by silica gel column chromatography (0-10 % MeOH in dichloromethane) to afford product 3.1.6a (0.44 g, 87.3 % yield). LCMS (m/z): 438.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.53 (s, 2H), 7.42 (t, J = 6.1 Hz, 2H), 4.79 (d, J = 9.9 Hz, 1 H), 4.32 - 4.21 (m, 3H), 3.85 - 3.79 (m, 1 H), 3.15 (d, J = 10.6 Hz, 3H), 2.68 (d, J = 12.8 Hz, 1 H), 2.40 - 2.34 (m, 1 H), 1.64 (s, 3H), 1.46 (s, 6H), 1.26 (t, J = 7.1 Hz, 3H).
Step 2. Synthesis of 3-((S)-3-(4-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanoic acid [3.1.6b]. 3.1.6a (0.22 g, 0.50 mmol, 1.0 equiv) was dissolved in THF (3 ml_), MeOH (1.5 ml_). LiOH.H20 (0.063 g, 1.51 mmol, 3.0 equiv) in water (1.5 ml_) was added to the reaction mixture and the resulting mixture was stirred at rt for 2 hours. The 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 a crude product. The product was triturated with n-pentane to afford product 3.1.6b (0.195 g, 94.7% yield). 1H NMR (400 MHz, DMSO) δ 14.25 - 13.99 (m, 3H), 7.54 (d, J = 8.9 Hz, 2H), 7.41 (d, J = 8.9 Hz, 2H), 4.79 (s, 1 H), 4.22 (t, J = 8.8 Hz, 1 H), 3.81 (d, J = 8.4 Hz, 1 H), 3.14 (d, J = 3.7 Hz, 3H), 2.64 (d, J = 14.9 Hz, 1 H), 2.35 - 2.28 (m, 1 H), 1.60 (s, 3H), 1.47 (d, J = 5.6 Hz, 6H). Step 3. Synthesis of 3-((S)-3-(4-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2- yl)oxy)propanamide [3.1.6c]. 3.1.6b (0.18 g, 0.44 mmol, 1.0 equiv) was dissolved in THF (7 ml_). N-methyl morpholine (0.22 g, 2.20 mmol, 5.0 equiv), EDC.HCI (0.13 g, 0.66 mmol, 1.5 equiv), HOBT (0.071 g, 0.53 mmol, 1.2 equiv), 0-(tetrahydro-2H-pyran-2- yl)hydroxylamine (0.103 g, 0.88 mmol, 2.0 equiv) were added and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (0-5 % MeOH in dichloromethane) to afford product 3.1.6c (0.14 g, 62.7% yield) which was used as such for next step. LCMS (m/z): 507.5 [M-H]. 1H NMR (400 MHz, DMSO) δ 7.70 - 7.36 (m, 4H), 5.71 (s, 1 H), 4.66 (m, 1 H), 4.17 (m, 1 H), 4.03 (m, 1 H), 3.73 (m, 4H), 3.12 - 3.02 (m, 3H), 2.77 (m, 1 H), 2.17 (m, 1 H), 1.67 - 1.37 (m, 15H).
Step 4. Synthesis of (R)-N-hydroxy-3-((S)-3-(4-(3-hydroxy-3-methylbut-1-yn-1- yl)phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide [3.1.6] 3.1.6c (0.14 g, 0.28 mmol, 1.0 equiv) dissolved in ethanol (5 mL) and cooled the solution at 0 °C. 35.5% aq. HCI (0.21 mL) was added and stirred the reaction mixture at room temperature for 1 hour. The reaction mixture was diluted with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC purification to afford 3.1.6 (0.045 g, 38.5% yield). LCMS (m/z): 423.4 [M-H]. 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1 H), 9.30 (s, 1 H), 7.54 (d, J = 8.9 Hz, 2H), 7.42 (d, J = 8.9 Hz, 2H), 5.47 (s, 1H), 4.65 (d, J = 7.2 Hz, 1H), 4.19 (t, J = 8.7 Hz, 1H), 3.84 - 3.74 (m, 1H), 3.08 (s, 3H), 2.76 (d, J = 14.2 Hz, 1H), 2.21 (dd, J = 14.5, 8.9 Hz, 1H), 1.59 (s, 3H), 1.46 (s, 6H).
111.1.8. Synthesis of compound 3.1.8
Compound 3.1.8 was synthesized by the process of example 3.1.1. LCMS (m/z): 437.4 [M-1]. 1H NMR (400 MHz, DMSO) δ 11.08 (s, 1 H), 9.21 (s, 1 H), 7.55 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 4.67 (s, 1H), 4.18 (t, J = 8.9 Hz, 1H), 3.85 - 3.73 (m, 1H), 3.30 (d, J = 5.6 Hz, 3H), 3.16-2.98 (m, 3H), 2.76 (d, J= 14.3 Hz, 1H), 2.20 (dd, J= 14.2, 8.4 Hz, 1H), 1.65-1.51 (m, 3H), 1.45 (d, J= 19.9 Hz, 6H).
111.1.9. Synthesis of compound 3.1.9
Compound 3.1.9 was synthesized by the process of example 3.1.1. LCMS (m/z): 442.4 [M+18]. 1H NMR (400 MHz, DMSO) δ 11.01 (s, 1H), 9.24 (s, 1H), 7.52 (d, J = 22.6 Hz, 4H), 4.67 (m, 1H), 4.35 (m, 1H), 4.18 (m, 1H), 3.80 (m, 1H), 3.08 (s, 3H), 2.75 (d, J = 13.7 Hz, 1H), 2.19 (m, 1H), 1.57 (s, 3H), 1.41 (d, J = 5.0 Hz, 3H).
111.1.10. Synthesis of compound 3.1.10
Compound 3.1.10 was synthesized by the process of example 3.1.1. LCMS (m/z): 411.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 9.32 (s, 1H), 7.52 (d, J= 8.8 Hz, 2H), 7.46 - 7.36 (m, 2H), 4.91 (t, J = 5.5 Hz, 1H), 4.63 (d, J = 6.5 Hz, 1H), 4.18 (t, J = 8.9 Hz, 1H), 3.81 - 3.72 (m, 1H), 3.58 (dd, J = 12.5, 6.7 Hz, 2H), 3.16 - 3.01 (m, 3H), 2.77 (d, J = 14.9 Hz, 1H), 2.55 (t, J= 6.8 Hz, 2H), 2.21 (dd, J= 14.4, 8.9 Hz, 1H), 1.66-1.52 (m, 3H).
111.1.11. Synthesis of compound 3.1.11
Step 1. Synthesis of ethyl (R)-3-((S)-3-(4-(4-methoxybut-1-yn-1-yl)phenyl)-2- oxooxazolidin -5-yl)-2-methyl-2-(methylsulfonyl)propanoate [3.1.11 b]
3.1.11a (which was synthesized by the process of example 3.1.1) (0.31 g, 0.73 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (10 mL). Ag20 (0.50 g, 2.19 mmol, 3.0 equiv), iodomethane (1.03 g, 7.3 mmol, 10.0 equiv) were added and the reaction mixture was stirred at 80 °C for 48 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. The residue was purified by silica gel column chromatography (0- 40 % EtOAc in Hexane) to afford product 3.1.11 b (0.21 g, 66.6 % yield). LCMS (m/z): 438.5 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.58 - 7.50 (m, 2H), 7.44 (dd, J = 16.2, 12.9 Hz, 2H), 4.94 - 4.74 (m, 1 H), 4.35 - 4.12 (m, 3H), 3.81 (dd, J = 11.1 , 5.5 Hz, 1 H), 3.51 (t, J = 6.7 Hz, 1 H), 3.28 (d, J = 12.1 Hz, 3H), 3.28 - 3.20 (m, 1 H), 3.17 (d, J = 3.9 Hz, 3H), 2.88 - 2.59 (m, 3H), 2.36 (dd, J = 14.8, 8.9 Hz, 1 H), 1.71 - 1.54 (m, 3H), 1.30 - 1.20 (m, 3H).
Step 2. Synthesis of (R)-N-hydroxy-3-((S)-3-(4-(4-methoxybut-1-yn-1-yl)phenyl)-2-oxo oxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide [3.1.11]
3.1.11 was synthesized by the process of example 3.1.1. LCMS (m/z): 425.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.1 1 (s, 1 H), 9.31 (s, 1 H), 7.52 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 4.64 (d, J = 7.3 Hz, 1 H), 4.18 (t, J = 8.9 Hz, 1 H), 3.78 (t, J = 8.0 Hz, 1 H), 3.51 (t, J = 6.6 Hz, 2H), 3.29 (s, 3H), 3.1 1 (d, J = 20.7 Hz, 3H), 2.77 (d, J = 16.1 Hz, 1 H), 2.66 (t, J = 6.6 Hz, 2H), 2.21 (dd, J = 14.3, 8.9 Hz, 1 H), 1.62 (d, J = 20.3 Hz, 3H).
III.1.14. Synthesis of compound 3.1.14
Step 1. Synthesis of pent-4-ynenitrile [3.1.14b]
But-3-yn-1-yl 4-methylbenzenesulfonate 3.1.14a (5 g, 21.0 mmol, 1.0 equiv) was dissolved in dimethyl sulfoxide (40 mL). NaCN (5.23 g, 106.0 mmol, 5 equiv) was added and the reaction mixture was stirred at 70 °C for 30 minutes. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (2-3 % MeOH in dichloromethane) to afford product 3.1.14b (1 g, 55 % yield). 1H NMR (400 MHz, DMSO) δ 4.13 (q, J = 5.3 Hz, 1 H), 3.17 (d, J = 5.2 Hz, 2H), 2.51 (dd, J = 3.6, 1.8 Hz, 2H)
Step 2. Synthesis of ethyl 2-methyl-2-(methylsulfonyl)-3-((S)-3-(4-(4-morpholinobut-1- yn-1-yl) phenyl)-2-oxooxazolidin-5-yl)propanoate [3.1.14c]. 1.1 d (0.5 g, 0.1 1 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (0.5 mL). PdCI2(PPh3)2 (0.04 g, 0.06 mmol, 0.05 equiv), Cul (0.010 g, 0.06 mmol, 0.05 equiv), triphenyl phosphine (0.06 g, 0.23 mmol, 0.2 equiv), diethyl amine (2.5 mL) were added and the reaction mixture was degassed for 5 minutes. Pent-4-ynenitrile (0.18 g, 2.3 mmol, 2.0 equiv) was added and the reaction mixture was stirred at 130 °C for 15 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. The residue was purified by silica gel column chromatography (40-50 % EtOAc in Hexane) to afford product 3.1.14c (0.35 g, 70 % yield). LCMS (m/z): 433.1 [M+H]. Step 3. Synthesis of (R)-3-((S)-3-(4-(4-cyanobut-1-yn-1-yl)phenyl)-2-oxooxazolidin-5- yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide [3.1.14]
3.1.14 was synthesized by the process of example 3.1.1. LCMS (m/z): 418.6 [M-1]. 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.32 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.50 - 7.38 (m, 2H), 4.64 (d, J = 8.0 Hz, 1H), 4.19 (t, J = 8.7 Hz, 1H), 3.85 - 3.73 (m, 1H), 3.15 - 2.99 (m, 3H), 2.88-2.67 (m, 5H), 2.22 (dd, J= 14.4, 9.0 Hz, 1H), 1.57 (d, J= 19.5 Hz, 3H).
III.1.15. Synthesis of compound 3.1.15
Compound 3.1.15 was synthesized by the process of 3.1.14. LCMS (m/z): 479.5 [M+H]. 1H NMR (400 MHz, CD3CN) δ 8.12 (s, 1H), 7.50 (d, J = 7.6 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 4.68 (m, 1H), 4.16 (m, 1H), 3.78 (d, J= 16.5 Hz, 1H), 3.66 (m, 4H), 3.11 -2.86 (m, 3H), 2.76 (d, J = 14.2 Hz, 1H), 2.63 (s, 3H), 2.54 (s, 4H), 2.33 (dd, J = 13.9, 8.5 Hz, 1H), 1.69 (s, 3H).
111.1.17. Synthesis of compound 3.1.17
Compound 3.1.17 was synthesized by the process of example 3.1.1. LCMS (m/z): 437.7 [M-1]. 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1 H), 9.32 (s, 1 H), 7.55 (d, J = 8.8 Hz, 2H), 7.52 - 7.38 (m, 2H), 4.64 (d, J = 8.0 Hz, 1H), 4.19 (t, J = 8.7 Hz, 1H), 3.84 - 3.75 (m, 1H), 3.17 - 2.99 (m, 3H), 2.89 - 2.67 (m, 5H), 2.22 (dd, J = 14.4, 9.0 Hz, 1H), 1.57 (d, J = 19.5 Hz, 3H).
111.1.18. Synthesis of compound 3.1.18
Compound 3.1.18 was synthesized by example 3.1.1. LCMS (m/z): 449.6 [M-1]. 1H NMR (400 MHz, DMSO) δ 11.08 (s, 1 H), 9.32 (s, 1 H), 7.60 - 7.50 (m, 2H), 7.43 (d, J = 8.8 Hz, 2H), 4.64 (d, J= 6.1 Hz, 1H), 4.19 (t, J = 8.8 Hz, 1H), 3.80 (ddd, J= 16.4, 10.5, 6.2 Hz, 3H), 3.50-3.38 (m, 2H), 3.06 (d, J= 19.8 Hz, 3H), 2.94-2.84 (m, 1H), 2.77 (d, J= 11.9 Hz, 1H), 2.22 (dd, J= 14.4, 8.9 Hz, 1H), 1.84 (d, J = 9.6 Hz, 2H), 1.69- 1.46 (m, 5H).
111.1.19. Synthesis of compound 3.1.19
Step 1. Synthesis of ethyl 3-((4-methoxybenzyl)oxy)cyclobutane-1-carboxylate
[3.1.19a]. Ethyl 3-hydroxycyclobutane-1-carboxylate (4 g, 27.4 mmol, 1.0 equiv) was dissolved in Ν,Ν-dimethylformamide and cooled to 0 °C. NaH (60 %) (1.66 g, 41.6 mmol, 1.5 equiv) was added portion wise and the reaction mixture was stirred at 0 °C for 24 hours. 1-(chloromethyl)-4-methoxybenzene (5.24 g, 33.3 mmol, 1.2 equiv) was added and the reaction mixture was stirred at room temperature for 24 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. The residue was purified by silica gel column chromatography (0-30 % EtOAc in Hexane) to afford product 3.1.19a (4.82 g, 65.8 % yield). LCMS (m/z): 265.5 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.27 - 7.21 (m, 2H), 6.94 - 6.84 (m, 2H), 4.29 (s, 2H), 4.12 - 3.99 (m, 2H), 3.99 - 3.83 (m, 1 H), 3.74 (s, 3H), 2.66 (tt, J = 9.7, 8.0 Hz, 1 H), 2.44 - 2.32 (m, 2H), 2.22 - 1.96 (m, 2H), 1.21 - 1.14 (m, 3H).
Step 2. Synthesis of (3-((4-methoxybenzyl)oxy)cyclobutyl)methanol [3.1.19b]. 3.1.19a (4.8 g, 18.18 mmol, 1.0 equiv) was dissolved in THF (48 mL). Lithium borohydride (2.0 M in THF) (18.18 mL, 36.36 mmol, 2.0 equiv) was added drop wise and the resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with saturated aqueous sodium sulfate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (0-40 % EtOAc in Hexane) to afford product 3.1.19b (3.87 g, 95.9 % yield). LCMS (m/z): 223.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.31 - 7.16 (m, 2H), 6.98 - 6.83 (m, 2H), 4.52 (dt, J = 28.6, 5.2 Hz, 1 H), 4.33 - 4.20 (m, 2H), 3.93 - 3.76 (m, 1 H), 3.76 - 3.60 (m, 3H), 2.29 - 2.03 (m, 2H), 2.04 - 1.66 (m, 2H).
Step 3. Synthesis of 3-((4-methoxybenzyl)oxy)cyclobutane-1-carbaldehyde [3.1.19c]
3.1.19b (3.85 g, 17.34 mmol, 1.0 equiv) was dissolved in dichloromethane (40 mL) and cooled to 10 °C. Dess-Martin periodinane (14.7 g, 34.68 mmol, 2.0 equiv) was added portion wise and the reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was filtered through celite bed. Filtrate was diluted with water, neutralized by aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by silica gel column chromatography (0-20 % EtOAc in Hexane) to afford product 3.1.19c (3.65 g, 95.5 % yield). LCMS (m/z): 239.5 [M+18]. 1H NMR (400 MHz, DMSO) δ 9.67 (dd, J = 79.4, 30.1 Hz, 1 H), 7.22 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.31 - 4.23 (m, 2H), 3.97 (dq, J = 15.6, 7.7 Hz, 1 H), 3.72 (s, 3H), 2.83 (dd, J = 66.9, 58.8 Hz, 1 H), 2.47 - 2.23 (m, 2H), 2.19 - 1.69 (m, 3H).
Step 4. Synthesis of 1-((3-ethynylcyclobutoxy)methyl)-4-methoxybenzene [3.1.19d]
3.1.19c (3.6 g, 16.36 mmol, 1.0 equiv) was dissolved in MeOH (36 mL). Ohira- Bestmann reagent (3.86 g, 49.09 mmol, 1.2 equiv) was added. K2C03 (4.65 g, 32.72 mmol, 2.0 equiv) and the resulting mixture was stirred at room temperature for 24 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. The residue was purified by silica gel column chromatography (0-20 % EtOAc in Hexane) to afford product 3.1.19d (1.99 g, 56.2 % yield). LCMS (m/z): 234.3 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.31 - 7.14 (m, 2H), 6.97 - 6.80 (m, 2H), 4.35 - 4.22 (m, 2H), 3.91 - 3.60 (m, 4H), 3.05 - 2.90 (m, 1 H), 2.59 - 2.51 (m, 2H), 2.29 - 2.09 (m, 1 H), 1.90 - 1.82 (m, 1 H). Step 5. Synthesis of ethyl (R)-3-((S)-3-(4-((3-((4-methoxybenzyl)oxy)cyclobutyl)ethynyl) phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoaten [3.1.19e]
1.1d (0.5 g, 1.16 mmol, 1.0 equiv) and 3.1.19d (0.5 g, 2.31 mmol, 2.0 equiv) were mixed with diethyl amine (10 ml.) and N,N-dimethylformamide (2 ml_). Cul (0.01 1 g, 0.058 mmol, 0.05 equiv), triphenyl phosphine (0.06 g, 0.23 mmol, 0.2 equiv) were added and the reaction mixture was degassed for 10 minutes. PdCI2(pph3)2 (0.040 g, 0.058 mmol, 0.05 equiv) was added and the reaction mixture was stirred at 125 °C for 2 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. The residue was purified by silica gel column chromatography (30-35 % EtOAc in Hexane) to afford product 3.1.19e (0.8 g, 61 % yield). LCMS (m/z): 570.6 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.56 - 7.49 (m, 2H), 7.41 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 4.79 (d, J = 8.0 Hz, 1 H), 4.34 - 4.19 (m, 4H), 4.12 (q, J = 5.2 Hz, 1 H), 3.87 (ddd, J = 28.5, 15.6, 7.9 Hz, 2H), 3.23 - 3.1 1 (m, 5H), 2.69 - 2.58 (m, 2H), 2.42 - 2.22 (m, 2H), 1.98 (dd, J = 18.7, 10.4 Hz, 1 H), 1.64 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 6. Synthesis of ethyl (R)-3-((S)-3-(4-((3-hydroxycyclobutyl)ethynyl)phenyl)-2-oxo oxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanoate [3.1.19f]
3.1.19e (0.8 g, 1.40 mmol, 1.0 equiv) was dissolved in dichloromethane (20 ml_) and cooled to 0 °C. TFA (1.07 ml_, 14.0 mmol, 10.0 equiv) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford crude residue. The residue was purified by silica gel column chromatography (80 % EtOAc in Hexane) to afford product 3.1.19f (0.55 g, 87 % yield). LCMS (m/z): 450.5 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.57 - 7.49 (m, 2H), 7.40 (d, J = 8.7 Hz, 2H), 4.79 (d, J = 7.4 Hz, 1 H), 4.24 (dt, J = 18.3, 8.0 Hz, 3H), 3.85 (dd, J = 34.9, 27.1 Hz, 2H), 3.72 (d, J = 15.0 Hz, 1 H), 3.28 - 3.09 (m, 3H), 2.75 - 2.56 (m, 3H), 2.40 - 2.14 (m, 2H), 2.01 - 1.89 (m, 1 H), 1.77 - 1.55 (m, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 7. Synthesis of ethyl (R)-3-((S)-3-(4-((3-ethoxycyclobutyl)ethynyl)phenyl)-2-oxo oxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanoate [3.1.19g]. 3.1.19f (0.5 g, 1.1 1 mmol, 1.0 equiv) was added in chloroform (15 ml_). DIPEA (0.57 g, 3.33 mmol, 3.0 equiv), Meerwein's reagent (0.63 g, 3.33 mmol, 3.0 equiv) in dichloromethane (3 ml_) were added and the reaction mixture was stirred at 5 °C for 15 minutes. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated to obtain crude residue. The residue was purified by silica gel column chromatography (40 % EtOAc in Hexane) to afford product 3.1.19g (0.26 g, 49 % yield). LCMS (m/z): 478.7 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.55 - 7.49 (m, 2H), 7.41 (d, J = 8.7 Hz, 2H), 4.79 (d, J = 7.8 Hz, 1 H), 4.24 (dt, J = 17.5, 7.9 Hz, 3H), 3.83 (dd, J = 15.5, 7.6 Hz, 2H), 3.17 (d, J = 5.5 Hz, 4H), 2.79 (d, J = 8.2 Hz, 1 H), 2.65 (dd, J = 21.6, 12.3 Hz, 2H), 2.39 - 2.31 (m, 1 H), 2.10 - 1.83 (m, 2H), 1.64 (s, 3H), 1.30 - 1.18 (m, 4H).
Step 8. Synthesis of (R)-3-((S)-3-(4-((3-ethoxycyclobutyl)ethynyl)phenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide [3.1.19]
3.1.19 was synthesized by the process of 3.1.1. 3.1.19-1: LCMS (m/z): 465.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 8.37 (s, 1 H), 7.52 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 4.66 (s, 1 H), 4.17 (s, 1 H), 3.82 (dd, J = 16.2, 8.7 Hz, 2H), 3.31 - 3.23 (m, 2H), 3.10 (d, J = 19.2 Hz, 3H), 2.78 (dd, J = 19.8, 1 1.5 Hz, 2H), 2.70 - 2.56 (m, 2H), 2.19 (s, 2H), 1.99 - 1.91 (m, 2H), 1.57 (s, 3H), 1.09 (t, J = 7.0 Hz, 4H). 3.1.19-11: LCMS (m/z): 465.2 [M+H].
III.1.20. Synthesis of compound 3.1.20
Figure imgf000104_0001
Reagents: Step 1 : Diethyl amine, triphenyl phosphine, Cul, PdCI2(pph3)2, N,N-dimethyl formamide, 1 10 °C. Step 2 : DAST, dichloromethane, -70 °C to room temperature. Step 3 : LiOH.H20, THF, MeOH, water, room temperature. Step 4 : NH2OTHP, EDC.HCI, HOBT, N- methyl morpholine, THF, room temperature. Step 5 : HCI (in IPA), room temperature.
Step 1. Synthesis of ethyl (R)-3-((S)-3-(4-(4-hydroxybut-1-yn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1.20a].
1.1d (0.3 g, 0.7 mmol, 1.0 equiv), but-3-yn-1-ol (0.053 g, 0.8 mmol, 1.1 equiv), triphenyl phosphine (0.036 g, 0.1 mmol, 0.2 equiv) were added in diethyl amine (5 mL), N, N- dimethylformamide (1 mL) and the reaction mixture was degassed for 10 minutes. PdCI2(pph3)2 (0.024 g, 0.03 mmol, 0.05 equiv), Cul (0.013 g, 0.07 mmol, 0.1 equiv) were added and the reaction mixture was stirred at 1 10 °C for 1 hour. 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 afford a crude residue. The crude residue was purified by silica gel column chromatography (1 % MeOH/dichloromethane) to afford the desired product 3.1.20a (0.25 g, 85.6 % yield). LCMS (m/z): 424.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.52 (d, J = 8.9 Hz, 2H), 7.42 (d, J = 8.9 Hz, 2H), 4.93 - 4.87 (m, 1 H), 4.79 (d, J = 7.5 Hz, 1 H), 4.32 - 4.18 (m, 3H), 3.86 - 3.78 (m, 1 H), 3.58 (dd, J = 12.5, 6.8 Hz, 2H), 3.16 (s, 3H), 2.69 (d, J = 15.0 Hz, 1 H), 2.55 (t, J = 6.8 Hz, 2H), 2.40 - 2.33 (m, 1 H), 1.65 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 2. Synthesis of ethyl (R)-3-((S)-3-(4-(4-fluorobut-1-yn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1.20b]. 3.1.20a (0.2 g, 0.5 mmol, 1.0 equiv) was dissolved in dichloromethane (10 ml_) and cooled to -70 °C. DAST (0.15 g, 1.0 mmol, 2.0 equiv) was added drop wise and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (25 % EtOAc/Hexane) to afford the desired product 3.1.20b (0.13 g, 52 % yield). LCMS (m/z): 426.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.54 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 4.83 - 4.75 (m, 1 H), 4.64 (t, J = 6.1 Hz, 1 H), 4.52 (t, J = 6.1 Hz, 1 H), 4.24 (dt, J = 16.4, 7.6 Hz, 3H), 3.86 - 3.78 (m, 1 H), 3.16 (s, 3H), 2.89 (t, J = 6.1 Hz, 1 H), 2.84 (t, J = 6.1 Hz, 1 H), 2.69 (d, J = 15.0 Hz, 1 H), 2.36 (dd, J = 14.8, 8.9 Hz, 1 H), 1.65 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 3. Synthesis of (R)-3-((S)-3-(4-(4-fluorobut-1-yn-1-yl) phenyl)-2-oxooxazolidin-5- yl)-2-methyl-2-(methylsulfonyl) propanoic acid [3.1.20c].
3.1.20b (0.13 g, 0.3 mmol, 1.0 equiv) was dissolved in THF (4 ml_), MeOH (1 mL) and water (1 mL). LiOH.H20 (0.026 g, 0.6 mmol, 2.0 equiv) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water, acidified by 1.0 N HCI aqueous solution to the pH 4 to 5 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford the desired product 3.1.20c (0.1 g, 82.6 % yield). LCMS (m/z): 398.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 14.12 (s, 1 H), 7.54 (d, J = 8.8 Hz, 2H), 7.46 (t, J = 1 1.7 Hz, 2H), 4.80 (d, J = 8.1 Hz, 1 H), 4.64 (t, J = 6.1 Hz, 1 H), 4.52 (t, J = 6.1 Hz, 1 H), 4.22 (t, J = 8.8 Hz, 1 H), 3.87 - 3.78 (m, 1 H), 3.15 (s, 3H), 2.89 (t, J = 6.0 Hz, 1 H), 2.83 (t, J = 6.0 Hz, 1 H), 2.64 (d, J = 14.7 Hz, 1 H), 2.32 (dd, J = 14.6, 8.5 Hz, 1 H), 1.61 (s, 3H).
Step 4. Synthesis of (2R)-3-((S)-3-(4-(4-fluorobut-1-yn-1-yl) phenyl)-2-oxooxazolidin-5- yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl) oxy) propanamide
[3.1.20d]. 3.1.20c (0.1 g, 0.2 mmol, 1.0 equiv) was dissolved in THF (5 mL). N-methyl morpholine (0.13 g, 1.2 mmol, 5.0 equiv), EDC.HCI (0.072 g, 0.4 mmol, 1.5 equiv), HOBT (0.061 g, 0.4 mmol, 1.8 equiv), 0-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.059 g, 0.5 mmol, 2.0 equiv) were added and the reaction mixture was stirred at room temperature for 24 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 afford a crude residue. The crude residue was purified by silica gel column chromatography (52 % EtOAc/Hexane) to afford the desired product 3.1.20d (0.09 g, 72.6 % yield). LCMS (m/z): 496.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.50 (s, 1 H), 7.53 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 4.97 (d, J = 8.5 Hz, 1 H), 4.64 (dd, J = 12.0, 5.9 Hz, 2H), 4.52 (t, J = 6.1 Hz, 1 H), 4.19 (t, J = 8.8 Hz, 1 H), 4.07 - 4.00 (m, 1 H), 3.80 (t, J = 8.2 Hz, 1 H), 3.52 (s, 1 H), 3.08 (d, J = 9.1 Hz, 3H), 2.86 (dt, J = 24.0, 6.0 Hz, 2H), 2.79 (d, J = 13.8 Hz, 1 H), 2.27 - 2.20 (m, 1 H), 1.69 (s, 3H), 1.62 (s, 3H), 1.54 (s, 3H).
Step 5. Synthesis of (R)-3-((S)-3-(4-(4-fluorobut-1-yn-1-yl) phenyl)-2-oxooxazolidin-5- yl)-N-hydroxy-2-methyl-2-(methylsulfonyl) propanamide [3.1.20]
3.1.20d (0.09 g, 0.2 mmol, 1.0 equiv) was dissolved in IPA (2 ml_). HCI (in IPA) (0.5 ml_) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude product. The crude product was purified by preparative HPLC purification to afford the desired product 3.1.20 (0.04 g, 53.3 % yield). LCMS (m/z): 413.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.07 (s, 1 H), 9.31 (s, 1 H), 7.54 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 4.64 (t, J = 6.0 Hz, 2H), 4.52 (t, J = 6.0 Hz, 1 H), 4.19 (s, 1 H), 3.84 - 3.74 (m, 1 H), 3.08 (s, 3H), 2.89 (t, J = 5.8 Hz, 1 H), 2.83 (t, J = 5.9 Hz, 1 H), 2.77 (d, J = 12.7 Hz, 1 H), 2.21 (dd, J = 14.3, 9.1 Hz, 1 H), 1.60 (s, 3H).
III.1.21. Synthesis of compound 3.1.21
Figure imgf000107_0001
Reagents: Step 1 Diethyl amine, triphenylphosphine, Cul, PdCI2(pph3)2, N,N- dimethylformamide, 100 °C. Step 2 : TFA, dichloromethane, 0 °C to room temperature. Step 3 : PTS-CI, TEA, DMAP, dichloromethane, 0 °C. Step 4 : NaCN, DMSO, 80 °C. Step 5 : LiOH.H20, THF, MeOH, water, room temperature. Step 6 : NH2OTHP, EDC.HCI, HOBT, N-methyl morpholine, THF, room temperature. Step 7: HCI (in IPA), MeOH, dichloromethane, room temperature.
Step 1. Synthesis of ethyl (R)-3-((S)-3-(4-((3-(((4-methoxybenzyl) oxy) methyl) cyclobutyl) ethynyl) phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1.21a]. (1.1d) (1.74 g, 4.01 mmol, 1.0 equiv) was suspended in diethyl amine (15 ml_) and N, N-dimethylformamide (3 ml_) in sealed tube. Cul (0.076 g, 0.40 mmol, 0.1 equiv), triphenyl phosphine (0.21 g, 0.08 mmol, 0.2 equiv) were added and the reaction mixture was degassed for 15 minutes. PdCI2(pph3)2 (0.14 g, 0.20 mmol, 0.05 equiv), 1-(((3- ethynylcyclobutyl)methoxy)methyl)-4-methoxybenzene (1.2 g, 5.2 mmol, 1.3 equiv) were added and the reaction mixture was stirred at 100 °C for 24 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 afford a crude residue, which was purified by silica gel chromatography (60-65 % EtOAc/Hexane) to afford the desired product 3.1.21a (2 g, 65.7 % yield). LCMS (m/z): 584.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.67 - 7.47 (m, 4H), 7.40 (t, J = 9.4 Hz, 1 H), 7.25 (dd, J = 8.7, 2.8 Hz, 1 H), 7.03 - 6.88 (m, 2H), 4.83 - 4.74 (m, 1 H), 4.40 (d, J = 8.8 Hz, 1 H), 4.31 - 4.20 (m, 3H), 3.88 - 3.81 (m, 1 H), 3.81 - 3.70 (m, 3H), 3.45 (d, J = 6.8 Hz, 1 H), 3.37 (d, J = 6.0 Hz, 2H), 3.32 - 3.21 (m, 1 H), 3.16 (t, J = 6.4 Hz, 3H), 2.67 (d, J = 3.9 Hz, 1 H), 2.57 (s, 1 H), 2.44 - 2.29 (m, 2H), 2.17 (dd, J = 16.2, 7.9 Hz, 1 H), 1.87 (d, J = 1 1.1 Hz, 1 H), 1.65 (d, J = 3.8 Hz, 3H), 1.27 (dt, J = 7.2, 3.6 Hz, 3H). Step 2. Synthesis of ethyl (R)-3-((S)-3-(4-((3-(hydroxymethyl) cyclobutyl) ethynyl) phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1.21 b]
3.1.21a (2 g, 3.43 mmol, 1.0 equiv) was suspended in dichloromethane (60 ml_) and cooled to 0 °C. TFA (2.6 ml_, 34.3 mmol, 10 equiv) was added drop wise and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, basified by solid sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (1.6 % MeOH/dichloromethane) to afford the desired product 3.1.21 b (0.9 g, 56.7 % yield). LCMS (m/z): 464.5 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.52 (dd, J = 8.9, 2.1 Hz, 2H), 7.44 - 7.38 (m, 2H), 4.84 - 4.74 (m, 1 H), 4.69 - 4.44 (m, 1 H), 4.32 - 4.17 (m, 3H), 3.85 - 3.68 (m, 2H), 3.55 - 3.34 (m, 2H), 3.31 - 3.04 (m, 4H), 2.68 (d, J = 12.9 Hz, 1 H), 2.48 - 2.21 (m, 3H), 2.14 (dd, J = 9.3, 5.4 Hz, 1 H), 1.94 - 1.78 (m, 1 H), 1.65 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 3. Synthesis of ethyl (R)-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-((3- ((tosyloxy) methyl) cyclobutyl) ethynyl) phenyl) oxazolidin-5-yl) propanoate [3.1.21c]. 3.1.21 b (0.45 g, 0.97 mmol, 1.0 equiv) was suspended in dichloromethane (80 ml_). TEA (0.49 g, 4.9 mmol, 5.0 equiv), DMAP (0.024 g, 0.2 mmol, 0.2 equiv) were added and the reaction mixture was cooled to 0 °C. 4-methylbenzenesulfonyl chloride (0.28 g, 1.45 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (50-55 % EtOAc/Hexane) to afford the desired product 3.1.21c (0.4 g, 66.8 % yield). LCMS (m/z): 618.9 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.87 - 7.73 (m, 2H), 7.50 (dt, J = 17.9, 8.1 Hz, 4H), 7.39 (t, J = 8.1 Hz, 2H), 4.79 (d, J = 7.8 Hz, 1 H), 4.24 (dt, J = 17.9, 8.1 Hz, 3H), 4.17 - 4.08 (m, 1 H), 4.04 - 4.00 (m, 1 H), 3.85 - 3.78 (m, 1 H), 3.76 - 3.62 (m, 1 H), 3.32 - 3.03 (m, 4H), 2.67 (s, 1 H), 2.43 (d, J = 6.2 Hz, 2H), 2.41 - 2.29 (m, 2H), 2.21 - 2.03 (m, 2H), 1.81 (dd, J = 20.7, 9.1 Hz, 1 H), 1.64 (s, 3H), 1.28 - 1.23 (m, 3H).
Step 4. Synthesis of ethyl (R)-3-((S)-3-(4-((3-(cyanomethyl) cyclobutyl) ethynyl) phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1.21d].
3.1.21c (0.3 g, 0.48 mmol, 1.0 equiv) was suspended in dimethylsulfoxide (12 ml_). NaCN (0.06 g, 1.21 mmol, 2.5 equiv) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was stirred at 80 °C for 2 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 afford a crude residue. The crude residue was purified by silica gel column chromatography (55 % EtOAc/Hexane) to afford product 3.1.21 d (0.14 g, 45.8 % yield). LCMS (m/z): 473.4 [M+H].
Step 5. Synthesis of (R)-3-((S)-3-(4-((3-(cyanomethyl) cyclobutyl) ethynyl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoic acid [3.1.21e].
3.1.21d (0.14 g, 0.29 mmol, 1.0 equiv) was suspended in THF (2.6 ml_), MeOH (0.6 mL) and water (0.6 mL). LiOH.H20 (0.016 g, 0.35 mmol, 1.2 equiv) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness. The residue was diluted with water and washed with EtOAc. The aqueous layer was acidified by 1.0 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 the desired product 3.1.21 e (0.1 1 g, 83.9 % yield). LCMS (m/z): 445.4 [M+H].
Step 6. Synthesis of (2R)-3-((S)-3-(4-((3-(cyanomethyl) cyclobutyl) ethynyl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl) oxy) propanamide [3.1.21†]. 3.1.21e (0.09 g, 0.2 mmol, 1.0 equiv) was suspended in THF (10 mL). N-methyl morpholine (0.1 g, 1.0 mmol, 5.0 equiv), HOBT (0.033 g, 0.24 mmol, 1.2 equiv), 0-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.048 g, 0.4 mmol, 2.0 equiv) were added and the reaction mixture was stirred at room temperature for 5 minutes. EDC.HCI (0.058 g, 0.3 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 24 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 afford crude residue. The crude residue was purified by silica gel column chromatography (1.6 % MeOH/dichloromethane) to afford the desired product 3.1.21† (0.1 g, 90.9 % yield). LCMS (m/z): 543.5 [M+H].
Step 7. Synthesis of (R)-3-((S)-3-(4-((3-(cyanomethyl) cyclobutyl) ethynyl) phenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl) propanamide [3.1.21]. 3.1.21† (0.1 g, 0.2 mmol, 1.0 equiv) was suspended in methanol (2 mL) and dichloromethane (2 mL). HCI (in IPA) (0.1 mL) was added and the reaction mixture was stirred at rt for 10 minutes. The reaction mixture was concentrated to dryness and co-distilled with dichloromethane to afford a crude residue. The crude residue was purified by preparative HPLC purification to afford the desired product 3.1.21 (0.018 g, 21.4 % yield). LCMS (m/z): 477.3 [M+18]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.32 (s, 1 H), 7.52 (dd, J = 8.9, 2.0 Hz, 2H), 7.42 (dd, J = 8.7, 6.3 Hz, 2H), 4.62 (dd, J = 14.4, 6.9 Hz, 1 H), 4.18 (t, J = 8.4 Hz, 1 H), 3.78 (t, J = 8.0 Hz, 1 H), 3.46 (ddd, J = 27.4, 10.3, 5.2 Hz, 1 H), 3.24 - 3.12 (m, 1 H), 3.08 (s, 3H), 2.81 - 2.71 (m, 2H), 2.67 (d, J = 6.2 Hz, 1 H), 2.49 - 2.42 (m, 1 H), 2.23 (dddd, J = 23.5, 16.1 , 1 1.6, 4.8 Hz, 3H), 1.92 (dd, J = 1 1.0, 4.7 Hz, 1 H), 1.62 (d, J = 16.2 Hz, 3H). III.1.22. Synthesis of compound 3.1.22
Step 1. Synthesis of (tetrahydro-2H-pyran-4-yl) methanol [3.1.22].
Methyl tetrahydro-2H-pyran-4-carboxylate (5 g, 34.68 mmol, 1.0 equiv) was dissolved in THF (60 ml_) and methanol (10 ml_). Sodium borohydride (2.62 g, 69.36 mmol, 2.0 equiv) was added in portions and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford the desired product 3.1.22a (3.2 g, 80 % yield). 1H NMR (400 MHz, DMSO) δ 3.96 - 3.75 (m, 2H), 3.66 - 3.58 (m, 2H), 3.36 (dd, J = 6.9, 4.7 Hz, 2H), 3.33 - 3.17 (m, 2H), 1.81 - 1.70 (m, 2H), 1.63 - 1.48 (m, 2H).
Step 2. Synthesis of (tetrahydro-2H-pyran-4-yl) methyl 4-methylbenzenesulfonate
[3.1.22b]. 3.1.22a (1 g, 8.62 mmol, 1.0 equiv) was dissolved in dichloromethane (20 ml_), TEA (4.36 g, 43.1 mmol, 5.0 equiv), DMAP (0.21 g, 1.72 mmol, 0.2 equiv) were added and cooled to 0 °C. 4-methylbenzenesulfonyl chloride (2.46 g, 12.9 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 24 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 afford a crude residue. The crude residue was purified by silica gel column chromatography (30-35 % EtOAc/Hexane) to afford the desired product 3.1.22b (0.8 g, 35 % yield). LCMS (m/z): 271.1 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.80 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 3.89 (dd, J = 1 1.9, 6.4 Hz, 2H), 3.80 (dd, J = 14.4, 6.9 Hz, 2H), 3.24 (dd, J = 22.0, 12.0 Hz, 2H), 2.43 (s, 3H), 1.90 -
I .71 (m, 2H), 1.51 (dd, J = 31.2, 12.6 Hz, 3H).
Step 3. Synthesis of 4-(prop-2-yn-1-yl) tetrahydro-2H-pyran [3.1.22c].
3.1.22b (0.5 g, 1.85 mmol, 1.0 equiv) was dissolved in dimethylsulfoxide (10 ml_). Lithium acetylide ethylene diamine (0.51 g, 5.56 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (15-20 % diethyl ether/n-pentane) to afford the desired product 3.1.22c (0.16 g, 69 % yield). 1H NMR (400 MHz, DMSO) δ 3.84 (dd, J =
I I .2, 4.2 Hz, 2H), 3.27 (td, J = 1 1.9, 1.9 Hz, 2H), 2.83 (t, J = 2.7 Hz, 1 H), 2.13 (dd, J = 6.2, 2.7 Hz, 2H), 1.70 - 1.57 (m, 3H), 1.24 (dd, J = 1 1.9, 4.3 Hz, 2H).
Step 4. Synthesis of (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(3- (tetrahydro-2H-pyran-4-yl) prop-1-yn-1-yl) phenyl) oxazolidin-5-yl) propanamide
[3.1.22]. 3.1.22c was converted to compound 3.1.22 by the precess of example 3.1.20. LCMS (m/z): 465.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.07 (s, 1 H), 9.31 (s, 1 H), 7.52 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 4.64 (d, J = 7.9 Hz, 1 H), 4.18 (t, J = 8.6 Hz, 1 H), 3.87 (d, J = 8.1 Hz, 2H), 3.84 - 3.74 (m, 1 H), 3.29 (d, J = 1 1.5 Hz, 2H), 3.08 (s, 3H), 2.77 (d, J = 12.8 Hz, 1 H), 2.39 (d, J = 6.2 Hz, 2H), 2.21 (dd, J = 14.5, 8.9 Hz, 1 H), 1.69 (d, J = 12.8 Hz, 3H), 1.60 (s, 3H), 1.38 - 1.26 (m, 2H).
III.1.23. Synthesis of compound 3.1.23
Step 1. Synthesis of ethyl (R)-3-((S)-3-(4-(4-hydroxybut-1-yn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1.23a]. 1.1d (0.25 g, 0.6 mmol, 1.0 equiv) was added to diethyl amine (5 ml_) and N,N-dimethylformamide (1 ml_). Cul (0.01 1 g, 0.06 mmol, 0.1 equiv), triphenylphosphine (0.03 g, 0.1 mmol, 0.2 equiv) were added and the reaction mixture was degassed for 10 minutes. But-3-yn-1-ol (0.048 g, 0.7 mmol, 1.2 equiv), PdCI2(pph3)2 (0.02 g, 0.03 mmol, 0.05 equiv) were added and the mixture was stirred at 1 10 °C for 3 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 afford a crude residue, which was purified by silica gel column chromatography (40-50 % EtOAc/Hexane) to afford the desired product 3.1.23a (0.2 g, 83.3 % yield). LCMS (m/z): 424.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.52 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 4.90 (t, J = 5.6 Hz, 1 H), 4.79 (d, J = 6.5 Hz, 1 H), 4.32 - 4.16 (m, 3H), 3.87 - 3.77 (m, 1 H), 3.58 (dd, J = 12.4, 6.7 Hz, 2H), 3.16 (s, 3H), 2.68 (d, J = 12.6 Hz, 1 H), 2.55 (t, J = 6.9 Hz, 2H), 2.37 - 2.31 (m, 1 H), 1.64 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 2. Synthesis of ethyl (R)-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(4-oxobut- 1-yn-1-yl) phenyl) oxazolidin-5-yl) propanoate [3.1.23b]. 3.1.23a (0.2 g, 0.5 mmol, 1.0 equiv) was dissolved in dichloromethane (5 ml_). Dess-Martin periodinane (0.3 g, 0.7 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with mixture of saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with sodium thiosulphate solution, brine, dried over sodium sulfate and concentrated to afford the desired product 3.1.23b (3.5 ml_ solution in dichloromethane due to we have observed degradation observed during drying). LCMS (m/z): 422.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.63 (dd, J = 1 1.9,
7.1 Hz, 4H), 4.80 (s, 1 H), 4.26 (s, 3H), 3.83 (s, 1 H), 3.17 (s, 3H), 2.68 (s, 1 H), 2.52 (s, 2H), 2.41 - 2.33 (m, 1 H), 2.09 (s, 3H), 1.65 (s, 3H), 1.25 (d, J = 9.2 Hz, 3H).
Step 3. Synthesis of ethyl (R)-3-((S)-3-(4-(4, 4-difluorobut-1-yn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanoate [3.1.23c]. 3.1.23b (3.5 ml_, 1.0 equiv) was dissolved in dichloromethane (5 ml_) and cooled to -70 °C. DAST (0.36 g,
2.2 mmol, 4.0 equiv) was added drop wise and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was added to saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel chromatography (30-32 % EtOAc/Hexane) to afford the desired product 3.1.23c (0.13 g, yield). LCMS (m/z): 444.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.62 (dd, J = 5.8, 4.8 Hz, 2H), 7.59 - 7.54 (m, 2H), 6.47 - 6.06 (m, 1 H), 4.79 (d, J = 9.8 Hz, 1 H), 4.30 - 4.22 (m, 2H), 4.14 (dd, J = 5.6, 3.5 Hz, 1 H), 3.87 - 3.77 (m, 1 H), 3.24 - 3.09 (m, 4H), 2.68 (d, J = 12.7 Hz, 1 H), 2.38 - 2.33 (m, 1 H), 1.64 (s, 3H), 1.28 - 1.23 (m, 3H).
Step 4. Synthesis of (R)-3-((S)-3-(4-(4, 4-difluorobut-1-yn-1-yl) phenyl)-2-oxooxazolidin- 5-yl)-2-methyl-2-(methylsulfonyl) propanoic acid [3.1.23d]. 3.1.23c (0.13 g, 0.3 mmol, 1.0 equiv) was dissolved in THF (1 ml_), MeOH (0.5 mL) and water (0.5 ml_). LiOH.H20 (0.018 g, 0.4 mmol, 1.5 equiv) was added and the reaction mixture was stirred at rt for 30 minutes. The reaction mixture was quenched with water and the aqueous layer was acidified by 1.0 N HCI to pH 2 to 3 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford the desired product 3.1.23d (0.1 1 g, 91.7 % yield). The product was used in the next step with no further purification. LCMS (m/z): 416.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 14.13 (s, 1 H), 7.55 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 6.26 (tt, J = 55.9 Hz, 1 H), 4.81 (m, 1 H), 4.23 (t, J = 8.8 Hz, 1 H), 3.84 (d, J = 7.5 Hz, 1 H), 3.23 - 3.06 (m, 5H), 2.67 (m, 1 H), 2.33 (m, 1 H), 1.61 (s, 3H). Step 5. Synthesis of (2R)-3-((S)-3-(4-(4, 4-difluorobut-1-yn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy) propanamide [3.1.23e]. 3.1.23d (0.1 1 g, 0.3 mmol, 1.0 equiv) was dissolved in THF (5 mL). N-methyl morpholine (0.13 mL, 1.3 mmol, 5.0 equiv), HOBT (0.043 g, 0.3 mmol, 1.2 equiv), 0-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.062 g, 0.5 mmol, 2.0 equiv), EDC.HCI (0.076 g, 0.4 mmol, 1.5 equiv) were added and the reaction mixture was stirred at room temperature for 24 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 afford a crude residue. The crude residue was purified by silica gel column chromatography (60-70 % EtOAc/Hexane) to afford the desired product 3.1.23e (0.1 g, 73.5 % yield). LCMS (m/z): 514.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.51 (s, 1 H), 7.55 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 6.26 (tt, J = 56.0 Hz, 1 H), 4.97 (d, J = 8.6 Hz, 1 H), 4.69 (s, 1 H), 4.20 (d, J = 8.9 Hz, 1 H), 4.17 - 4.12 (m, 2H), 3.81 (d, J = 8.8 Hz, 1 H), 3.51 (s, 1 H), 3.16 (td, J = 17.2, 4.0 Hz, 2H), 3.08 (d, J = 9.2 Hz, 3H), 2.79 (d, J = 13.9 Hz, 1 H), 2.22 (s, 1 H), 1.69 (s, 3H), 1.62 (s, 3H), 1.54 (s, 3H).
Step 6. Synthesis of (R)-3-((S)-3-(4-(4, 4-difluorobut-1-yn-1-yl) phenyl)-2-oxooxazolidin- 5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl) propanamide [3.1.23]. 3.1.23e (0.1 g, 0.2 mmol, 1.0 equiv) was dissolved in DCM (2 mL) and methanol (1 mL). HCI (in IPA) (2 mL) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude product was purified by preparative HPLC purification to afford the desired product 3.1.23 (0.023 g, 27.7 % yield). LCMS (m/z): 429.1 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 9.31 (s, 1 H), 7.55 (d, J = 8.9 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 6.26 (tt, J = 56.0, 3.8 Hz, 1 H), 4.65 (d, J = 7.8 Hz, 1 H), 4.19 (t, J = 8.7 Hz, 1 H), 3.83 - 3.76 (m, 1 H), 3.16 (td, J = 17.2, 3.9 Hz, 2H), 3.08 (s, 3H), 2.78 (d, J = 14.3 Hz, 1 H), 2.22 (dd, J = 14.5, 8.9 Hz, 1 H), 1.60 (s, 3H).
III.1.24. Synthesis of compound 3.1.24
Step 1. Synthesis of methyl 3-hydroxy-3-methylcyclobutane-1-carboxylate [3.1.24a]
Methyl 3-oxocyclobutane-1-carboxylate (5 g, 39.02 mmol, 1.0 equiv) was dissolved in diethyl ether (75 ml.) and cooled to -78 °C. Methyl magnesium bromide (13 ml_, 39.02 mmol, 1.0 equiv) was added and the reaction mixture was stirred at -10 °C for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (10-20 % EtOAc/Hexane) to afford the desired product 3.1.24a (2.2 g, 40 % yield). 1H NMR (400 MHz, DMSO) δ 5.07 (d, J = 36.9 Hz, 1 H), 3.59 (d, J = 3.5 Hz, 3H), 2.80 - 2.57 (m, 1 H), 2.26 - 2.04 (m, 4H), 1.21 (d, J = 14.2 Hz, 3H).
Step 2. Synthesis of methyl 3-((4-methoxybenzyl) oxy)-3-methylcyclobutane-1- carboxylate [3.1.24b]. 3.1.24a (2.1 g, 14.57 mmol, 1.0 equiv), DIPEA (5.6 g, 43.7 mmol, 3.0 equiv) were dissolved in Dichloromethane (20 ml_). 1-(Chloromethyl)-4-methoxybenzene (4.5 g, 29.2 mmol, 2.0 equiv) was added and the reaction mixture was stirred at 100 °C for 24 hours. The reaction mixture was concentrated to afford a crude residue, which was purified by silica gel chromatography (5 % EtOAc/Hexane) to afford 3.1.24b (2.5 g, 75% yield). LCMS (m/z): 282.2 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.24 (t, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.45 - 4.24 (m, 2H), 3.83 - 3.69 (m, 3H), 3.62 (d, J = 7.0 Hz, 3H), 2.95 - 2.77 (m, 1 H), 2.41 - 2.20 (m, 2H), 2.19 - 2.02 (m, 2H), 1.36 (d, J = 19.2 Hz, 3H). Step 3. Synthesis of (3-((4-methoxybenzyl) oxy)-3-methylcyclobutyl) methanol
[3.1.24c]. 3.1.24b (5.2 g, 19.2 mmol, 1.0 equiv) was dissolved in THF (40 mL) and methanol (4 mL). Sodium borohydride (1.42 g, 38.58 mmol, 2.0 equiv) was added in portions and the reaction mixture was stirred at rt for 24 hours. The reaction mixture was poured in to water and extracted by EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (10-20 % EtOAc/Hexane) to afford the desired product 3.1.24c (2.6 g, 57 % yield). LCMS (m/z): 237.1 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.24 (t, J = 8.6 Hz, 2H), 6.93 - 6.84 (m, 2H), 4.52 - 4.39 (m, 1 H), 4.25 (d, J = 6.6 Hz, 2H), 3.74 (s, 3H), 3.39 (dt, J = 1 1.1 , 5.6 Hz, 2H), 2.05 - 1.69 (m, 4H), 1.33 (d, J = 17.1 Hz, 3H). Step 4. Synthesis of 3-((4-methoxybenzyl) oxy)-3-methylcyclobutane-1-carbaldehyde
[3.1.24d]. 3.1.24c (1.3 g, 5.5 mmol, 1.0 equiv) was dissolved in dichloromethane (20 ml_). PCC (2.3 g, 1 1.0 mmol, 2.0 equiv) was added in portions and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with diethyl ether and filtered. The filtrate was concentrated to afford the desired product 3.1.24d (1.2 g, 100 % yield). The product was used in the next step with no further purification. 1H NMR (400 MHz, DMSO) δ 9.69 (t, J = 18.9 Hz, 1 H), 7.25 (dd, J = 12.3, 8.6 Hz, 2H), 6.89 (dd, J = 8.6, 3.6 Hz, 2H), 4.28 (d, J = 10.0 Hz, 2H), 3.73 (t, J = 5.7 Hz, 3H), 2.99 - 2.80 (m, 1 H), 2.33 - 2.01 (m, 4H), 1.44 - 1.20 (m, 3H).
Step 5. Synthesis of 1-((3-ethynyl-1-methylcyclobutoxy) methyl)-4-methoxybenzene
[3.1.24e]. 3.1.24d (1.2 g, 5.12 mmol, 1.0 equiv) was dissolved in MeOH (20 ml_). K2C03 (1.4 g, 10.3 mmol, 2.0 equiv), Ohira-Bestmann reagent (1.2 g, 6.15 mmol, 1.2 equiv) was added and the reaction mixture was stirred at rt for 24 hours. The reaction mixture was concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (5 % EtOAc/Hexane) to afford the desired product 3.1.24e (0.7 g, 63 % yield). LCMS (m/z): 248.2 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.24 (d, J = 8.6 Hz, 2H), 6.93 - 6.82 (m, 2H), 4.25 (s, 2H), 3.75 (d, J = 6.6 Hz, 3H), 3.02 (dd, J = 1 1.8, 2.4 Hz, 1 H), 2.71 (dd, J = 17.5, 8.0 Hz, 1 H), 2.30 - 2.19 (m, 2H), 2.12 (t, J = 10.2 Hz, 2H), 1.33 (s, 3H). Step 6. Synthesis of ethyl (R)-3-((S)-3-(4-((3-((4-methoxybenzyl) oxy)-3- methylcyclobutyl) ethynyl) phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.2.24f]. 1.1d (0.88 g, 2.0 mmol, 1.0 equiv) was added to diethyl amine (10 ml.) and N, N-dimethylformamide (2 ml_). Cul (0.038 g, 0.2 mmol, 0.1 equiv) and triphenylphosphine (0.1 g, 0.4 mmol, 0.2 equiv) were added and the reaction mixture was degassed for 5 minutes. 3.1.24e (0.7 g, 3.03 mmol, 1.5 equiv), PdCI2(pph3)2 (0.07 g, 0.1 mmol, 0.05 equiv) were added and the reaction mixture was stirred at 100 °C for 24 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 afford a crude residue, which was purified by silica gel chromatography (10 % EtOAc/Hexane) to afford the desired product 3.1.24f (0.9 g, 81 % yield). LCMS (m/z): 584.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.52 (d, J = 8.9 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.79 (d, J = 7.1 Hz, 1 H), 4.37 - 4.17 (m, 5H), 3.83 (d, J = 7.4 Hz, 1 H), 3.74 (s, 3H), 3.25 (dd, J = 1 1.6, 7.1 Hz, 1 H), 3.16 (s, 3H), 3.03 - 2.93 (m, 1 H), 2.68 (d, J = 15.3 Hz, 2H), 2.39 - 2.21 (m, 4H), 1.64 (s, 3H), 1.44 (d, J = 52.2 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H). Step 7. Synthesis of ethyl (R)-3-((S)-3-(4-((3-hydroxy-3-methylcyclobutyl) ethynyl) phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1 -24g] 3.1.24f (0.8 g, 1.37 mmol, 1.0 equiv) was dissolved in dichloromethane (20 ml_) and cooled to 0 °C. TFA (0.8 ml_) in dichloromethane (10 ml_) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude product. The crude product was purified by silica gel column chromatography (10 % EtOAc/Hexane) to afford the desired product 3.1.24g (0.5 g, 78 % yield). LCMS (m/z): 464.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.52 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 4.79 (d, J = 8.3 Hz, 1 H), 4.24 (dt, J = 18.2, 8.0 Hz, 3H), 3.86 - 3.77 (m, 1 H), 3.16 (s, 3H), 2.85 - 2.74 (m, 1 H), 2.68 (d, J = 14.1 Hz, 1 H), 2.42 - 2.25 (m, 3H), 2.17 (d, J = 9.6 Hz, 1 H), 1.64 (s, 3H), 1.27 - 1.20 (m, 3H).
Step 8. Synthesis of (R)-3-((S)-3-(4-((3-hydroxy-3-methylcyclobutyl) ethynyl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoic acid [3.1.24h].
3.1.24g (0.5 g, 1.08 mmol, 1.0 equiv) was dissolved in THF (6 mL) and MeOH (2 ml_). LiOH (0.068 g, 1.61 mmol, 1.5 equiv) in water (2 mL) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, quenched with water, acidified by 1.0 N HCI aqueous solution to the pH 4 to 5 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford the desired product 3.1.24h (0.4 g, 85 % yield). LCMS (m/z): 436.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 14.10 (s, 1 H), 7.51 (d, J = 8.9 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 4.80 (d, J = 6.2 Hz, 1 H), 4.22 (t, J = 8.7 Hz, 1 H), 3.85 - 3.78 (m, 1 H), 3.15 (s, 3H), 2.79 (t, J = 8.1 Hz, 1 H), 2.64 (d, J = 14.4 Hz, 2H), 2.36 - 2.28 (m, 3H), 2.16 (t, J = 10.1 Hz, 2H), 1.62 (d, J = 1 1.2 Hz, 3H), 1.23 (d, J = 5.6 Hz, 3H).
Step 9. Synthesis of (2R)-3-((S)-3-(4-((3-hydroxy-3-methylcyclobutyl) ethynyl) phenyl)- 2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy) propanamide [3.1.24i]. 3.1.24h (0.3 g, 0.68 mmol, 1.0 equiv) was dissolved in THF (6 mL). EDC.HCI (0.24 g, 1.23 mmol, 1.8 equiv), HOBT (0.14 g, 1.03 mmol, 1.5 equiv), N-methyl morpholine (0.39 g, 3.44 mmol, 5.0 equiv), 0-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.14 g, 1.17 mmol, 1.7 equiv) were added and the reaction mixture was stirred at room temperature for 24 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 afford a crude residue. The crude residue was purified by silica gel column chromatography (40 % EtOAc/Hexane) to afford the desired product 3.1.24i (0.33 g, 88 % yield). LCMS (m/z): 533.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 11.48 (d, J = 3.2 Hz, 1 H), 7.51 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 5.03 - 4.95 (m, 1 H), 4.66 (s, 1 H), 4.18 (t, J = 8.6 Hz, 1 H), 3.84 - 3.73 (m, 1 H), 3.51 (s, 1 H), 3.10 (t, J = 13.9 Hz, 3H), 2.75 (t, J = 23.7 Hz, 2H), 2.42 - 2.27 (m, 3H), 2.27 - 2.1 1 (m, 3H), 1.70 (s, 3H), 1.62 (s, 3H), 1.54 (s, 3H). Step 10. Synthesis of (R)-N-hydroxy-3-((S)-3-(4-((3-hydroxy-3-methylcyclobutyl) ethynyl) phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanamide
[3.1.24 & 3.1.25]. 3.1.24i (0.3 g, 0.56 mmol, 1.0 equiv) was dissolved in methanol (5 mL). PTSA.H20 (0.13 g, 0.56 mmol, 1.0 equiv) was added and the reaction mixture was stirred at rt for 2 hours. The reaction mixture was diluted with water, precipitated solid was filtered and dried to afford a crude product. The crude product was purified by preparative HPLC purification to afford the desired product 3.1.24 as isomer-A (0.015 g, 6 % yield). LCMS (m/z): 451.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1 H), 9.32 (s, 1 H), 7.51 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 5.02 (s, 1 H), 4.65 (s, 1 H), 4.18 (t, J = 8.7 Hz, 1 H), 3.79 (d, J = 7.8 Hz, 1 H), 3.20 (s, 1 H), 3.08 (s, 3H), 2.77 (d, J = 15.8 Hz, 2H), 2.44 - 2.32 (m, 3H), 2.23 (d, J = 8.2 Hz, 1 H), 2.1 1 - 1.97 (m, 2H), 1.60 (s, 3H), 1.38 (s, 3H). 3.1.25 as Isomer-B (0.040 g, 15.8 % yield). LCMS (m/z): 451.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.33 (s, 1 H), 7.51 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 5.17 (s, 1 H), 4.63 (d, J = 6.6 Hz, 1 H), 4.18 (t, J = 8.8 Hz, 1 H), 3.85 - 3.68 (m, 1 H), 3.08 (s, 3H), 2.78 (dd, J = 16.8, 8.7 Hz, 2H), 2.35 - 2.26 (m, 2H), 2.19 (dt, J = 21.1 , 9.8 Hz, 3H), 1.60 (s, 3H), 1.22 (s, 3H).
III.1.26. Synthesis of compound 3.1.26
Step 1. Synthesis of 5-(4-bromophenyl) pent-4-yn-1-ol [3.1.26a].
1-Bromo-4-iodobenzene (1 g, 3.5 mmol, 1.0 equiv) was dissolved in diethyl amine (5 ml_) and N, N-dimethylformamide (2 ml_). Cul (0.067 g, 0.35 mmol, 0.1 equiv), triphenylphosphine (0.18 g, 0.7 mmol, 0.2 equiv) were added and the reaction mixture was degassed for 15 minutes. Pent-4-yn-1-ol (0.36 g, 4.2 mmol, 1.2 equiv), PdCI2(pph3)2 (0.12 g, 0.17 mmol, 0.05 equiv) were added and the reaction mixture was stirred at 120 °C for 6 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 afford a crude residue. The crude residue was purified by silica gel column chromatography (25-30 % EtOAc/Hexane) to afford the desired product 3.1.26a (0.65 g, 76.47 % yield). 1H NMR (400 MHz, CDCI3) δ 7.47 - 7.40 (m, 2H), 7.27 (d, J = 8.5 Hz, 2H), 3.84 (t, J = 5.9 Hz, 2H), 2.55 (t, J = 7.0 Hz, 2H), 1.94 - 1.80 (m, 2H), 1.65 (s, 1 H).
Step 2. Synthesis of 1-bromo-4-(5-fluoropent-1-yn-1-yl) benzene [3.1.26b]. 3.1.26a
(0.25 g, 1.05 mmol, 1.0 equiv) was dissolved in dichloromethane (10 ml_) and cooled to -78 °C. DAST (0.25 g, 1.56 mmol, 1.5 equiv) was added drop wise and the reaction mixture was stirred at -78 °C for 10 minutes. The reaction mixture was stirred at rt for 1 hour. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue that was purified by silica gel chromatography (10 % EtOAc/Hexane) to afford 3.1.26b (0.13 g, 51.6% yield). 1H NMR (400 MHz, DMSO) δ 7.56 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 4.63 (t, J = 5.8 Hz, 1 H), 4.51 (t, J = 5.8 Hz, 1 H), 2.54 (m, 2H), 1.93 (ddd, J = 25.7, 12.4, 6.0 Hz, 2H). Step 3. Synthesis of (R)-3-((S)-3-(4-(5-fluoropent-1-yn-1 -yl) phenyl)-2-oxooxazolidin-5- yl)-N-hydroxy-2-methyl-2-(methylsulfonyl) propanamide [3.1.26].
3.1.26b was converted to 3.1.26 by the process described in the synthesis of 2.4. LCMS (m/z): 427.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.32 (s, 1 H), 7.52 (d, J = 8.9 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 4.63 (t, J = 5.8 Hz, 2H), 4.51 (t, J = 5.8 Hz, 1 H), 4.18 (t, J = 8.8 Hz, 1 H), 3.83 - 3.75 (m, 1 H), 3.08 (s, 3H), 2.77 (d, J = 12.0 Hz, 1 H), 2.54 (d, J = 7.1 Hz, 2H), 2.26 - 2.20 (m, 1 H), 1.98 - 1.87 (m, 2H), 1.60 (s, 3H).
111.1.27. Synthesis of compound 3.1.27
Step 1. Synthesis of ethyl (R)-3-((S)-3-(4-(6-methoxyhex-1-yn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1.27b]. (R)-ethyl 3-((S)- 3-(4-(6-hydroxyhex-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate (0.23 g, 0.5 mmol, 1.0 equiv) was suspended in acetonitrile (2.3 mL) in sealed tube. Ag20 (0.47 g, 2.04 mmol, 4.0 equiv), iodomethane (0.65 g, 10.2 mmol, 20.0 equiv) were added and the reaction mixture was stirred at reflux for 4 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 afford a crude product, which was purified by silica gel column chromatography (48-55 % EtOAc/Hexane) to afford product 3.1.27b (0.18 g, 76 % yield). LCMS (m/z): 466.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.52 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 4.79 (d, J = 7.9 Hz, 1 H), 4.20 (t, J = 8.6 Hz, 1 H), 3.80 (d, J = 2.2 Hz, 4H), 3.37 (d, J = 6.1 Hz, 2H), 3.23 (s, 3H), 3.16 (s, 3H), 2.69 (d, J = 15.0 Hz, 1 H), 2.43 (t, J = 6.8 Hz, 2H), 2.36 (dd, J = 14.9, 9.0 Hz, 1 H), 1.71 - 1.54 (m, 7H).
Step 4. Synthesis of (R)-N-hydroxy-3-((S)-3-(4-(6-methoxyhex-1-yn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanamide [3.1.27]. 3.1.27b was converted to 3.1.27 using the precess described in the synthesis of 3.1.20. LCMS (m/z): 470.3 [M+18]. 1H NMR (400 MHz, DMSO) δ 1 1.07 (s, 1 H), 9.31 (s, 1 H), 7.51 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 4.64 (d, J = 7.5 Hz, 1 H), 4.18 (t, J = 8.5 Hz, 1 H), 3.83 - 3.75 (m, 1 H), 3.37 (d, J = 6.0 Hz, 2H), 3.23 (s, 3H), 3.08 (s, 3H), 2.77 (d, J = 13.1 Hz, 1 H), 2.43 (t, J = 6.7 Hz, 2H), 2.21 (dd, J = 14.0, 8.8 Hz, 1 H), 1.70 - 1.51 (m, 7H).
111.1.28. Synthesis of compound 3.1.28
Step 1. Synthesis of ethyl (R)-3-((S)-3-(4-(6-hydroxyhex-1-yn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanoate [3.1.28a]. 1.1d (0.6 g, 1.38 mmol, 1.0 equiv) was dissolved in diethyl amine (15 mL) and N, N-dimethylformamide (3 mL). Triphenylphosphine (0.073 g, 0.27 mmol, 0.2 equiv), Cul (0.27 g, 0.13 mmol, 0.1 equiv) were added and the reaction mixture was degassed for 15 minutes. PdCI2(pph3)2 (0.049 g, 0.07 mmol, 0.05 equiv), hex-5-yn-1-ol (0.18 g, 1.79 mmol, 1.3 equiv) were added and the reaction mixture was stirred at 100 °C for 24 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 afford a crude residue. The crude residue was purified by silica gel column chromatography (65-70 % EtOAc/Hexane) to afford the desired product 3.1.28a (0.53 g, 85.1 % yield). LCMS (m/z): 452.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.54 - 7.49 (m, 2H), 7.43 - 7.35 (m, 2H), 4.83 - 4.74 (m, 1 H), 4.46 - 4.41 (m, 1 H), 4.30 - 4.18 (m, 3H), 3.82 (dd, J = 9.0, 7.6 Hz, 1 H), 3.44 (dd, J = 6.7, 4.6 Hz, 2H), 3.16 (s, 3H), 2.68 (dd, J = 14.9, 2.5 Hz, 1 H), 2.42 (t, J = 6.6 Hz, 2H), 2.34 (dd, J = 15.2, 6.3 Hz, 1 H), 1.64 (s, 3H), 1.57 (dt, J = 6.5, 3.3 Hz, 4H), 1.26 (dd, J = 8.7, 5.5 Hz, 3H).
Step 2. Synthesis of (R)-N-hydroxy-3-((S)-3-(4-(6-hydroxyhex-1-yn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanamide [3.1.28]
3.1.28b was converted to 3.1.28 using the precess described in the synthesis of 3.1.20. LCMS (m/z): 437.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 11.08 (s, 1 H), 9.32 (s, 1 H), 7.51 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 4.64 (d, J = 7.2 Hz, 1 H), 4.44 (t, J = 5.2 Hz, 1 H), 4.18 (t, J = 8.9 Hz, 1 H), 3.82 - 3.74 (m, 1 H), 3.44 (d, J = 5.2 Hz, 2H), 3.08 (s, 3H), 2.78 (d, J = 14.2 Hz, 1 H), 2.42 (s, 2H), 2.25 - 2.18 (m, 1 H), 1.60 (s, 3H), 1.57 (d, J = 2.9 Hz, 4H).
III.1.29. Synthesis of compound 3.1.29
Step 1. Synthesis of 5-(4-bromophenyl) pent-4-ynal [3.1.29a]
5-(4-bromophenyl)pent-4-yn-1-ol (0.6 g, 2.49 mmol, 1.0 equiv) was dissolved in dichloromethane (10 ml_) and cooled to 0 °C. Dess-Martin periodinane (1.79 g, 4.23 mmol, 1.7 equiv) was added in portion wise and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution, sodium thiosulphate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (10-15 % EtOAc/Hexane) to afford the desired product 3.1.29a (0.25 g, 42 % yield). 1H NMR (400 MHz, DMSO) δ 9.71 (s, 1 H), 7.60 - 7.51 (m, 2H), 7.36 - 7.29 (m, 2H), 2.77 (t, J = 6.9 Hz, 2H), 2.67 (t, J = 6.8 Hz, 2H).
Step 2. Synthesis of 1-bromo-4-(5, 5-difluoropent-1-yn-1-yl) benzene [3.1.29b].
3.1.29a (0.25 g, 1.05 mmol, 1.0 equiv) was dissolved in dichloromethane (10 ml_) and cooled to -78 °C. DAST (0.67 g, 4.18 mmol, 4.0 equiv) was added drop wise and the reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was diluted with water, neutralized with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (3-5 % EtOAc/Hexane) to afford the desired product 3.1.29b (0.13 g, 47.6 % yield). 1H NMR (400 MHz, DMSO) δ 7.62 - 7.53 (m, 2H), 7.40 - 7.31 (m, 2H), 6.19 (tt, J = 56.4, 4.5 Hz, 1 H), 2.58 (t, J = 7.3 Hz, 2H), 2.20 - 2.06 (m, 2H).
Step 3. Synthesis of (R)-3-((S)-3-(4-(5, 5-difluoropent-1-yn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl) propanamide [3.1.29]
3.1.29b was converted to 3.1.29 using the process described for the synthesis of 2.4. LCMS (m/z): 445.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.07 (s, 1 H), 9.28 (s, 1 H), 7.53 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.7 Hz, 2H), 6.19 (tt, J = 56.5, 4.5 Hz, 1 H), 4.64 (d, J = 7.0 Hz, 1 H), 4.18 (t, J = 8.8 Hz, 1 H), 3.79 (t, J = 8.1 Hz, 1 H), 3.08 (s, 3H), 2.77 (d, J = 14.1 Hz, 1 H), 2.58 (t, J = 7.3 Hz, 2H), 2.24 - 2.18 (m, 1 H), 2.17 - 2.05 (m, 2H), 1.60 (s, 3H).
111.1.30. Synthesis of compound 3.1.30
3.1.30 was prepared using the process described for the synthesis of 3.1.27. LCMS (m/z): 456.0 [M+18]. 1H NMR (400 MHz, DMSO) δ 1 1.07 (s, 1 H), 9.28 (s, 1 H), 7.52 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 4.63 (s, 1 H), 4.18 (s, 1 H), 3.78 (s, 1 H), 3.44 (t, J = 6.0 Hz, 2H), 3.26 (s, 3H), 3.08 (s, 3H), 2.77 (d, J = 13.9 Hz, 1 H), 2.44 (d, J = 7.1 Hz, 2H), 2.25 - 2.17 (m, 1 H), 1.80 - 1.71 (m, 2H), 1.59 (s, 3H).
111.1.31. Synthesis of compound 3.1.31
3.1.31 was prepared using the process described for the synthesis of 3.1.28. LCMS (m/z): 425.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 11.08 (s, 1 H), 9.16 (s, 1 H), 7.51 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 4.66 (s, 1 H), 4.54 (t, J = 5.2 Hz, 1 H), 4.17 (t, J = 8.6 Hz, 1 H), 3.82 - 3.75 (m, 1 H), 3.52 (dd, J = 11.5, 6.0 Hz, 2H), 3.08 (s, 3H), 2.75 (d, J = 1 1.5 Hz, 1 H), 2.45 (t, J = 7.2 Hz, 2H), 2.23 - 2.16 (m, 1 H), 1.72 - 1.64 (m, 2H), 1.58 (s, 3H).
111.1.32. Synthesis of compound 3.1.32
Step 1. Synthesis of ethyl (R)-3-((S)-3-(4-ethynylphenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl) propanoate [3.1.32a]. 1.1d (0.8 g, 1.8 mmol, 1.0 equiv), propiolic acid (0.19 g, 2.7 mmol, 1.5 equiv), 1 ,4-bis(diphenylphosphino) butane (0.017 g, 0.04 mmol, 0.02 equiv), DBU(0.54 g, 3.7 mmol, 2.0 equiv) were added in DMSO (10 mL) and degassed for 10 minutes. PdCI2(PPh3)2 (0.012 g, 0.02 mmol, 0.01 equiv) was added and the reaction mixture was stirred at 100 °C for 24 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (35-40 % EtOAc/Hexane) to afford the desired product 3.1.32a (0.44 g, 62.8 % yield). LCMS (m/z): 380.1 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.58 (dd, J = 1 1.2, 9.0 Hz, 2H), 7.51 (d, J = 9.0 Hz, 2H), 4.80 (d, J = 8.3 Hz, 1 H), 4.25 (dt, J = 13.4, 7.8 Hz, 3H), 4.15 (s, 1 H), 3.87 - 3.79 (m, 1 H), 3.16 (s, 3H), 2.69 (d, J = 12.5 Hz, 1 H), 2.42 - 2.35 (m, 1 H), 1.65 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 2. Synthesis of ethyl (R)-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(4,4,4- trifluorobut-1-yn-1-yl)phenyl)oxazolidin-5-yl) propanoate [3.1.32b]. Mixture of Pd2(dba)3 (0.036 g, 0.04 mmol, 0.05 equiv), DEP- phos (0.085 g, 0.2 mmol, 0.2 equiv), DABCO (0.18 g, 1.6 mmol, 2.0 equiv) were added in sealed tube and the sealed tube was evacuated and backfilled with argon thrice. 1 , 1 , 1-Trifluoro-2-iodoethane (0.33 g, 1.6 mmol, 2.0 equiv), 3.1.32a (0.3 g, 0.8 mmol, 1.0 equiv) in toluene (10 mL) was added and the reaction mixture was stirred at 80 °C for 24 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue, which was purified by silica gel chromatography (30- 40 % EtOAc/Hexane) to afford the desired product 3.1.32b (0.29 g, 59.2 % yield). LCMS (m/z): 462.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.57 (d, J = 8.8 Hz, 2H), 7.51 (t, J = 7.2 Hz, 2H), 4.83 - 4.76 (m, 1 H), 4.30 - 4.19 (m, 3H), 3.80 (dt, J = 21.0, 9.2 Hz, 3H), 3.16 (s, 3H), 2.69 (d, J = 12.2 Hz, 1 H), 2.40 - 2.35 (m, 1 H), 1.65 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). Step 3. Synthesis of (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4- (4,4,4-trifluorobut-1-yn-1-yl)phenyl)oxazolidin-5-yl) propanamide [3.1.32]. 3.1.32b was converted to 3.1.32 using the process described for the synthesis of 3.1.20. LCMS (m/z): 449.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.32 (s, 1 H), 7.57 (d, J = 8.9 Hz, 2H), 7.50 (d, J = 8.9 Hz, 2H), 4.65 (d, J = 7.2 Hz, 1 H), 4.20 (t, J = 8.9 Hz, 1 H), 3.86 - 3.70 (m, 3H), 3.08 (s, 3H), 2.77 (d, J = 12.4 Hz, 1 H), 2.22 (dd, J = 14.6, 9.1 Hz, 1 H), 1.60 (s, 3H).
III.1.33. Synthesis of compound 3.1.33
Step 1. Synthesis of 3-methylenecyclobutane-1-carboxylic acid [3.1.33a]
3-Methylenecyclobutane-1-carbonitrile (24 g, 258.0 mmol, 1.0 equiv) was dissolved in ethanol (160 mL). KOH (72.3 g, 1290.3 mmol, 5.0 equiv) in water (160 mL) was added and the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was concentrated, acidified by 1.0 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 the desired product 3.1.33a (26.2 g, 91 % yield). 1H NMR (400 MHz, DMSO) δ 12.22 (s, 1 H), 4.89 - 4.66 (m, 2H), 3.13 - 2.98 (m, 1 H), 2.95 - 2.73 (m, 4H).
Step 2. Synthesis of methyl 3-methylenecyclobutane-1-carboxylate [3.1.33b]
3.1.33a (26.2 g, 233.9 mmol, 1.0 equiv) was dissolved in acetone (200 mL). K2C03 (64.6 g, 467.8 mmol, 2.0 equiv) was added and cooled to 0 °C. Me2S04 (35.4 g, 280.7 mmol, 1.2 equiv) was added drop wise and the reaction mixture was stirred at 50 °C for 2 hours. The reaction mixture was quenched with water and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel chromatography (30-35 % diethyl ether/n-pentane) to afford the desired product 3.1.33b (25.3 g, 86 % yield). 1H NMR (400 MHz, DMSO) δ 4.85 - 4.76 (m, 2H), 3.62 (s, 3H), 3.23 - 3.12 (m, 1 H), 2.91 - 2.83 (m, 4H). Step 3. Synthesis of methyl 3-(hydroxymethyl) cyclobutane-1-carboxylate [3.1.33c] 3.1.33b (25.3 g, 200.8 mmol, 1.0 equiv) was dissolved in THF (150 mL) and cooled to -20 °C. BH3.Me2S (2.0 M) (100 mL, 200.8 mmol, 1.0 equiv) was added dropwise and the reaction mixture was stirred at rt for 4 hours. The reaction mixture was cooled to -10 °C. Methanol (20 mL) was added within 10 minutes. H202 (30 %) (13.7 g, 200.8 mmol, 1.0 equiv) and NaOH (3.0 M) (30 mL) were added dropwise and the reaction mixture was stirred at rt for 2 hours. The reaction mixture was quenched with saturated aqueous sodium hydrogen sulfate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel chromatography (35-40 % EtOAc/Hexane) to afford the desired product 3.1.33c (17.3 g, 60 % yield). 1H NMR (400 MHz, DMSO) δ 4.62 - 4.39 (m, 1 H), 3.58 (t, J = 6.9 Hz, 3H), 3.36 (d, J = 46.0 Hz, 2H), 3.16 - 2.96 (m, 1 H), 2.35 - 2.26 (m, 1 H), 2.14 (ddd, J = 18.0, 10.2, 5.6 Hz, 2H), 1.92 (dddd, J = 18.7, 1 1.7, 9.7, 3.6 Hz, 2H). Step 4. Synthesis of methyl 3-(((methylsulfonyl) oxy) methyl) cyclobutane-1- carboxylate [3.1.33d]. 3.1.33c (3 g, 20.8 mmol, 1.0 equiv) was dissolved in dichloromethane (30 mL) and cooled to 0 °C. TEA (14.6 g, 104.16 mmol, 5 equiv), MsCI (4.86 g, 62.5 mmol, 3.0 equiv) were added dropwise and the reaction mixture was stirred at rt for 6 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 a crude residue, which was purified by silica gel chromatography (40-45 % EtOAc/Hexane) to afford the desired product 3.1.33d (3 g, 65 % yield). 1H NMR (400 MHz, DMSO) δ 4.25 (d, J = 7.0 Hz, 1 H), 4.14 (d, J = 6.4 Hz, 1 H), 3.62 (t, J = 10.1 Hz, 3H), 3.19 (t, J = 8.7 Hz, 3H), 3.14 - 2.98 (m, 1 H), 2.67 - 2.55 (m, 1 H), 2.31 - 2.21 (m, 2H), 2.07 - 1.96 (m, 2H).
Step 5. Synthesis of methyl 3-((methylthio) methyl) cyclobutane-1-carboxylate
[3.1.33e]. 3.1.33d (3 g, 13.5 mmol, 1.0 equiv) was dissolved in N, N-dimethylformamide (25 mL). CH3SNa (1.42 g, 20.3 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 2 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 afford the desired product 3.1.33e (2.23 g, 95 % yield). The product was directly used in the next step with no further purification. 1H NMR (400 MHz, CDCI3) δ 3.70 (d, J = 10.4 Hz, 3H), 3.16 - 2.99 (m, 1 H), 2.65 - 2.60 (m, 1 H), 2.60 - 2.55 (m, 1 H), 2.52 - 2.35 (m, 3H), 2.10 (t, J = 2.5 Hz, 3H), 2.06 - 1.94 (m, 2H).
Step 6. Synthesis of methyl 3-((methylsulfonyl) methyl) cyclobutane-1-carboxylate
[3.1.33f]. 3.1.33e (2.23 g, 12.82 mmol, 1.0 equiv) was dissolved in dichloromethane (30 ml_). m-CPBA (70%) (6.3 g, 25.63 mmol, 2.0 equiv) was added in portions and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (50-55 % EtOAc/Hexane) to afford the desired product 3.1.33f (1.2 g, 47 % yield). 1H NMR (400 MHz, DMSO) δ 3.64 - 3.58 (m, 3H), 3.32 (s, 1 H), 3.23 (d, J = 7.3 Hz, 1 H), 3.19 - 3.06 (m, 1 H), 2.90 (t, J = 3.3 Hz, 3H), 2.85 - 2.65 (m, 1 H), 2.40 - 2.30 (m, 2H), 2.15 (ddd, J = 12.5, 9.5, 6.9 Hz, 1 H), 2.02 (ddd, J = 19.2, 9.6, 2.6 Hz, 1 H).
Step 7. Synthesis of (3-((methylsulfonyl) methyl) cyclobutyl) methanol [3.1.33g] 3.1.33f (0.45 g, 2.18 mmol, 1.0 equiv) was dissolved in THF (15 mL) and methanol (2 ml_). The reaction mixture was cooled to 0 °C. Sodium borohydride (0.17 g, 4.37 mmol, 2.0 equiv) was added in portions and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (5 % MeOH/dichloromethane) to afford the desired product 3.1.33g (0.42 g, 40 % yield). 1H NMR (400 MHz, DMSO) δ 4.12 - 3.93 (m, 1 H),
3.64 - 3.57 (m, 2H), 3.15 (ddd, J = 26.8, 15.7, 6.6 Hz, 4H), 2.95 - 2.86 (m, 3H), 2.34 (dd, J = 15.6, 6.7 Hz, 2H), 2.19 - 2.10 (m, 1 H), 2.06 - 1.98 (m, 1 H).
Step 8. Synthesis of 3-((methylsulfonyl) methyl) cyclobutane-1-carbaldehyde [3.1.33h] 3.1.33g (0.42 g, 2.36 mmol, 1.0 equiv) was dissolved in dichloromethane (10 mL). PCC (0.92 g, 4.25 mmol, 1.8 equiv) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through celite bed, washed with dichloromethane and the filtrate was concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (70 % EtOAc/Hexane) to afford the desired product 3.1.33h (0.31 g, 75 % yield). 1H NMR (400 MHz, DMSO) δ 9.62 (dt, J = 149.4, 50.5 Hz, 1 H), 3.64 - 3.58 (m, 1 H), 3.25 - 3.05 (m, 2H), 2.94 - 2.87 (m, 3H), 2.85 -
2.65 (m, 1 H), 2.43 - 2.26 (m, 2H), 2.20 - 1.99 (m, 2H).
Step 9. Synthesis of 1-ethynyl-3-((methylsulfonyl) methyl) cyclobutane [3.1.33Ϊ] 3.1.33h (0.3 g, 1.7 mmol, 1.0 equiv) was dissolved in methanol (10 mL). K2C03 (0.47 g, 3.4 mmol, 2.0 equiv), Ohira bestmann reagent (0.43 g, 2.21 mmol, 1.3 equiv) was added and the reaction mixture was stirred at room temperature for 3 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 afford a crude residue. The crude residue was purified by silica gel column chromatography (50 % EtOAc/Hexane) to afford the desired product 3.1.33Ϊ (0.13 g, 44 % yield). 1H NMR (400 MHz, DMSO) δ 3.62 - 3.58 (m, 2H), 3.34 - 3.17 (m, 3H), 2.94 - 2.88 (m, 3H), 2.49 - 2.41 (m, 1 H), 2.23 - 2.13 (m, 2H). Step 10. Synthesis of (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-3-(4-((3- ((methylsulfonyl) methyl) cyclobutyl) ethynyl) phenyl)-2-oxooxazolidin-5-yl) propanamide [3.1.33]. 3.1.33 was synthesized from 3.1.33Ϊ using the precess described for the synthesis of 3.1.20. LCMS (m/z): 513.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.32 (s, 1 H), 7.52 (dd, J = 8.8, 2.8 Hz, 2H), 7.42 (t, J = 10.0 Hz, 2H), 4.64 (d, J = 6.2 Hz, 1 H), 4.19 (d, J = 9.1 Hz, 1 H), 3.78 (t, J = 8.4 Hz, 1 H), 3.37 (s, 1 H), 3.30 (d, J = 7.2 Hz, 1 H), 3.26 - 3.13 (m, 1 H), 3.08 (s, 3H), 2.93 (d, J = 9.1 Hz, 3H), 2.77 (d, J = 14.4 Hz, 1 H), 2.66 (d, J = 8.0 Hz, 1 H), 2.38 - 2.15 (m, 3H), 2.02 (d, J = 1 1.3 Hz, 1 H), 1 .60 (s, 3H).
III.1.34. Synthesis of compound 3.1.34
Step 1. Synthesis of ethyl (R)-3-((S)-3-(4-(5-hydroxypent-1-yn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1.34a]
1.1d (0.5 g, 1.15 mmol, 1.0 equiv), pent-4-yn-1-ol (0.13 g, 1.49 mmol, 1.3 equiv), Cul (0.022 g, 0.12 mmol, 0.1 equiv), triphenylphosphine (0.061 g, 0.23 mmol, 0.2 equiv) were dissolved in diethyl amine (5 ml_) and N, N-dimethylformamide (1 ml_) in sealed tube. The reaction mixture was degassed for 10 minutes. PdCI2(pph3)2 (0.041 g, 0.057 mmol, 0.05 equiv) was added and the reaction mixture was stirred at 100 °C for 24 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 afford a crude residue. The crude residue was purified by silica gel chromatography (70 % EtOAc/Hexane) to afford the desired product 3.1.34a (0.46 g, 92 % yield). LCMS (m/z): 438.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.52 (d, J = 8.9 Hz, 2H), 7.41 (d, J = 8.9 Hz, 2H), 4.79 (dd, J = 14.2, 8.1 Hz, 1 H), 4.54 (dd, J = 6.4, 3.9 Hz, 1 H), 4.31 - 4.15 (m, 3H), 3.86 - 3.77 (m, 1 H), 3.51 (dd, J = 1 1.5, 6.2 Hz, 2H), 3.16 (s, 3H), 2.68 (dd, J = 14.9, 2.4 Hz, 1 H), 2.45 (t, J = 7.1 Hz, 2H), 2.36 (dd, J = 1 1.6, 5.7 Hz, 1 H), 1.69 (dd, J = 13.5, 6.7 Hz, 2H), 1.64 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). Step 2. Synthesis of ethyl (R)-2-methyl-2-(methylsulfonyl)-3-((S)-3-(4-(5- ((methylsulfonyl) oxy) pent-1-yn-1-yl) phenyl)-2-oxooxazolidin-5-yl) propanoate
[3.1.34b]. 3.1.34a (0.2 g, 0.46 mmol, 1.0 equiv) was dissolved in dichloromethane (10 ml.) and cooled to 0 °C. TEA (0.32 g, 2.29 mmol, 5.0 equiv), MeS02CI (0.1 1 g, 1.37 mmol, 3.0 equiv) were added and the reaction mixture was stirred at room temperature for 3 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 afford the desired product 3.1.34b (0.21 g, 88 % yield). LCMS (m/z): 516.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.53 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H), 4.79 (d, J = 6.8 Hz, 1 H), 4.30 - 4.21 (m, 3H), 3.86 - 3.78 (m, 1 H), 3.21 (s, 3H), 3.08 (dd, J = 7.3, 4.8 Hz, 2H), 2.69 (d, J = 15.0 Hz, 1 H), 2.55 (d, J = 7.0 Hz, 2H), 2.46 - 2.29 (m, 4H), 1.95 (dt, J = 13.6, 6.8 Hz, 2H), 1.64 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 3. Synthesis of ethyl (R)-3-((S)-3-(4-(5-(2H-1, 2, 3-triazol-2-yl) pent-1-yn-1-yl) phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1.34c]
3.1.34b (0.21 g, 0.41 mmol, 1.0 equiv) was dissolved in N, N-dimethylformamide (8 mL) in sealed tube. 2A7-1 , 2, 3-triazole (0.056 g, 0.82 mmol, 2.0 equiv), Cs2CO3 (0.27 g, 0.82 mmol, 2.0 equiv) were added and the reaction mixture was stirred at 100 °C for 24 hours. The reaction mixture was quenched with water extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (40 % EtOAc/Hexane) to afford the desired product 3.1.34c (0.085 g, 42 % yield). LCMS (m/z): 489.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.95 (d, J = 5.9 Hz, 2H), 7.53 (d, J = 8.9 Hz, 2H), 7.43 (d, J = 8.9 Hz, 2H), 4.79 (d, J = 7.1 Hz, 1 H), 4.56 (t, J = 6.8 Hz, 2H), 4.24 (dt, J = 17.4, 7.6 Hz, 3H), 3.86 - 3.77 (m, 1 H), 3.16 (s, 3H), 2.69 (d, J = 15.0 Hz, 1 H), 2.43 (t, J = 7.0 Hz, 2H), 2.40 - 2.35 (m, 1 H), 2.13 (dt, J = 15.3, 7.5 Hz, 2H), 1.64 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 4. Synthesis of (R)-3-((S)-3-(4-(5-(2H-1, 2, 3-triazol-2-yl) pent-1 -yn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl) propanamide [3.1.34]
3.1.34 was prepared by the process of example 3.1.20.. LCMS (m/z): 476.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 9.31 (s, 1 H), 7.80 (s, 2H), 7.52 (d, J = 8.9 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 4.64 (d, J = 6.0 Hz, 1 H), 4.56 (t, J = 6.8 Hz, 2H), 4.18 (t, J = 8.8 Hz, 1 H), 3.83 - 3.75 (m, 1 H), 3.08 (s, 3H), 2.77 (d, J = 12.3 Hz, 1 H), 2.43 (t, J = 7.0 Hz, 2H), 2.24 - 2.18 (m, 1 H), 2.17 - 2.10 (m, 2H), 1.60 (s, 3H).
III.1.35. Synthesis of compound 3.1.35
Step 1. Synthesis of allyl 4-nitrobenzoate [3.1.35a]. 4-Nitrobenzoyl chloride (15.9 g, 86.0 mmol, 1.0 equiv), prop-2-en-1-ol (5 g, 86.0 mmol, 1.0 equiv) were dissolved in dichloromethane (100 mL) and cooled to 0 °C. TEA (9.58 g, 94.0 mmol, 1.1 equiv) was added and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford the desired product 3.1.35a (9.7 g, 54.5 % yield). 1H NMR (400 MHz, DMSO) δ 8.41 - 8.31 (m, 2H), 8.28 - 8.17 (m, 2H), 6.07 (ddt, J = 17.2, 10.7, 5.5 Hz, 1 H), 5.44 (dq, J = 17.2, 1.6 Hz, 1 H), 5.32 (ddd, J = 10.5, 2.7, 1.3 Hz, 1 H), 4.87 (dt, J = 5.4, 1.4 Hz, 2H).
Step 2. Synthesis of (2, 2-difluorocyclopropyl) methyl 4-nitrobenzoate [3.1.35b]. 3.1.35a (8.7 g, 42.0 mmol, 1.0 equiv) was mixed with CsF (0.05 g) and heated to 90 °C. TFDA (23.1 g, 92.0 mmol, 2.2 equiv) was added within 10 hours. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude product. The crude residue was purified by silica gel column chromatography (4-5 % EtOAc/Hexane) to afford the desired product 3.1.35b (2.9 g, 24.2 % yield). 1H NMR (400 MHz, DMSO) δ 8.44 - 8.33 (m, 2H), 8.28 - 8.19 (m, 2H), 4.60 - 4.46 (m, 1 H), 4.37 - 4.25 (m, 1 H), 2.36 - 2.19 (m, 1 H), 1.84 - 1.68 (m, 1 H), 1.60 (dtd, J = 12.2, 7.7, 4.4 Hz, 1 H).
Step 3. Synthesis of (2, 2-difluorocyclopropyl) methanol [3.1.35c]. 3.1.35b (2.4 g, 9.3 mmol, 1.0 equiv) was added to 10 % NaOH solution (1.1 g, 28.0 mmol, 3.0 equiv) and the reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was quenched with water and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford the desired product 3.1.35c (0.77 g, 77 % yield). 1H NMR (400 MHz, DMSO) δ 4.89 (t, J = 5.6 Hz, 1 H), 3.52 (dtd, J = 6.5, 5.2, 2.6 Hz, 1 H), 3.41 - 3.33 (m, 2H), 1.86 (dddd, J = 14.1 , 1 1.6, 9.7, 7.1 Hz, 1 H), 1.57 - 1.45 (m, 1 H), 1.19 (dtd, J = 13.7, 7.6, 4.0 Hz, 1 H).
Step 4. Synthesis of 2, 2-difluorocyclopropane-1-carbaldehyde [3.1.35d]. 3.1.35c (0.4 g, 3.7 mmol, 1.0 equiv) was dissolved in dichloromethane (5 mL) and cooled to 0 °C. PCC (1.2 g, 5.6 mmol, 1.5 equiv) was added and the reaction mixture was stirred at rt for 5 hours. The reaction mixture was diluted with diethyl ether, the solvent was decanted and concentrated without applying vacuum at 45 °C to afford the desired product 3.1.35d (1 mL solution in dichloromethane). The product was used as such in dichloromethane solution. Step 5. Synthesis of 2-ethynyl-1, 1-difluorocyclopropane [3.1.35e]. 3.1.35d (0.2 g, 1.9 mmol, 1.0 equiv) and ohira bestmann reagent (0.55 g, 2.8 mmol, 1.5 equiv) were added in ethanol (5 mL). K2C03 (0.52 g, 3.8 mmol, 2.0 equiv) was added and the reaction mixture was stirred at rt for 24 hours. The product was isolated by fractional distillation at 55 °C without applying vacuum to afford product 3.1.35e (2 mL solution in EtOH and diethyl ether). The product was used as such with solution in ethanol & diethyl ether.
Step 6. Synthesis of (2R)-3-((5S)-3-(4-((2, 2-difluorocyclopropyl) ethynyl) phenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl) propanamide [3.1.35] 3.1.35e was synthesized by the process of example 3.1.20. LCMS (m/z): 443.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.07 (s, 1 H), 9.30 (s, 1 H), 7.55 (d, J = 8.9 Hz, 2H), 7.46 (d, J = 8.9 Hz, 2H), 4.64 (d, J = 7.5 Hz, 1 H), 4.19 (t, J = 8.8 Hz, 1 H), 3.82 - 3.75 (m, 1 H), 3.08 (s, 3H), 2.86 - 2.74 (m, 2H), 2.25 - 2.19 (m, 1 H), 2.10 - 2.01 (m, 1 H), 1.80 (dd, J = 12.9, 5.2 Hz, 1 H), 1.60 (s, 3H).
III.1.36. Synthesis of compound 3.1.36
Step 1. Synthesis of methyl (1 r, 3r)-3-ethynylcyclobutane-1-carboxylate [3.1.36a].
Methyl (1 r, 3r)-3-formylcyclobutane-1-carboxylate (0.23 g, 1.62 mmol, 1.0 equiv) was dissolved in methanol (10 ml_). K2C03 (0.45 g, 3.23 mmol, 2.0 equiv) was added and the reaction mixture was stirred at room temperature for 5 minutes. Ohira Bestmann reagent (0.38 g, 1.94 mmol, 1.2 equiv) was added and the reaction mixture was stirred at rt for 1 hour. 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 afford a crude residue. The crude residue was purified by silica gel column chromatography (5 % diethyl ether/n-pentane) to afford the desired product 3.1.36a (0.2 g, 89.5 % yield). 1H NMR (400 MHz, CDCI3) δ 3.75 - 3.65 (m, 3H), 3.27 (dd, J = 13.3, 7.2 Hz, 1 H), 3.19 (d, J = 8.7 Hz, 1 H), 2.66 - 2.50 (m, 2H), 2.46 - 2.32 (m, 2H), 2.22 (dd, J = 16.0, 2.5 Hz, 1 H).
Step 2. Synthesis of methyl (1 r, 3r)-3-((4-bromophenyl) ethynyl) cyclobutane-1- carboxylate [3.1.36b]. 3.1.36a (0.19 g, 1.41 mmol, 1.0 equiv), 1-bromo-4-iodobenzene (0.4 g, 1.41 mmol, 1.0 equiv) were mixed in diethyl amine (9 ml_) and N, N- dimethylformamide (1 ml_). Cul (0.026 g, 0.14 mmol, 0.1 equiv), triphenylphosphine (0.074 g, 0.28 mmol, 0.2 equiv) were added and the reaction mixture was degassed for 10 minutes. PdCI2(pph3)2 (0.049 g, 0.07 mmol, 0.05 equiv) was added and the reaction mixture was stirred at 120 °C for 3 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 afford a crude residue. The residue was purified by silica gel column chromatography (0-10 % EtOAc/Hexane) to afford the desired product 3.1.36b (0.18 g, 43.4 % yield). 1H NMR (400 MHz, CDCI3) δ 7.49 - 7.40 (m, 2H), 7.30 - 7.25 (m, 2H), 3.74 (s, 3H), 3.46 - 3.35 (m, 1 H), 3.35 - 3.25 (m, 1 H), 2.72 - 2.62 (m, 2H), 2.52 - 2.41 (m, 2H). Step 3. Synthesis of 2-((1r, 3r)-3-((4-bromophenyl) ethynyl)cyclobutyl)propan-2-ol
[3.1.36c]. 3.1.36b (0.18 g, 0.61 mmol, 1.0 equiv) was dissolved THF (5 mL) and cooled to - 20 °C. MeMgBr (3M in ether) (0.82 g, 2.45 mmol, 4.0 equiv) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (0-10 % EtOAc/Hexane) to afford the desired product 3.1.36c (0.17 g, 94.4 % yield). 1H NMR (400 MHz, CDCI3) δ 7.48 - 7.40 (m, 2H), 7.29 (dd, J = 6.6, 1.9 Hz, 2H), 3.16 - 3.06 (m, 1 H), 2.70 - 2.59 (m, 1 H), 2.44 - 2.30 (m, 2H), 2.21 - 2.10 (m, 2H), 1.16 (d, J = 8.1 Hz, 6H).
Step 4. Synthesis of (R)-N-hydroxy-3-((S)-3-(4-(((1 r, 3S)-3-(2-hydroxypropan-2- yl)cyclobutyl) ethynyl)phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanamide [3.1.36]. 3.1.36 was synthesized by the process of example 2.4. LCMS (m/z): 479.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.32 (s, 1 H), 7.52 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 4.65 (s, 1 H), 4.20 (d, J = 8.3 Hz, 2H), 3.80 (d, J = 8.4 Hz, 1 H), 3.06 (d, J = 14.5 Hz, 4H), 2.77 (d, J = 15.1 Hz, 1 H), 2.45 (d, J = 7.9 Hz, 2H), 2.39 - 2.30 (m, 2H), 2.26 - 2.16 (m, 1 H), 1.97 (s, 2H), 1.60 (s, 3H), 1.00 (s, 6H).
III.1.37. Synthesis of compound [3.1.37]
Step 1. Synthesis of ethyl (R)-3-((S)-3-(4-ethynylphenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl) propanoate [3.1.37a]. 1.1 d (0.5 g, 1.15 mmol, 1.0 equiv) was dissolved in DMSO (10 ml_). 1 ,4-Bis(diphenylphosphino) butane (0.01 1 g, 0.026 mmol, 0.023 equiv), DBU(0.35 g, 2.3 mmol, 2.0 equiv) were added and the reaction mixture was degassed for 10 minutes. Propiolic acid (0.12 g, 1.73 mmol, 1.5 equiv), PdCI2(PPh3)2 (0.0088 g, 0.012 mmol, 0.01 equiv) were added and the reaction mixture was stirred at 1 10 °C for 4 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (40-50 % EtOAc in Hexane) to afford the desired product 3.1.37a (4.3 g, 96 % yield). LCMS (m/z): 380.1 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.66 - 7.45 (m, 4H), 4.80 (d, J = 8.3 Hz, 1 H), 4.24 (dt, J = 13.2, 7.9 Hz, 3H), 4.15 (s, 1 H), 3.83 (t, J = 8.2 Hz, 1 H), 3.17 (s, 3H), 2.69 (d, J = 14.2 Hz, 1 H), 2.37 (dd, J = 14.7, 8.9 Hz, 1 H), 1.65 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 2. Synthesis of ethyl (R)-3-((S)-3-(4-(5-hydroxypenta-1, 3-diyn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1.37b]. Cul (0.0075 g, 0.039 mmol, 0.05 equiv) and NiCI2.6H20 (0.01 1 g, 0.039 mmol, 0.05 equiv) were added in THF (5 ml_). TMEDA (0.018 g, 0.16 mmol, 0.2 equiv) was added and the reaction mixture was stirred at room temperature for 2 minutes. 3.1.37a (0.3 g, 0.79 mmol, 1.0 equiv), prop- 2-yn-1-ol (0.044 g, 0.79 mmol, 1.0 equiv) were added and the reaction mixture was stirred at room temperature for 24 hours under air. The reaction mixture was concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (50 % EtOAc/Hexane) to afford the desired product 3.1.37b (0.13 g, 37 % yield). LCMS (m/z): 434.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.71 - 7.51 (m, 4H), 5.47 (s, 1 H), 4.81 (d, J = 6.8 Hz, 1 H), 4.33 - 4.13 (m, 5H), 3.89 - 3.79 (m, 1 H), 3.16 (s, 3H), 2.69 (d, J = 12.9 Hz, 1 H), 2.37 (dd, J = 14.9, 8.9 Hz, 1 H), 1.64 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 3. Synthesis of (R)-N-hydroxy-3-((S)-3-(4-(5-hydroxypenta-1, 3-diyn-1-yl) phenyl)- 2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanamide [3.1.37]. 3.1.37 was synthesized from 3.1.37b by the process of example 3.1.20. LCMS (m/z): 438.1 [M+18]. 1H NMR (400 MHz, DMSO) δ 11.07 (s, 1 H), 9.31 (s, 1 H), 7.68 - 7.53 (m, 4H), 5.48 (t, J = 6.1 Hz, 1 H), 4.66 (d, J = 7.6 Hz, 1 H), 4.26(d, J = 6.1 Hz, 2H), 4.20(t, J = 8.8 Hz, 1 H), 3.84 - 3.76 (m, 1 H), 3.08 (s, 3H), 2.78 (d, J = 14.6 Hz, 1 H), 2.22 (dd, J = 14.5, 8.9 Hz, 1 H), 1.60 (s, 3H).
III.1.38. Synthesis of compound 3.1.38 3.1.38 was prepared from 3.1.37 by the process of example 3.1.27. LCMS (m/z): 433.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.32 (s, 1 H), 7.61 (q, J = 8.9 Hz, 4H), 4.66 (s, 1 H), 4.31 (s, 2H), 4.21 (s, 1 H), 3.81 (dd, J = 16.2, 8.0 Hz, 1 H), 3.31 (s, 3H), 3.08 (s, 3H), 2.77 (d, J = 13.4 Hz, 1 H), 2.22 (dd, J = 14.4, 9.2 Hz, 1 H), 1.60 (s, 3H).
111.1.39. Synthesis of compound 3.1.39
Step 1. Synthesis of hex-5-ynal [3.1.39a]. Hex-5-yn-1-ol (0.3 g, 3.06 mmol, 1.0 equiv) was dissolved in dichloromethane (10 ml_). PCC (1.32 g, 6.12 mmol, 2.0 equiv) was added in portion wise and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with diethyl ether and filtered through celite bed. The filtrate was concentrated to afford the desired product 3.1.39 (0.19 g, 64.6 % yield). 1H NMR (400 MHz, DMSO) δ 9.68 (t, J = 1.3 Hz, 1 H), 2.82 (q, J = 2.3 Hz, 1 H), 2.56 - 2.51 (m, 2H), 2.19 (td, J = 7.1 , 2.6 Hz, 2H), 1.71 (dd, J = 14.3, 7.1 Hz, 2H).
Step 2. Synthesis of hept-6-yn-2-ol [3.1.39b]. 3.1.39a (0.19 g, 1.97 mmol, 1.0 equiv) was dissolved in THF (5 ml_) and cooled to -78 °C. Methyl magnesium bromide (3.0 M in THF) (0.47 g, 3.95 mmol, 2.0 equiv) was added and the reaction mixture was stirred at -20 °C for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 3.1.39b (0.13 g, 58.6 % yield). 1H NMR (400 MHz, DMSO) δ 4.39 (d, J = 4.8 Hz, 1 H), 3.58 (dd, J = 1 1.0, 5.8 Hz, 1 H), 2.75 (t, J = 2.6 Hz, 1 H), 2.17 - 2.13 (m, 2H), 1.44 (ddd, J = 20.7, 13.2, 6.6 Hz, 4H), 1.04 (d, J = 6.1 Hz, 3H). Step 3. Synthesis of (2R)-N-hydroxy-3-((5S)-3-(4-(6-hydroxyhept-1-yn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanamide [3.1.39]. 3.1.39 was synthesized from 3.1.39b by the process of example 3.1.20.. LCMS (m/z): 451.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.30 (s, 1 H), 7.51 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 4.63 (s, 1 H), 4.41 (d, J = 4.7 Hz, 1 H), 4.18 (s, 1 H), 3.82 - 3.76 (m, 1 H), 3.66 - 3.58 (m, 1 H), 3.08 (s, 3H), 2.77 (d, J = 14.7 Hz, 1 H), 2.41 (t, J = 6.9 Hz, 2H), 2.23 (d, J = 9.2 Hz, 1 H), 1.59 (s, 3H), 1.54 (d, J = 8.1 Hz, 2H), 1.49 - 1.42 (m, 2H), 1.06 (d, J = 6.1 Hz, 3H).
111.1.40. Synthesis of compound 3.1.40
Step 1. Synthesis of hept-6-yn-2-one [3.1.40a]. 3.1.39b (0.27 g, 2.41 mmol, 1.0 equiv) was dissolved in dichloromethane (15 ml_). PDC (1.81 g, 4.82 mmol, 2.0 equiv) was added in portion wise and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with diethyl ether and filtered through celite bed. The filtrate was concentrated to afford product 3.1.40a (0.22 g, 83 % yield). The crude product was used as such in next step without further purification. Step 2. Synthesis of 2-methylhept-6-yn-2-ol [3.1.40b]. 3.1.40a (0.22 g, 2.0 mmol, 1.0 equiv) was dissolved in THF (5 mL) and cooled to -78 °C. Methyl magnesium bromide (3.0 M in THF) (0.47 g, 4.0 mmol, 2.0 equiv) was added and the mixture was stirred at -20 °C for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford 3.1.40b (0.2g, 80% yield). 1H NMR (400 MHz, DMSO) 5 4.15 (s, 1 H), 2.75 (t, J = 2.6 Hz, 1 H), 2.16 - 2.10(m, 2H), 1.45(m, 4H), 1.07(s, 6H). Step 3. Synthesis of (R)-N-hydroxy-3-((S)-3-(4-(6-hydroxy-6-methylhept-1-yn-1-yl) phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide [3.1.40]
Compound 3.1.40 was synthesized from 3.1.40b by the process of example 3.1.20. LCMS (m/z): 466.1 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.06 (s, 1 H), 9.28 (s, 1 H), 7.51 (d, J = 8.9 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 4.69 - 4.60 (m, 1 H), 4.22 - 4.13 (m, 2H), 3.82 - 3.76 (m, 1 H), 3.08 (s, 3H), 2.78 (d, J = 14.4 Hz, 1 H), 2.40 (t, J = 6.9 Hz, 2H), 2.21 (dd, J = 14.5, 8.9 Hz, 1 H), 1.60 (s, 3H), 1.59 - 1.53 (m, 2H), 1.51 - 1.45 (m, 2H), 1.10 (s, 6H).
III.1.41. Synthesis of compound 3.1.41
Step 1. Synthesis of ethyl (2R)-3-((5S)-3-(4-(5-hydroxyhexa-1, 3-diyn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1.41a]. (R)-ethyl 3-((S)- 3-(4-ethynylphenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanoate (0.25 g, 0.65 mmol, 1.0 equiv), CuCI (0.004 g, 0.033 mmol, 0.05 equiv) and NH2OH.HCI (0.003 g, 0.033 mmol, 0.05 equiv) were dissolved in n-butyl amine (8 mL). 4-Bromobut-3-yn-2-ol (0.15 g, 0.98 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 5 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 afford a crude residue, which was purified by silica gel chromatography (15- 20 % EtOAc/Hexane) to afford product 3.1.41a (0.14 g, 48 % yield). LCMS (m/z): 448.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.64 - 7.54 (m, 4H), 5.63 (d, J = 5.5 Hz, 1 H), 4.81 (dd, J = 14.3, 7.9 Hz, 1 H), 4.58 - 4.49 (m, 1 H), 4.31 - 4.15 (m, 3H), 3.83 (dd, J = 15.2, 6.3 Hz, 1 H), 3.15 (d, J = 13.5 Hz, 3H), 2.69 (dd, J = 14.8, 2.3 Hz, 1 H), 2.37 (dd, J = 14.9, 9.0 Hz, 1 H), 1.64 (d, J = 5.3 Hz, 3H), 1.35 (d, J = 6.6 Hz, 3H), 1.26 (dd, J = 8.5, 5.7 Hz, 4H).
Step 2. Synthesis of (2R)-N-hydroxy-3-((5S)-3-(4-(5-hydroxyhexa-1, 3-diyn-1-yl) phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanamide [3.1.41]
3.1.41 was synthesized from 3.1.41a using the proecess of example 3.1.20. LCMS (m/z): 435.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 9.31 (s, 1 H), 7.59 (s, 4H), 5.63 (d, J = 5.7 Hz, 1 H), 4.65 (s, 1 H), 4.59 - 4.48 (m, 1 H), 4.20 (s, 1 H), 3.80 (s, 1 H), 3.08 (s, 3H), 2.78 (d, J = 13.8 Hz, 1 H), 2.24 (d, J = 8.8 Hz, 1 H), 1.60 (s, 3H), 1.35 (d, J = 6.6 Hz, 3H). 111.1.42. Synthesis of compound 3.1.42 & 3.1.43. 3.1.36 (0.04 g, 0.084 mmol, 1.0 equiv) was dissolved in acetonitrile (2 mL) and cooled to 0 °C. Cone. H2S04 (0.057 g, 0.59 mmol, 7.0 equiv) was added and the reaction mixture was stirred at rt for 3 hours. The reaction mixture was quenched with water, neutralized with solid sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to a crude product, which was purified by preparative HPLC to afford the product: Isomer-A 3.1.42 (0.006 g, 14 % yield). LCMS (m/z): 520.5 [M+H]. 1H NMR (400 MHz, DMSO) 58.42 (s, 1H), 7.61 (d, J = 9.1 Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 4.66 (s, 1H), 4.16 (s, 1H), 4.04 (d, J= 8.3 Hz, 1H), 3.79 (s, 1H), 3.13 (s, 1H), 3.08 (s, 3H), 2.74 (d, J= 15.0 Hz, 1H), 2.18 (s, 1H), 1.95 (dd, J = 25.3, 13.3 Hz, 3H), 1.84 (s, 3H), 1.58 (d, J = 11.6 Hz, 4H), 1.00 (s, 3H), 0.82 (s, 3H). Isomer-B 3.1.43 (0.003 g, 7 % yield). LCMS (m/z): 520.4 [M+H]. 1H NMR (400 MHz, MeOD) δ 8.55 (s, 1H), 7.53 (s, 2H), 7.41 (s, 2H), 4.79-4.75(m, 2H), 4.23(s, 1H), 3.87 (s, 1H), 3.12 (s, 4H), 2.88 (s, 1H), 2.33 (d, J= 9.5 Hz, 3H), 2.10 (s, 2H), 1.91 (s, 3H), 1.76 (s, 3H), 1.31 (s, 6H).
III.1.45. Synthesis of compound 3.1.45 & 3.1.46
Compounds 3.1.45 & 3.1.46 were synthesized from 3.1.19f by the process of example 3.1.1. The diastereomers were separated by reverse phase HPLC.3.1.45: LCMS (m/z): 453.9 [M+18].1H NMR (400 MHz, DMSO) δ 7.50 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 4.61 (s, 1H), 4.16 (t, J = 8.8 Hz, 1H), 3.99-3.90 (m, 1H), 3.78 (d, J= 8.1 Hz, 1H), 3.12 - 2.96 (m, 3H), 2.75 (d, J = 13.6 Hz, 1H), 2.69 - 2.61 (m, 1H), 2.56 (s, 2H), 2.25 - 2.14 (m, 1H), 1.92 (d, J = 9.1 Hz, 2H), 1.58 (s, 3H). 3.1.46 (0.015 g, 9.4 % yield). LCMS (m/z): 453.9 [M+18]. 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.32 (s, 1H), 7.52 (d, J= 8.8 Hz, 2H), 7.48-7.34 (m, 2H), 5.21 (d, J = 6.1 Hz, 1H), 4.64 (d, J= 9.7 Hz, 1H), 4.39(dd, J= 13.8, 6.8 Hz, 1H), 4.18 (t, J= 8.9 Hz, 1H), 3.85 -3.72 (m, 1H), 3.19-3.11 (m, 1H), 3.11 -2.99 (m, 3H), 2.81 -2.74 (m, 1H), 2.34-2.25 (m, 2H), 2.26-2.12 (m, 3H), 1.66- 1.52 (m, 3H).
III.1.47. Synthesis of compound 3.1.47 & 3.1.48
Compounds 3.1.47 & 3.1.48 were synthesized by the process of example 3.1.19. Compound 3.1.47: LCMS (m/z): 467.7 [M+18]. 1H NMR (400 MHz, DMSO) δ 11.29 - 10.91 (m, 1H), 9.35 (s, 1H), 7.52 (d, J= 8.3 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 4.65 (s, 1H), 4.18 (s, 1H), 3.84 - 3.70 (m, 2H), 3.07 (t, J = 26.2 Hz, 6H), 2.79 (dd, J = 22.9, 12.0 Hz, 2H), 2.63 (d, J= 7.2 Hz, 2H), 2.27-2.15 (m, 1H), 1.94 (d, J = 8.4 Hz, 2H), 1.58 (s, 3H). Compound 3.1.48: LCMS (m/z): 467.7 [M+18]. 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.33 (s, 1H), 7.52 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 4.64 (d, J= 7.0 Hz, 1H), 4.18 (t, J = 8.6 Hz, 1H), 4.15 - 4.09 (m, 1H), 3.83 - 3.75 (m, 1H), 3.23 (s, 1H), 3.12 (d, J = 27 A Hz, 6H), 2.77 (d, J = 14.5 Hz, 1H), 2.35-2.18 (m, 5H), 1.60 (s, 3H). 111.1.49. Synthesis of compound 3.1.49
Compound 3.1.49 was synthesized by the process of example 3.1.14. LCMS (m/z): 447.1. 1H NMR (MeOD-d4): 7.82 (s, 1H), 7.61 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.8 Hz, 2H), 4.23 (t, J=8.7 Hz, 1H), 3.82-3.92 (m, 5H), 3.09 (s, 3H), 2.87 (d, J=14.2 Hz, 1H), 2.33 (dd, J=14.5, 9.1 Hz, 1H), 1.74 (s, 3H)
111.1.50. Synthesis of compound 3.1.50
Compound 3.1.50 was synthesized by the process of example 3.1.14. LCMS (m/z): 409.2 [M+H].1H NMR (MeOD-d4) 7.48-7.54 (m, 2H), 7.34-7.41 (m, 2H), 4.69-4.79 (m, 1H), 4.17-4.25 (m, 1H), 3.82-3.87 (m, 1H), 3.06-3.11 (m, 3H), 2.82-2.89 (m, 1H), 2.36-2.41 (m, 2H), 2.28-2.35 (m, 1H), 1.69-1.77 (m, 3H), 1.57-1.66 (m, 2H), 1.01-1.11 (m, 3H)
111.1.51. Synthesis of compound 3.1.51
Compound 3.1.51 was synthesized by the process of example 3.1.14. LCMS (m/z):
451.1 [M+H].1H NMR (MeOD-d4) 7.53 (d, J=9.1 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H), 4.70-4.78 (m, 1H), 4.22 (t, J=8.8 Hz, 1H), 3.75-3.95 (m, 4H), 3.60 (dd, J=8.5, 5.7 Hz, 1H), 3.09 (s, 3H), 2.87 (dd, J=14.7, 2.4 Hz, 1H), 2.52 (s, 3H), 2.33 (dd, J=14.5, 8.8 Hz, 1H), 2.14 (dd, J=13.1, 5.5 Hz, 2H), 1.76-1.84 (m, 1H), 1.74 (s, 3H)
111.1.52. Synthesis of compound 3.1.52
Compound 3.1.52 was synthesized by the process of example 3.1.14. LCMS (m/z):
429.2 [M+H].1H NMR (DMSO-d6): 8.55 (d, J=6.0 Hz, 2H), 7.64-7.69 (m, 2H), 7.58-7.63 (m, 2H), 7.54 (d, J=6.0 Hz, 2H), 4.72-4.80 (m, 1H), 4.26 (t, J=8.8 Hz, 1H), 3.85-3.92 (m, 1H), 3.10 (s, 3H), 2.89 (dd, J=14.5, 2.2 Hz, 1H), 2.34 (dd, J=14.5, 8.8 Hz, 1H), 1.75 (s, 3H)
111.1.53. Synthesis of compound 3.1.53. Compound 3.1.53 was synthesized by the process of example 3.1.14. LCMS (m/z) 409.3 [M+H]
111.1.54. Synthesis of compound 3.1.54
Compound 3.1.54 was synthesized by the process of example 3.1.14. LCMS (m/z): 512.4 [M+18].1H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 9.31 (s, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 4.64 (d, J = 6.9 Hz, 1H), 4.18 (t, J = 8.8 Hz, 1H), 3.82 - 3.74 (m, 1H), 3.62 (d, J = 4.5 Hz, 2H), 3.28 (d, J = 2.8 Hz, 6H), 3.08 (s, 3H), 2.94 - 2.86 (m, 1H), 2.77 (d, J= 12.3 Hz, 1H), 2.21 (dd, J= 14.3, 9.0 Hz, 3H), 1.82- 1.70 (m, 2H), 1.60 (s, 3H).
III.1.55. Synthesis of compound 3.1.55 Compound 3.1.55 was synthesized by the process of example 3.1.14. LCMS (m/z): 458.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 8.78 (s, 1 H), 8.16 (d, J = 8.5 Hz, 1 H), 7.62 (s, 4H), 7.59 (d, J = 8.2 Hz, 1 H), 4.65 (d, J = 6.8 Hz, 1 H), 4.20 (t, J = 8.7 Hz, 1 H), 3.82 (d, J = 8.5 Hz, 1 H), 3.07 (s, 3H), 2.77 (d, J = 13.4 Hz, 1 H), 2.59 (s, 3H), 2.21 (dd, J = 14.5, 9.3 Hz, 1 H), 1.59 (s, 3H).
111.1.56. Synthesis of compound 3.1.56
Compound 3.1.56 was synthesized by the process of example 3.1.14. LCMS (m/z) 437.1 [M+H]. 1H NMR (400 MHz, DMSO-c/6) δ 1 1.06 (s, 1 H), 9.27 (s, 1 H), 7.51 (d, J = 8.9 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 4.70 - 4.56 (m, 1 H), 4.17 (t, J = 8.8 Hz, 1 H), 4.09 - 3.90 (m, 1 H), 3.90 - 3.66 (m, 3H), 3.57 (dd, J = 8.0, 6.8 Hz, 1 H), 3.31 - 3.15 (m, 1 H), 3.07 (s, 3H), 2.83 - 2.71 (m, 1 H), 2.31 - 2.14 (m, 3H), 2.02 - 1.85 (m, 1 H), 1.59 (s, 3H).
111.1.57. Synthesis of compound 3.1.57 & 3.1.58
Step 1. Synthesis of 3-methylenecyclobutane-1-carboxylic acid [3.1.57a]. 3- methylenecyclobutane-1-carbonitrile (24 g, 258.0 mmol, 1.0 equiv) was dissolved in ethanol (180 ml.) and water (180 ml_). Potassium hydroxide (72.25 g, 1290.3 mmol, 5 equiv) was added and the reaction mixture was stirred at 100 °C for 4 hours. The reaction mixture was concentrated. The residue was quenched with water, acidified by 1.0 N HCI aqueous solution to the pH 2 to 4 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 3.1.57a (27.3 g, 94.5 % yield). LCMS (m/z): 1 1 1 [M+H]. 1H NMR (400 MHz, DMSO) δ 12.25 (s, 1 H), 4.89 - 4.64 (m, 2H), 3.06 (dt, J = 16.3, 8.0 Hz, 1 H), 2.83 (d, J = 8.1 Hz, 4H).
Step 2. Synthesis of methyl 3-methylenecyclobutane-1-carboxylate [3.1.57b]. 3.1.57a
(24.2 g, 216 mmol, 1.0 equiv) was dissolved in acetone (100 mL). K2C03 (59.6 g, 432.1 mmol, 2.0 equiv), Me2S04 (32.7 g, 259.2 mmol, 1.2 equiv) was added and the reaction mixture was stirred at 100 °C for 2 hours. The reaction mixture was filtered and filtrate was concentrated to afford a crude residue which was purified by silica gel chromatography (100 % n-pentane) to afford product 3.1.57b (24 g, 88 % yield). 1H NMR (400 MHz, DMSO) δ 4.82 - 4.77 (m, 2H), 3.62 (s, 3H), 3.22 - 3.12 (m, 1 H), 2.91 - 2.83 (m, 4H).
Step 3. Synthesis of methyl 3-(hydroxymethyl) cyclobutane-1-carboxylate [3.1.57c]
3.1.57b (24 g, 190.4 mmol, 1.0 equiv) was dissolved in THF and cooled to -15 °C. BH3.Me2S (14.4 g, 190.4 mmol, 1.0 equiv) was added drop wise and the reaction mixture was stirred at room temperature for 4 hours. Cooled the reaction mixture at -15 °C, NaOH (3M) (25 mL), H202 (50%) (12.9 g, 190.4 mmol, 1.0 equiv) were added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with sodium bisulphate and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (70 % EtOAc in Hexane) to afford product 3.1.57c (18.7 g, 68 % yield). 1H NMR (400 MHz, DMSO) δ 4.54 (d, J = 29.8 Hz, 1 H), 3.62 - 3.55 (m, 3H), 3.41 (d, J = 6.5 Hz, 1 H), 3.30 (d, J = 6.0 Hz, 1 H), 3.13 - 2.95 (m, 1 H), 2.37 - 2.27 (m, 1 H), 2.15 (ddt, J = 8.7, 7.8, 6.2 Hz, 2H), 1.98 - 1.84 (m, 2H).
Step 4. Synthesis of methyl 3-(((4-methoxybenzyl) oxy) methyl) cyclobutane-1- carboxylate [3.1.57d]. 3.1.57c (5.8 g, 40.3 mmol, 1.0 equiv) was dissolved in DCM. DIPEA (15.62 g, 120.8 mmol, 3.0 equiv), PMB-CI (9.42 g, 60.41 mmol, 1.5 equiv) were added and the reaction mixture was stirred at 100 °C for 6 hours. The reaction mixture was concentrated to afford crude residue. The crude residue was purified by silica gel column chromatography (5-10 % EtOAc in Hexane) to afford product 3.1.57d (4.2 g, 40 % yield). 1H NMR (400 MHz, DMSO) δ 7.30 - 7.20 (m, 3H), 6.95 - 6.86 (m, 2H), 4.38 (m, 2H), 3.74 (s, 3H), 3.59 (dd, J = 13.7, 8.0 Hz, 3H), 3.42 (d, J = 6.7 Hz, 1 H), 3.30 (d, J = 6.2 Hz, 1 H), 3.08 (m, 1 H), 2.45 (m, 1 H), 2.27 - 2.14 (m, 2H), 2.02 - 1.84 (m, 2H).
Step 5. Synthesis of (3-((4-methoxybenzyl) oxy)cyclobutyl)methanol [3.1.57e]
3.1.57d (4.2 g, 15.9 mmol, 1.0 equiv) was dissolved in THF (50 ml_) and methanol (5 ml_). Sodium borohydride (1.2 g, 31.8 mmol, 2.0 equiv) was added in portions and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was quenched with aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford crude residue. The crude residue was purified by silica gel column chromatography (50-60 % EtOAc/Hexane) to afford product 3.1.57e (3.1 g, 82 % yield). LCMS (m/z): 237.5 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.27 - 7.20 (m, 2H), 6.90 (m, 2H), 4.48 - 4.39 (m, 1 H), 4.37 (d, J = 9.6 Hz, 2H), 3.74 (s, 3H), 3.43 - 3.36 (m, 2H), 3.28 (dd, J = 9.1 , 4.8 Hz, 2H), 2.47 - 2.20 (m, 2H), 1.99 - 1.92 (m, 1 H), 1.81 - 1.65 (m, 2H), 1.42 (m, 1 H).
Step 6. Synthesis of 3-(((4-methoxybenzyl) oxy) methyl) cyclobutane-1-carbaldehyde
[3.1.57f]. 3.1.57e (3.1 g, 13.13 mmol, 1.0 equiv) was dissolved in dichloromethane (50 ml_). Dess-Martin periodinane (11.13 g, 26.27 mmol, 2.0 equiv) was added in portions and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was quenched with aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (20-30 % EtOAc/Hexane) to afford product 3.1.57f (1.9 g, 63 % yield). LCMS (m/z): 252.2 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.24 (t, J = 8.4 Hz, 2H), 6.91 (dd, J = 8.7, 2.7 Hz, 2H), 4.38 (d, J = 13.5 Hz, 2H), 3.75 (s, 3H), 3.42 (d, J = 6.5 Hz, 1 H), 3.28 (d, J = 6.3 Hz, 1 H), 3.1 1 (m, 1 H), 2.61 - 2.52 (m, 1 H), 2.46 - 2.36 (m, 1 H), 2.24 (m, 1 H), 2.13 (m, 1 H), 1.91 (m, 2H). Step 7. Synthesis of 1-(((3-ethynylcyclobutyl)methoxy)methyl)-4-methoxybenzene
[3.1.57g]. 3.1.57f (1.9 g, 8.1 1 mmol, 1.0 equiv) was dissolved in MeOH (30 ml_). Ohira- Bestmann reagent (1.9 g, 9.74 mmol, 1.2 equiv) was added. K2C03 (2.24 g, 16.23 mmol, 2.0 equiv) and the reaction mixture was stirred at rt for 5 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel chromatography (5 % EtOAc in Hexane) to afford product 3.1.57g (1.6 g, 85 % yield). 1H NMR (400 MHz, DMSO) δ 7.24 (d, J = 6.9 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 4.38 (d, J = 7.3 Hz, 2H), 3.74 (s, 3H), 3.40 (d, J = 6.8 Hz, 1 H), 3.32 (d, J = 6.1 Hz, 1 H), 2.99 (m, 1 H), 2.83 (m, 1 H), 2.46 - 2.37 (m, 1 H), 2.28 (m, 1 H), 2.05 (m, 2H), 1.81 - 1.74 (m, 1 H). Step 8. Synthesis of ethyl (R)-3-((S)-3-(4-((3-(((4-methoxybenzyl) oxy) methyl) cyclobutyl)ethynyl)phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1.57h]. 1.1d (0.8 g, 1.84 mmol, 1.0 equiv), 3.1.57g (0.51 g, 2.1 1 mmol, 1.2 equiv) were mixed with diethyl amine (10 ml_) and N, N-dimethylformamide (2 ml_). Cul (0.035 g, 0.18 mmol, 0.1 equiv), triphenylphosphine (0.09 g, 0.37 mmol, 0.2 equiv) were added and the reaction mixture was degassed for 15 minutes. PdCI2(pph3)2 (0.065 g, 0.092 mmol, 0.05 equiv) was added and the reaction mixture was stirred at 100 °C for 24 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 afford a crude residue. The crude residue was purified by silica gel column chromatography (40-45 % EtOAc in Hexane) to afford product 3.1.57h (0.74 g, 70 % yield). LCMS (m/z): 584.6 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.52 (dd, J = 9.0, 3.0 Hz, 2H), 7.46 - 7.34 (m, 2H), 7.25 (dd, J = 8.7, 2.8 Hz, 2H), 6.94 - 6.89 (m, 2H), 4.79 (m, 1 H), 4.40 (d, J = 8.8 Hz, 2H), 4.24 (m, 3H), 3.84 - 3.79 (m, 1 H), 3.75 (d, J = 3.0 Hz, 3H), 3.45 (d, J = 6.7 Hz, 1 H), 3.37 (d, J = 6.0 Hz, 1 H), 3.28 - 3.21 (m, 2H), 3.17 (s, 3H), 2.68 (m, 1 H), 2.41 - 2.35 (m, 2H), 2.17 (m, 2H), 1.87 (m, 1 H), 1.64 (s, 3H), 1.26 (m, 3H).
Step 9. Synthesis of ethyl (R)-3-((S)-3-(4-((3-(hydroxymethyl)cyclobutyl)ethynyl) phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1.57i]. 3.1.57h (0.74 g, 1.26 mmol, 1.0 equiv) was dissolved in dichloromethane (50 ml_). TFA (0.72 g, 6.35 mmol, 5.0 equiv) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The residue was triturated with n-pentane, the solvent was decanted to afford product 3.1.57i (0.44 g, 75 % yield). LCMS (m/z): 464.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.52 (dd, J = 8.9, 2.0 Hz, 2H), 7.41 (dd, J = 8.7, 4.9 Hz, 2H), 5.37 (s, 1 H), 4.79 (m, 1 H), 4.30 - 4.19 (m, 3H), 3.84 - 3.79 (m, 1 H), 3.73 (dd, J = 10.9, 6.5 Hz, 1 H), 3.44 (d, J = 6.7 Hz, 1 H), 3.25 (m, 2H), 3.15 (s, 3H), 2.67 (m, 1 H), 2.40 - 2.28 (m, 2H), 2.13 (m, 2H), 1.88 (m, 1 H), 1.64 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 10. Synthesis of ethyl (R)-3-((S)-3-(4-((3-(methoxymethyl) cyclobutyl) ethynyl) phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1.57j]
3.1.57i (0.44 g, 0.95 mmol, 1.0 equiv) was dissolved with acetonitrile (10 ml_) in sealed tube. Ag20 (0.66 g, 2.85 mmol, 3 equiv), iodomethane (0.13 g, 9.5 mmol, 10.0 equiv) were added and the reaction mixture was stirred at 100 °C for 24 hours in seal tube. The reaction mixture was filtered through celite bed and filtrate was concentrated to afford a crude product. The crude product was purified by silica gel column chromatography (30-50 % EtOAc in Hexane) to afford product 3.1.57j (0.18 g, 39 % yield). LCMS (m/z): 478.6 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.52 (dd, J = 8.9, 2.0 Hz, 2H), 7.41 (dd, J = 8.7, 4.9 Hz, 2H), 5.37 (s, 1 H), 4.79 (m, 1 H), 4.30 - 4.19 (m, 3H), 3.84 - 3.79 (m, 1 H), 3.73 (dd, J = 10.9, 6.5 Hz, 1 H), 3.44 (d, J = 6.7 Hz, 1 H), 3.25 (m, 5H), 3.15 (s, 3H), 2.67 (m, 1 H), 2.40 - 2.28 (m, 2H), 2.13 (m, 2H), 1.88 (m, 1 H), 1.64 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 11. Synthesis of (R)-N-hydroxy-3-((S)-3-(4-((3-(methoxymethyl) cyclobutyl)ethynyl) phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanamide [3.1.57 & 3.1.58]. Compound 3.1.57 & 3.1.58 were synthesized from 3.1.57Ϊ by the process of example 3.1.1. The two diastereomers were separated by reverse phase HPLC. Compound 3.1.57: LCMS (m/z): 465.5 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.06 (s, 1 H), 9.22 (s, 1 H), 7.51 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 4.66 (m, 1 H), 4.17 (t, J = 8.4 Hz, 1 H), 3.84 - 3.75 (m, 1 H), 3.30 (d, J = 5.9 Hz, 2H), 3.24 (s, 3H), 3.18 - 3.12 (m, 1 H), 3.08 (s, 3H), 2.75 (d, J = 12.6 Hz, 1 H), 2.44 (m, 1 H), 2.36 (m, 2H), 2.19 (m, 1 H), 1.94 - 1.80 (m, 2H), 1.58 (s, 3H). Compound 3.1.58: LCMS (m/z): 465.5 [M+H]. 1H NMR (400 MHz, DMSO) 5 1 1.12 - 10.81 (m, 1 H), 9.29 (s, 1 H), 7.52 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 4.67 (m, 1 H), 4.15 (m, 1 H), 3.80 (m, 1 H), 3.38 (d, J = 6.9 Hz, 2H), 3.32 - 3.21 (m, 4H), 3.08 (s, 3H), 2.76 (m, 1 H), 2.55 (m, 1 H), 2.25 - 2.06 (m, 5H), 1.5
III.1.59. Synthesis of compound 3.1.59 & 3.1.60
Step 1. Synthesis of methyl (1s, 3s)-3-((methylsulfonyl) oxy) cyclobutane-1- carboxylate [3.1.59]. Methyl 3-hydroxycyclobutane-1-carboxylate (25 g, 192.3 mmol, 1.0 equiv) was mixed with dichloromethane (300 mL) and cooled to 15 °C. TEA (77.7 g, 769 mmol, 4.0 equiv), Methanesulfonyl chloride (28.5 g, 0.250 mmol, 1.3 equiv) was added and the reaction mixture was stirred at rt for 6 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 afford a crude residue. The crude residue was purified by silica gel chromatography (0-25 % EtOAc in Hexane) to afford product 3.1.59a (39.3 g, 98.1 % yield). LCMS (m/z): 209.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 5.00 - 4.84 (m, 1 H), 3.61 (s, Hz, 3H), 3.21 - 3.13 (s, 3H), 2.82 (m, 1 H), 2.70 - 2.60 (m, 2H), 2.40 - 2.28 (m, 2H). Step 2. Synthesis of methyl (1 r, 3r)-3-acetoxycyclobutane-1-carboxylate [3.1.59b]
3.1.59a (39.2 g, 188.0 mmol, 1.0 equiv) was dissolved in N, N-dimethylformamide (392 ml_). KOAc (94.3 g, 962.1 mmol, 5.1 equiv) was added and the reaction mixture was stirred at 120 °C for 21 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 afford a crude residue. The crude residue was purified by silica gel column chromatography (0-10 % EtOAc in Hexane) to afford product 3.1.59b (25.3 g, 78.9 % yield). LCMS (m/z): 190.2 [M+18]. 1H NMR (400 MHz, CDCI3) δ 5.27 - 5.08 (m, 1 H), 3.76 - 3.67 (s, 3H), 3.21 - 3.06 (m, 1 H), 2.73 - 2.61 (m, 2H), 2.42 - 2.31 (m, 2H), 2.05 (s, 3H).
Step 3. Synthesis of methyl (1 r, 3r)-3-hydroxycyclobutane-1-carboxylate [3.1.59c]. 3.1.59b (29.02 g, 168.7 mmol, 1.0 equiv) was dissolved in MeOH (290 ml_). NaOMe (25 % solu" in MeOH) (7.28 g, 33.74 mmol, 0.2 equiv) was added and the reaction mixture was stirred at rt for 12 hours. The reaction mixture was concentrated, the residue was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford 3.1.59c (16.8 g, 87.6% yield). The product was used in the next step with no further purification. 1H NMR (400 MHz, CDCI3) δ 4.64 - 4.52 (m, 1 H), 3.71 (s, 3H), 3.1 1 - 2.99 (m, 1 H), 2.63 - 2.55 (m, 2H), 2.23 (m, 2H), 2.14 (s, 1 H). Step 4. Synthesis of methyl (1 r, 3r)-3-((tert-butyldiphenylsilyl) oxy) cyclobutane-1- carboxylate [3.1.59d]. 3.1.59c (19.5 g, 150.0 mmol, 1.0 equiv) was mixed with dichloromethane (195 mL) and cooled to 0 °C. Imidazole (20.42 g, 300.0 mmol, 2.0 equiv), TBDPS-CI (53.6 g, 195.0 mmol, 1.3 equiv) was added and the reaction mixture was stirred at rt for 6 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (0-6 % dichloromethane in Hexane) to afford product 3.1.59d (36 g, 65.4 % yield). LCMS (m/z): 369.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.65 - 7.55 (m, 4H), 7.53 - 7.38 (m, 6H), 4.49 - 4.35 (m, 1 H), 3.53 (s, 3H), 3.05 - 2.91 (m, 1 H), 2.32 (t, J = 6.9 Hz, 4H), 0.98 (s, 9H). Step 5. Synthesis of ((1 r, 3r)-3-((tert-butyldiphenylsilyl) oxy) cyclobutyl) methanol
[3.1.59e]. 3.1.59d (17 g, 46.1 mmol, 1.0 equiv) was dissolved in THF (170 mL). LiBH4 (2M in THF) (45.1 g, 92.3 mmol, 2.0 equiv) was added drop wise and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated aqueous sodium sulfate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue, which was purified by silica gel chromatography (0-14 % EtOAc in Hexane) to afford 3.1.59e (13.7 g, 87.3 % yield). LCMS (m/z): 358.4 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.60 (dd, J = 7.5, 1.8 Hz, 4H), 7.49 - 7.40 (m, 6H), 4.50 (t, J = 5.3 Hz, 1 H), 4.34 (p, J = 6.9 Hz, 1 H), 3.29 - 3.23 (m, 2H), 2.22 - 2.14 (m, 1 H), 2.14 - 2.04 (m, 2H), 2.03 - 1.90 (m, 2H), 0.97 (s, 9H). Step 6. Synthesis of (1 r, 3r)-3-((tert-butyldiphenylsilyl) oxy) cyclobutane-1- carbaldehyde [3.1.59f]. 3.1.59e (13.7 g, 46.2 mmol, 1.0 equiv) was dissolved in dichloromethane (140 ml.) and cooled to 10 °C. Dess-Martin periodinane (35.3 g, 83.2 mmol, 1.8 equiv) was added in portions and the reaction mixture was stirred at room temperature for 8 hours. The reaction mixture was filtered through celite bed and filtrate was concentrated under reduced pressure to afford a crude residue. The crude residue was purified by silica gel column chromatography (0-8 % EtOAc in Hexane) to afford product 3.1.59f (9.97 g, 73.1 % yield). LCMS (m/z): 339.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 9.64 (d, J = 1.7 Hz, 1 H), 7.61 - 7.58 (m, 4H), 7.49 - 7.42 (m, 6H), 4.24 (m, 1 H), 3.03 (m, 1 H), 2.46 - 2.36 (m, 2H), 2.29 - 2.19 (m, 2H), 0.98 (s, 9H).
Step 7. Synthesis of tert-butyl ((1 r, 3r)-3-ethynylcyclobutoxy)diphenylsilane [3.1.59g]
3.1.59f (9.9 g, 29.2 mmol, 1.0 equiv) was dissolved in MeOH (100 ml_). Ohira- Bestmann reagent (5.68 g, 29.3 mmol, 1.1 equiv), K2C03 (8.08 g, 58.6 mmol, 2.0 equiv) was asdded and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated, the residue was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (0-2 % EtOAc in Hexane) to afford product 3.1.59g (6.6 g, 67.5 % yield). LCMS (m/z): 335.4 [M+H]. (as mixture of cis:trans 70:30):- 1H NMR (400 MHz, DMSO) δ 7.64 - 7.55 (m, 4H), 7.49 - 7.41 (m, 6H), 4.52 - 4.44 (m, 0.3H), 4.14 - 4.03 (m, 0.7H), 2.96 (d, J = 2.0 Hz, 0.6H), 2.87 (d, J = 2.1 Hz, 0.4H), 2.49 - 1.95 (m, 5H).
Step 8. Synthesis of ethyl (R)-3-((S)-3-(4-(((1s, 3R)-3-((tert-butyldiphenylsilyl) oxy) cyclobutyl) ethynyl)phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1.59h]. 1.1d (1 g, 2.3 mmol, 1.0 equiv), 3.1.59g (1.54 g, 4.6 mmol, 2.0 equiv) were mixed with diethyl amine (10 ml_) and N, N-dimethylformamide (2 ml_). Cul (0.006 g, 0.14 mmol, 0.06 equiv), triphenylphosphine (0.06 g, 0.23 mmol, 0.1 equiv) were added and the reaction mixture was degassed for 15 minutes. PdCI2(pph3)2 (0.097 g, 0.14 mmol, 0.06 equiv) was added and the reaction mixture was stirred at 125 °C for 3 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 afford a crude residue, which was purified by silica gel chromatography (0-40 % EtOAc in Hexane) to afford 3.1.59h (1.24g, 78.5% yield). LCMS (m/z): 688.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.61 (dd, J = 7.4, 1.5 Hz, 4H), 7.56 - 7.36 (m, 10H), 4.84 - 4.72 (m, 1 H), 4.30 - 4.09 (m, 3H), 3.86 - 3.74 (m, 1 H), 3.17 (m, 4H), 2.77 - 2.59 (m, 2H), 2.58 - 2.53 (m, 1 H), 2.36 (m, 3H), 2.12 (m, 2H), 1.64 (d, J = 5.3 Hz, 3H), 1.25 (dt, J = 7.1 , 3.5 Hz, 3H), 0.98 (s, 9H). Step 9. Synthesis of ethyl (R)-3-((S)-3-(4-(((1s, 3R)-3-hydroxycyclobutyl) ethynyl) phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1.59Ϊ]
3.1.59h (1.23 g, 1.79 mmol, 1.0 equiv) was dissolved in THF (30 ml.) and cooled to 10 °C. TBAF (2.15 g, 2.14 mmol, 1.2 equiv) was added drop wise and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (0-80 % EtOAc in Hexane) to afford product 3.1.59i (0.71 g, 88.7 % yield). LCMS (m/z): 450.5 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.49 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 4.77 (d, J = 8.2 Hz, 1 H), 4.21 (dt, J = 21.4, 8.1 Hz, 3H), 3.99 - 3.89 (m, 1 H), 3.14 (m, 4H), 2.66 (d, J = 12.5 Hz, 2H), 2.56 (s, 1 H), 2.38 - 2.14 (m, 3H), 1.92 (d, J = 7.7 Hz, 1 H), 1.62 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H).
Step 10. Synthesis of ethyl (R)-3-((S)-3-(4-((3-fluorocyclobutyl) ethynyl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.1.59j]. 3.1.59Ϊ (0.7 g, 1.56 mmol, 1.0 equiv) was dissolved with dichloromethane (29 ml_) and cooled to -78 °C. DAST (0.45 g, 2.8 mmol, 1.8 equiv) was added drop wise and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude product. The crude product was purified by silica gel column chromatography (0-1 % MeOH/ dichloromethane) to afford product 3.1.59j (0.25 g, 39 % yield). LCMS (m/z): 452.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.59 (d, J = 8.9 Hz, 2H), 7.56 - 7.46 (m, 2H), 6.01 - 5.81 (m, 1 H), 5.58 (m, 1 H), 5.36 - 5.1 1 (m, 2H), 4.81 (m, 1 H), 4.34 - 4.16 (m, 3H), 3.83 (m, 1 H), 3.17 (s, 3H), 2.76 - 2.59 (m, 3H), 2.42 - 2.32 (m, 1 H), 1.65 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 11. Synthesis of (R)-3-((S)-3-(4-((3-fluorocyclobutyl)ethynyl)phenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide [3.1.59 & 3.1.60]. 3.1.59 & 3.1.60 were synthesized from 3.1.59j by the process of example 3.1.1. The two diastereomers were separated by reverse phase HPLC. Compound 3.1.59: LCMS (m/z): 439.4 [M+H]. 1H NMR (400 MHz, MeOD) δ 7.54 (d, J = 7.8 Hz, 2H), 7.43 (dd, J = 23.1 , 7.7 Hz, 2H), 5.40 - 5.31 (m, 0.5H), 5.22 (m, 0.5H), 4.76 (m, 1 H), 4.24 (m, 1 H), 3.85 (m, 1 H), 3.1 1 (s, 3H), 2.89 (d, J = 14.2 Hz, 1 H), 2.60 (m, 4H), 2.40 - 2.27 (m, 1 H), 1.75 (s, 3H). Compound 3.1.60: LCMS (m/z): 439.3 [M+H]. 1H NMR (400 MHz, MeOD) δ 7.61 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 5.94 (m, 1 H), 5.45 (t, J = 6.2 Hz, 0.5H), 5.33 (t, J = 6.1 Hz, 0.5H), 5.23 (dd, J = 19.4, 13.7 Hz, 2H), 4.77 (m, 1 H), 4.25 (m, 1 H), 3.87 (m, 1 H), 3.1 1 (s, 3H), 2.89 (d, J = 14.1 Hz, 1 H), 2.69 (dt, J = 13.2, 6.3 Hz, 2H), 2.35 (m, 1 H), 1.78 (s, 3H).
III.2.1 Synthesis of compound 3.2.1
Figure imgf000139_0001
Reagents: Step 1 : DBU, dppb, PdCI2(PPh3)2, DMSO, 80°C. Step 2: LiOH, THF, MeOH, Water, room temperature. Step 3: NH2OTHP, EDC.HCI, HOBt, TEA, THF, room temperature. Step 4: Methanolic-HCI (8% w/w), MeOH, 0°C to room temperature.
Step 1. Synthesis of ethyl (R)-2-methyl-3-((S)-3-(2-methyl-4-(prop-1-yn-1-yl)phenyl)-2- oxooxazolidin-5-yl)-2-(methylsulfonyl)propanoate [3.2.1a]
1.1d (0.20 g, 0.45 mmol, 1.0 equiv), but-2-ynoic acid(0.031 g, 0.38 mmol, 1.0 equiv), PdCI2(PPh3)2 (0.003 g, 0.004 mmol, 0.01 equiv), 1 ,4-bis(diphenylphosphino)butane (0.003 g, 0.009 mmol, 0.02 equiv) and DBU(0.13 g, 0.89 mmol, 2.0 equiv) were added in DMSO (4 ml_) in sealed tube. The reaction mixture was stirred at 80°C for 6 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. The residue was purified by silica gel column chromatography (20-25 % EtOAc in Hexane) to afford product 3.2.1a (0.15 g, 82.5 % yield). LCMS (m/z): 408.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.50 - 7.19 (m, 3H), 4.83 (s, 1 H), 4.26 (d, J = 7.1 Hz, 2H), 4.03 (d, J = 9.7 Hz, 1 H), 3.73 (d, J = 8.8 Hz, 1 H), 3.30 - 3.12 (m, 3H), 2.68 (d, J = 14.6 Hz, 1 H), 2.46 - 2.32 (m, 1 H), 2.20 (d, J = 10.5 Hz, 3H), 2.14 - 1.96 (m, 3H), 1.67 (d, J = 10.1 Hz, 3H), 1.25 (dd, J = 8.1 , 5.9 Hz, 3H). Step 2. Synthesis of (R)-2-methyl-3-((S)-3-(2-methyl-4-(prop-1-yn-1-yl)phenyl)-2-oxo oxazolidin-5-yl)-2-(methylsulfonyl)propanoic acid [3.2.1 b]. 3.2.1a (0.15 g, 0.36 mmol, 1.0 equiv) was dissolved in THF (5 ml_), MeOH (2 ml_). LiOH (0.017 g, 0.73 mmol, 2.0 equiv) in water (1 ml_) was added and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness; the residue was diluted with water, acidified by 1 N HCI aqueous solution to the pH 4 to 5 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 3.2.1 b (0.13 g, 96.2 % yield). LCMS (m/z): 380.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 14.13 (s, 1 H), 7.32 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 9.8 Hz, 1 H), 4.83 (d, J = 5.8 Hz, 1 H), 4.04 (dt, J = 8.5, 3.9 Hz, 1 H), 3.72 (t, J = 8.1 Hz, 1 H), 3.15 (s, 3H), 2.63 (d, J = 1 1.8 Hz, 1 H), 2.34 (dd, J = 14.5, 8.8 Hz, 1 H), 2.21 (d, J = 10.7 Hz, 3H), 2.05 (s, 3H), 1.61 (s, 3H). Step 3. Synthesis of (2R)-2-methyl-3-((S)-3-(2-methyl-4-(prop-1-yn-1-yl)phenyl)-2-oxo oxazolidin-5-yl)-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide
[3.2.1c]. 3.2.1 b (0.13 g, 0.342 mmol, 1.0 equiv) was dissolved in THF (7 ml_). Et3N (0.17 g, 1.7 mmol, 5.0 equiv), EDC.HCI (0.12 g, 0.61 mmol, 1.8 equiv) and HOBT (0.07 g, 0.51 mmol, 1.5 equiv) were added and the reaction mixture was stirred at room temperature for 10 minutes. 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.08 g, 0.68 mmol, 2.0 equiv) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated to dryness. The residue was purified by silica gel column chromatography (2-3% MeOH in dichloromethane) to afford product 3.2.1c which was carry forwarded for next step. (0.12 g, 73.2 % yield). LCMS (m/z): 496.4 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.70 - 7.48 (m, 1 H), 7.35 - 7.26 (m, 2H), 4.95 (d, J = 9.4 Hz, 1 H), 4.81 - 4.65 (m, 1 H), 4.04 - 3.98 (m, 1 H), 3.77 (ddd, J = 1 1.1 , 7.8, 3.0 Hz, 2H), 3.48 - 3.38 (m, 3H), 3.16 - 3.00 (m, 3H), 2.75 (dd, J = 25.4, 14.5 Hz, 1 H), 2.33 - 2.12 (m, 4H), 2.07 - 1.96 (m, 3H), 1.64 - 1.60 (m, 3H), 1.49 - 1.42 (m, 6H).
Step 8. Synthesis of (R)-N-hydroxy-2-methyl-3-((S)-3-(2-methyl-4-(prop-1-yn-1- yl)phenyl)-2-oxooxazolidin-5-yl)-2-(methylsulfonyl)propanamide [3.2.1]
3.2.1c (0.12 g, 0.24 mmol, 1.0 equiv) was dissolved in methanol (1 ml_) and cooled the solution at 0°C. Methanolic-HCI solution (8% w/w, 2.0 ml_) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness and the crude product was purified by preparative HPLC to afford product 3.2.1 as desired diastereomer (0.053 g, 55.9 % yield). LCMS (m/z): 395.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 9.29 (s, 1 H), 7.30 (dd, J = 21.6, 8.7 Hz, 3H), 4.67 (d, J = 5.8 Hz, 1 H), 3.99 (t, J = 8.4 Hz, 1 H), 3.69 (t, J = 8.1 Hz, 1 H), 3.09 (s, 3H), 2.74 (t, J = 22.8 Hz, 1 H), 2.29 - 2.20 (m, 1 H), 2.19 (s, 3H), 2.04 (s, 3H), 1.60 (s, 3H).
Figure imgf000140_0001
Reagents: Step 1 : DBU, dppb, PdCI2(PPh3)2, DMSO, 90°C. Step 2: LiOH.H20, THF, MeOH, Water, room temperature. Step 3: NH2OTHP, 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-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-2-oxooxazolidin- 5-yl)-2-methyl-2-(methylsulfonyl)propanoate [3.3.1a]. 1.3d (0.19 g, 0.42 mmol, 1.0 equiv), but-2-ynoic acid (0.035 g, 0.42 mmol, 1.0 equiv), PdCI2(PPh3)2 (0.003 g, 0.004 mmol, 0.01 equiv), 1 ,4-bis(diphenylphosphino)butane (0.004 g, 0.0096 mmol, 0.02 equiv) and DBU (0.13 g, 0.84 mmol, 2.0 equiv) were added in DMSO (10 mL) in sealed tube. The reaction mixture was stirred at 90°C for 4 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 3.3.1a (0.14 g, 70 % yield). LCMS (m/z): 412.4 [M+H]. Step 2. Synthesis of 3-((S)-3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)- 2-methyl-2-(methylsulfonyl)propanoic acid [3.3.1 b]. 3.3.1a (0.14 g, 0.34 mmol, 1.0 equiv) was dissolved in THF (6 mL), MeOH (2 mL). LiOH.H20 (0.043 g, 1.02 mmol, 3.0 equiv) in water (2 mL) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness; 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 3.3.1 b (0.12 g, 92.3 % yield). LCMS (m/z): 401.3 [M+18]. 1H NMR (400 MHz, DMSO) δ 12.01 (s, 1 H), 7.53 (t, J = 8.3 Hz, 1 H), 7.38 (dd, J = 1 1.8, 1.7 Hz, 1 H), 7.28 (dd, J = 8.3, 1.6 Hz, 1 H), 4.92 - 4.77 (m, 1 H), 4.13 (t, J = 8.5 Hz, 1 H), 3.81 (t, J = 8.1 Hz, 1 H), 3.17 (s, 3H), 2.71 - 2.59 (m, 1 H), 2.39 - 2.28 (m, 1 H), 1.67 - 1.57 (s, 3H).
Step 3. Synthesis of 3-((S)-3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-5-yl)- 2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [3.3.1c]
3.3.1b (0.12 g, 0.31 mmol, 1.0 equiv) was dissolved into THF (5 mL). N-methyl morpholine (0.16 g, 1.57 mmol, 5.0 equiv), HOBT (0.051 g, 0.38 mmol, 1.2 equiv), O- (tetrahydro -2H-pyran-2-yl) hydroxylamine (0.073 g, 0.63 mmol, 2.0 equiv) were added and the reaction mixture was stirred at room temperature for 10 minutes. EDC.HCI (0.09 g, 0.47 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated to afford a residue. The residue was purified by silica gel column chromatography (2-3 % MeOH in dichloromethane) to afford product 3.3.1c which was carry forwarded for next step. (0.12 g, 74.5 % yield). LCMS (m/z): 481.5 [M-H]. 1H NMR (400 MHz, DMSO) 5 7.50 (s, 1 H), 7.31 (dd, J = 36.4, 10.0 Hz, 2H), 4.70 (d, J = 7.7 Hz, 1 H), 4.05 (d, J = 18.5 Hz, 2H), 3.89 (s, 2H), 3.07 (d, J = 9.6 Hz, 3H), 2.80 - 2.72 (m, 1 H), 2.17 (m, 4H), 1.74 (s, 3H), 1.69 - 1.59 (m, 6H).
Step 4. Synthesis of (R)-3-((S)-3-(2-fluoro-4-(prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-5- yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide [3.3.1] 3.3.1c (0.12 g, 0.25 mmol, 1.0 equiv) was dissolved in ethanol (5 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 dryness to afford a residue. The residue was diluted with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford the crude product. The crude product was purified by preparative HPLC purification to afford 3.3.1 as desired diastereomer (0.065 g, 65.7 % yield). LCMS (m/z): 399 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.07 (s, 1 H), 9.29 (s, 1 H), 7.52 (t, J = 8.3 Hz, 1 H), 7.38 (d, J = 1 1.8 Hz, 1 H), 7.28 (d, J = 8.2 Hz, 1 H), 4.67 (d, J = 5.6 Hz, 1 H), 4.09 (t, J = 8.5 Hz, 1 H), 3.77 (t, J = 8.2 Hz, 1 H), 3.09 (s, 3H), 2.78 (d, J = 12.9 Hz, 1 H), 2.21 (dd, J = 14.3, 8.7 Hz, 1 H), 2.06 (s, 3H), 1.59 (s, 3H).
III.3.3. Synthesis of compound 3.3.3
3.3.3 was synthesized using the process of example 3.3.2. LCMS (m/z): 486.3 [M+18]. 1H NMR (400 MHz, DMSO) δ 1 1.14 (s, 1 H), 9.28 (s, 1 H), 7.54 (t, J = 8.3 Hz, 1 H), 7.44 - 7.35 (m, 1 H), 7.29 (d, J = 8.2 Hz, 1 H), 4.68 (d, J = 7.9 Hz, 1 H), 4.1 1 (dd, J = 13.4, 6.8 Hz, 2H), 3.78 (t, J = 8.3 Hz, 1 H), 3.29 - 3.22 (m, 1 H), 3.14 (d, J = 6.6 Hz, 3H), 3.07 (d, J = MA Hz, 3H), 2.78 (d, J = 13.9 Hz, 1 H), 2.36 - 2.23 (m, 5H), 1.59 (s, 3H).
Figure imgf000142_0001
Reagents: Step 1 : CBZ-CI, NaHC03, 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, dichloromethane, room temperature. Step 4: NaH (60%), N,N- dimethylformamide, 0°C to room temperature. Step 5: DBU, dppb, PdCI2(PPh3)2, DMSO, 100°C. Step 6: LiOH.H20, THF, MeOH, Water, room temperature. Step 7: NH2OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, room temperature. Step 8: 35.5% aq. HCI, EtOH, room temperature.
Step 1. Synthesis of benzyl (4-bromo-3-fluorophenyl)carbamate [3.4.1a]. 4-bromo-3- fluoroaniline (2.5 g, 13.1 mmol, 1.0 equiv) was dissolved in acetone: water (2:1 , 30 ml_) and the solution was cooled to 0°C. NaHC03 (2.20 g, 26.3 mmol, 2.0 equiv), CBZ-CI (2.68 g, 15.8 mmol, 1.2 equiv) were added and the reaction mixture was stirred at room temperature for 24 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 afford product 3.4.1a (4.0 g, 94 % yield). LCMS (m/z): 322.1 [M-2]. 1 H NMR (400 MHz, DMSO) δ 10.17 (s, 1 H), 7.65 - 7.51 (m, 2H), 7.48 - 7.32 (m, 5H), 7.27 - 7.17 (m, 1 H), 5.17 (s, 2H). Step 2. Synthesis of (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2- one [3.4.1 b]. 3.4.1a (2.5 g, 7.7 mmol, 1.0 equiv) was dissolved in THF (20 ml_) and cooled to -78°C. n-BuLi (2.5M in hexane) (0.59 g, 9.3 mmol, 1.2 equiv) was gradually added and the reaction mixture was stirred at -78 °C for 1 hour. (R)-oxiran-2-ylmethyl butyrate (1.33 g, 9.3 mmol, 1.2 equiv) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (80-100 % EtOAc in Hexane) to afford product 3.4.1 b which was carry forwarded for next step. (1.46 g, 65% yield). LCMS (m/z): 292.1 [M+H].
Step 3. Synthesis of (R)-3-(4-bromo-3-fluorophenyl)-5-(iodomethyl)oxazolidin-2-one
[3.4.1c]. Triphenylphosphine (1.64 g, 6.3 mmol, 1.3 equiv) was dissolved in dichloromethane (20 ml_). imidazole (0.45 g, 6.8 mmol, 1.4 equiv) was added and the reaction mixture was stirred at room temperature for 5 minutes. Iodine (1.59 g, 6.3 mmol, 1.3 equiv) was added and the reaction mixture was stirred at room temperature for 10 minutes. A solution of 3.4.1 b (1.40 g, 4.8 mmol, 1.0 equiv) in dichloromethane (10 mL) was added drop wise and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (5-20 % EtOAc in Hexane) to afford product 3.4.1c (1.3 g, 67 % yield). LCMS (m/z): 400.0 [M+H].
Step 4. Synthesis of ethyl (R)-3-((S)-3-(4-bromo-3-fluorophenyl)-2-oxooxazolidin-5-yl)- 2-methyl-2-(methylsulfonyl)propanoate [3.4.1 d]. Ethyl 2-(methylsulfonyl)propanoate (1.98 g, 1 1.0 mmol, 4.0 equiv) was dissolved in N,N-dimethylformamide (15 mL) and cooled to 0-5 °C. NaH (60%) (0.13 g, 5.5 mmol, 2.0 equiv) was added in portion wise and the reaction mixture was stirred at room temperature for 1 hour. A solution of 3.4.1c (1.10 g, 2.8 mmol, 1.0 equiv) in N,N-dimethylformamide (5 mL) was added drop wise at 0-5°C. The reaction mixture was allowed to stir at rt for 6 hours. The reaction 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. The residue was purified by silica gel chromatography (20-30% EtOAc in Hexane) to afford 3.4.1 d as mixture of diastereomers. The product was further purified by preparative HPLC to afford product 3.4.1 d as desired diastereomer (1.0 g, 80% yield). LCMS (m/z): 471.2 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.79 - 7.70 (m, 1 H), 7.64 (dd, J = 1 1.5, 2.5 Hz, 1 H), 7.33 (dd, J = 8.5, 2.3 Hz, 1 H), 4.81 (dd, J = 14.2, 8.3 Hz, 1 H), 4.34 - 4.14 (m, 3H), 3.91 - 3.74 (m, 1 H), 3.16 (s, 3H), 2.77 - 2.61 (m, 1 H), 2.38 (dd, J = 14.9, 8.9 Hz, 1 H), 1.64 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 5. Synthesis of ethyl (R)-3-((S)-3-(3-fluoro-4-(prop-1-yn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanoate [3.4.1 e]
3.4.1d (0.26 g, 0.57 mmol, 1.0 equiv), but-2-ynoic acid (0.048 g, 0.57 mmol, 1.0 equiv), DBU (0.18 g, 1.15 mmol, 2.0 equiv) were dissolved in DMSO (10 ml.) in sealed tube and the reaction mixture was degassed for 10 minutes. PdCI2(PPh3)2 (0.004 g, 0.0057 mmol, 0.01 equiv), 1 ,4-bis(diphenylphosphino)butane (0.005 g, 0.013 mmol, 0.02 equiv) were added and the reaction mixture was stirred at 100°C for 20 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 that was purified by silica gel chromatography (50-70 % EtOAc in Hexane) to afford product 3.4.1e (0.2 g, 84 % yield). LCMS (m/z): 429.4 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.70-7.43 (m, 2H), 7.31 (dd, J = 8.6, 2.2 Hz, 1 H), 4.80 (dd, J = 14.9, 7.3 Hz, 1 H), 4.25 (tt, J = 1 1.1 , 7.4 Hz, 2H), 3.90 - 3.73 (m, 1 H), 3.17 (d, J = 8.8 Hz, 3H), 2.67 (dd, J = 14.9, 2.4 Hz, 1 H), 2.37 (dd, J = 14.9, 9.0 Hz, 1 H), 2.16 - 2.03 (m, 3H), 1.68 (d, J = 29.0 Hz, 3H), 1.26 (dd, J = 8.7, 5.5 Hz, 3H). Step 6. Synthesis of (R)-3-((S)-3-(3-fluoro-4-(prop-1-yn-1-yl) phenyl)-2-oxooxazolidin-5- yl)-2-methyl-2-(methylsulfonyl)propanoic acid [3.4.1 f]
3.4.1e (0.2 g, 0.49 mmol, 1.0 equiv) was dissolved in THF (8 ml_), MeOH (1 ml_). LiOH.H20 (0.06 g, 1.46 mmol, 3.0 equiv) in water (1 ml_) was added and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness, the residue was dissolved in water, acidified by 1.0 N HCI aqueous solution to the pH 4 to 5 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 3.4.1f (0.14 g, 75 % yield). The crude product was used in the next step with no further purification. LCMS (m/z): 384.4 [M+H]. Step 7. Synthesis of (2R)-3-((S)-3-(3-fluoro-4-(prop-1-yn-1-yl)phenyl)-2-oxooxazolidin- 5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide
[3.4.1g]. 3.4.1f (0.14 g, 0.37 mmol, 1.0 equiv) was dissolved in THF (10 mL). N-methyl morpholine (0.18 g, 1.8 mmol, 5.0 equiv), HOBT (0.06 g, 0.4 mmol, 1.2 equiv), EDC.HCI (0.1 1 g, 0.5 mmol, 1.5 equiv) and 0-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.09 g, 0.7 mmol, 2.0 equiv) were added to the solution and the reaction mixture was stirred at room temperature for 24 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. The residue was purified by silica gel column chromatography (50-70 % EtOAc in Hexane) to afford product 3.4.1 g which was carry forwarded for next step. (0.1g, 87 % yield). LCMS (m/z): 500.4 [M+18].
Step 8. Synthesis of (R)-3-((S)-3-(3-fluoro-4-(prop-1-yn-1-yl) phenyl)-2-oxooxazolidin-5- yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide [3.4.1]. 3.4.1g (0.1 g, 0.21 mmol, 1.0 equiv) was dissolved in ethanol (5 ml_), 35.5% aq. HCI (0.5 ml_) was added and reaction mixture was stirred at rt for 2 hours. The reaction mixture was diluted with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by preparative HPLC to afford product 3.4.1 as desired diastereomer (0.022 g, 26 % yield). LCMS (m/z): 399.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1 H), 9.31 (s, 1 H), 7.60 - 7.44 (m, 2H), 7.31 (dd, J = 8.6, 2.0 Hz, 1 H), 4.65 (d, J = 8.9 Hz, 1 H), 4.19 (t, J = 8.8 Hz, 1 H), 3.84 - 3.71 (m, 1 H), 3.08 (s, 3H), 2.76 (d, J = 12.7 Hz, 1 H), 2.23 (dd, J = 14.4, 8.9 Hz, 1 H), 2.08 (s, 3H), 1.60 (s, 3H).
Figure imgf000145_0001
Reagents: Step 1 : CBZ-CI, NaHC03, Acetone: Water, 5 °C to room temperature. Step 2: n- BuLi (2.5M in THF), THF, -70°C to room temperature. Step 3: Iodine, triphenylphosphine, imidazole, THF, room temperature. Step 4: NaH (60%), N,N-dimethyl formamide, 0 °C to room temperature. Step 5: DBU, dppb, PdCI2(PPh3)2, DMSO, 1 10 °C. Step 6: LiOH.H20, THF, Water, room temperature. Step 7: NH2OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, room temperature. Step 8: 35.5% aq. HCI, EtOH, room temperature. Step 1. Synthesis of benzyl (4-bromo-3-methylphenyl)carbamate [3.5.1a]. 4-bromo-3- methylaniline (3.0 g, 22.0 mmol, 1.0 equiv) was dissolved in acetone: water (2:1 , 45 mL) and cooled it to 5 °C. NaHC03 (3.76 g, 44.0 mmol, 2.0 equiv), CBZ-CI (5.70 g, 33.0 mmol, 1.5 equiv) were added to the reaction mixture. The reaction mixture was stirred at rt for 24 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 afford a crude residue that was purified by silica gel chromatography (10-12 % EtOAc in Hexane) to afford product 3.5.1a (6.59 g, 92% yield). LCMS (m/z): 320.2 [M-H]. 1H NMR (400 MHz, DMSO) 5 9.88 (s, 1 H), 7.50 - 7.31 (m, 8H), 5.16 (s, 2H), 2.31 (d, J = 12.3 Hz, 3H).
Step 2. Synthesis of (R)-3-(4-bromo-3-methylphenyl)-5-(hydroxymethyl)oxazolidin-2- one [3.5.1 b]. 3.5.1a (2.0 g, 6.2 mmol, 1.0 equiv) was dissolved in THF (60 mL) and cooled to -70°C. n-BuLi (2.5M in THF) (1.20 g, 18.0 mmol, 3.0 equiv) was gradually added and the reaction mixture was stirred at -70 °C for 1.5 hours. (R)-oxiran-2-ylmethyl butyrate (0.88 g, 6.2 mmol, 1.0 equiv) was added and the reaction mixture was allowed to stir at rt for 7 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (40-50 % EtOAc in Hexane) to afford 3.5.1 b (1.60 g, 71 % yield). LCMS (m/z): 286.2 [M-H]. 1H NMR (400 MHz, DMSO) δ 7.56 (dd, J = 12.9, 5.7 Hz, 2H), 7.43 (dd, J = 8.8, 2.7 Hz, 1 H), 5.23 (t, J = 5.6 Hz, 1 H), 4.70 (td, J = 9.5, 3.6 Hz, 1 H), 4.13 - 3.99 (m, 1 H), 3.82 (dd, J = 8.8, 6.3 Hz, 1 H), 3.67 (ddd, J = 12.3, 5.5, 3.4 Hz, 1 H), 3.56 (ddd, J = 12.3, 5.6, 4.1 Hz, 1 H), 2.35 (s, 3H). Step 3. Synthesis of (R)-3-(4-bromo-3-methylphenyl)-5-(iodomethyl)oxazolidin-2-one
[3.5.1c]. Triphenylphosphine (1.66 g, 6.3 mmol, 1.3 equiv) was dissolved in THF (10 mL) imidazole (0.33 g, 6.3 mmol, 1.3 equiv) was added. Iodine (1.23 g, 6.3 mmol, 1.3 equiv) was added and the reaction mixture was stirred at room temperature for 10 minutes. A solution of 3.5.1 b (1.4 g, 4.8 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. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by silica gel column chromatography (20 % EtOAc in Hexane) to afford product 3.5.1c (1.70 g, 76 % yield). LCMS (m/z): 398.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.59 (d, J = 8.8 Hz, 1 H), 7.53 (d, J = 2.7 Hz, 1 H), 7.42 (dd, J = 8.8, 2.8 Hz, 1 H), 4.74 (td, J = 10.7, 5.1 Hz, 1 H), 4.18 (t, J = 9.1 Hz, 1 H), 3.72 - 3.51 (m, 3H), 2.36 (s, 3H).
Step 4. Synthesis of ethyl 3-((S)-3-(4-bromo-3-methylphenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoate [3.5.1 d]. NaH (60%) (0.099 g, 7.5 mmol, 2.0 equiv) was dissolved in DMF (40 mL) at 0-5 °C. Ethyl 2-(methylsulfonyl)propanoate (1.36 g, 7.5 mmol, 2.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 hours. A solution of 3.5.1c (1.5 g, 3.7 mmol, 1 .0 equiv) in N,N-dimethylformamide (10 ml_) was added drop wise at 0-5 °C and the reaction mixture was stirred at room temperature for 24 hour. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (15-20 % EtOAc in Hexane) to afford product 3.5.1d (0.92 g, 48 % yield). LCMS (m/z): 467.1 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.59 (dd, J = 8.8, 3.5 Hz, 1 H), 7.51 (s, 1 H), 7.37 (dd, J = 8.7, 2.6 Hz, 1 H), 4.95 - 4.73 (m, 1 H), 4.23 (ddd, J = 17.7, 13.9, 7.7 Hz, 3H), 3.80 (t, J = 8.3 Hz, 1 H), 3.22 - 3.1 1 (m, 3H), 2.66 (s, 1 H), 2.32 - 2.20 (m, 1 H), 1.61 (d, J = 26.7 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H). Step 5. Synthesis of ethyl 2-methyl-3-((S)-3-(3-methyl-4-(prop-1-yn-1-yl)phenyl)-2- oxooxazolidin-5-yl)-2-(methylsulfonyl)propanoate [3.5.1 e]
3.5.1d (0.40 g, 0.9 mmol, 1.0 equiv), but-2-ynoic acid (0.075 g, 0.9 mmol, 1.0 equiv) and DBU (0.27 g, 1.0 mmol, 2.0 equiv) were dissolved in DMSO (20 ml.) in sealed tube and the reaction mixture was degassed for 10 minutes. PdCI2(PPh3)2 (0.006 g, 0.009 mmol, 0.01 equiv) and 1 , 4-bis(diphenylphosphino)butane (0.007 g, 0.018 mmol, 0.02 equiv) were added and the reaction mixture was stirred at 1 10°C for 15 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 afford a residue. The residue was purified by silica gel column chromatography (10 % EtOAc in Hexane) to afford product 3.5.1e (0.2 g, 55 % yield). LCMS (m/z): 408.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.38 (dd, J = 13.0, 4.8 Hz, 3H), 4.78 (d, J = 7.3 Hz, 1 H), 4.30 - 4.16 (m, 3H), 3.84 - 3.75 (m, 1 H), 3.14 (d, J = 14.2 Hz, 3H), 2.68 (d, J = 15.0 Hz, 1 H), 2.39 - 2.34 (m, 3H), 2.25 (d, J = 14.1 Hz, 1 H), 2.06 (d, J = 16.5 Hz, 3H), 1.61 (d, J = 27.0 Hz, 3H), 1.25 (d, J = 6.9 Hz, 3H).
Step 6. Synthesis of 2-methyl-3-((S)-3-(3-methyl-4-(prop-1-yn-1-yl)phenyl)-2-oxo oxazolidin-5-yl)-2-(methylsulfonyl)propanoic acid [3.5.1f]. 3.5.1e (0.2 g, 0.49 mmol, 1.0 equiv) was dissolved in THF (10 mL) and water (10 ml_). LiOH.H20 (0.04 g, 0.99 mmol, 2.0 equiv) was added and the resulting mixture was stirred at rt for 4 hours. The reaction mixture was concentrated to dryness and the residue was diluted in water, acidified by 1 N HCI aqueous solution to the pH 4 to 5 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude product. The crude product was triturated with n-hexane, decanted the solvent and dried to afford product 3.5.1f which was used for next step (0.17 g, 91 % yield). LCMS (m/z): 380.4 [M+H]. Step 7. Synthesis of 2-methyl-3-((S)-3-(3-methyl-4-(prop-1-yn-1-yl) phenyl)-2- oxazolidin-5-yl)-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide
[3.5.1g]. 3.5.1f (0.17 g, 0.45 mmol, 1.0 equiv) was dissolved in THF (20 mL). N-methyl morpholine (0.22 g, 2.24 mmol, 5.0 equiv), HOBT (0.091 g, 0.67 mmol, 1.5 equiv), EDC.HCI (0.150 g, 0.81 mmol, 1.8 equiv) and 0-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.1g, 0.89 mmol, 2.0 equiv) were added and the reaction mixture was stirred at rt for 24 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by silica gel column chromatography (10-15% EtOAc in Hexane) to afford 3.5.1g which was used for next step (0.14 g, 65% yield). LCMS (m/z): 496.5 [M+18]. Step 8. Synthesis of (R)-N-hydroxy-2-methyl-3-((S)-3-(3-methyl-4-(prop-1-yn-1- yl)phenyl)-2-oxooxazolidin-5-yl)-2-(methylsulfonyl)propanamide [3.5.1]. 3.5.1g (0.14 g, 0.290 mmol, 1.0 equiv) was dissolved in ethanol (10 mL), 35.5% aq. HCI (0.2 mL) was added and reaction mixture was stirred at rt for 4 hours. The reaction mixture was diluted with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude product that was purified by preparative HPLC to afford 3.5.1 (0.025 g, 21 % yield). LCMS (m/z): 412.3 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.38 (d, J = 20.6 Hz, 3H), 4.65 (m, 1 H), 4.25 - 4.1 1 (m, 1 H), 3.87-3.73 (m, 1 H), 3.07 (d, J = 4.6 Hz, 3H), 2.75 (d, J = 12.6 Hz, 1 H), 2.36 (s, 3H), 2.19 (m, 1 H), 2.08 (s, 3H), 1.56 (d, J = 9.7 Hz, 3H).
Figure imgf000148_0001
Reagents: Step 1 : CBZ-CI, NaHC03, 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, dichloromethane, room temperature. Step 4: NaH (60%), N,N-dimethylformamide, 0 °C to room temperature. Step 5: DBU, dppb, PdCI2(PPh3)2, DMSO, 80 °C. Step 6: LiOH, THF, MeOH, Water, room temperature. Step 7: NH2OTHP, EDC.HCI, HOBt, TEA, THF, room temperature. Step 8: HCI (8 %w/w in MeOH), MeOH, room temperature. Step 1. Synthesis of benzyl (4-bromo-3-chlorophenyl)carbamate [3.6.1a]. 4-bromo-3- chloroaniline (6.0 g, 29.0 mmol, 1.0 equiv) was dissolved in acetone: water (2:1 , 54 mL) and the solution was cooled to 0-5 °C. NaHC03 (5.13 g, 61.0 mmol, 2.1 equiv), CBZ-CI (4.95 g, 29.0 mmol, 1.0 equiv) were added and the reaction mixture was stirred at rt for 24 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. That was purified by silica gel chromatography (2-8% EtOAc in Hexane) to afford 3.6.1a (4.4 g, 44.5 % yield). LCMS (m/z): 340.1 [M-H]. 1H NMR (400 MHz, DMSO) δ 10.14 (s, 1 H), 7.79 (d, J = 2.3 Hz, 1 H), 7.67 (d, J = 8.8 Hz, 1 H), 7.55 - 7.28 (m, 6H), 5.17 (s, 2H).
Step 2. Synthesis of (R)-3-(4-bromo-3-chlorophenyl)-5-(hydroxymethyl)oxazolidin-2- one [3.6.1 b]. 3.6.1a (4.3 g, 12.6 mmol, 1.0 equiv) was dissolved in THF (80 mL) and cooled to -78 °C. n-BuLi (2.5M in hexane) (0.89 g, 13.8 mmol, 1.1 equiv) was gradually added and the reaction mixture was stirred at -78 °C for 45 minutes. (R)-oxiran-2-ylmethyl butyrate (2.0 g, 13.8 mmol, 1.1 equiv) was added and the reaction mixture was stirred at rt for 24 hours. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (20-35 % EtOAc in Hexane) to afford product 3.6.1 b (2.1 1 g, 54.5 % yield). LCMS (m/z): 306.1 [M-H]. 1H NMR (400 MHz, DMSO) δ 7.89 (d, J = 2.6 Hz, 1 H), 7.76 (dd, J = 7.6, 5.5 Hz, 1 H), 7.45 (ddd, J = 22.3, 1 1.7, 4.4 Hz, 1 H), 5.24 (s, 1 H), 4.79 - 4.66 (m, 1 H), 4.09 (tt, J = 7.4, 3.7 Hz, 1 H), 3.89 - 3.79 (m, 1 H), 3.68 (dd, J = 12.3, 3.0 Hz, 1 H), 3.56 (dd, J = 12.4, 3.8 Hz, 1 H). Step 3. Synthesis of (R)-3-(4-bromo-3-chlorophenyl)-5-(iodomethyl)oxazolidin-2-one
[3.6.1c]. Triphenylphosphine (2.32 g, 8.9 mmol, 1.3 equiv) and imidazole (0.60 g, 8.9 mmol, 1.3 equiv) were dissolved in dichloromethane (20 mL). Iodine (2.25 g, 8.9 mmol, 1.3 equiv) was added and the reaction mixture was stirred at room temperature for 15 minutes. A solution of 3.6.1 b (2.10 g, 6.9 mmol, 1.0 equiv) in dichloromethane (8 mL) was added drop wise and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated to dryness to afford a crude residue. The residue was purified by silica gel column chromatography (10-30 % EtOAc in Hexane) to afford product 3.6.1c (2.1g, 73.8 % yield). LCMS (m/z): 418 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.89 (d, J = 2.7 Hz, 1 H), 7.82 - 7.73 (m, 1 H), 7.46 (ddd, J = 22.8, 10.5, 5.5 Hz, 1 H), 4.83 - 4.69 (m, 1 H), 4.21 (td, J = 9.1 , 3.0 Hz, 1 H), 3.68 (dd, J = 9.3, 5.8 Hz, 1 H), 3.65 - 3.51 (m, 2H).
Step 4. Synthesis of (R)-ethyl 3-((S)-3-(4-bromo-3-chlorophenyl)-2-oxooxazolidin-5-yl)- 2-methyl-2-(methylsulfonyl)propanoate [3.6.1 d]. Ethyl 2-(methylsulfonyl)propanoate (1.82 g, 10.0 mmol, 2.0 equiv) dissolved in N,N-dimethylformamide (20 mL) and cooled the reaction mixture to 0-5 °C. NaH (60%) (0.181 g, 7.5 mmol, 1.5 equiv) was added portion wise and the reaction mixture was stirred at room temperature for 1 hour. A solution of 3.6.1c (2.10 g, 5.0 mmol, 1.0 equiv) in N,N-dimethylformamide (5 ml_) was added drop wise at 0-5 °C. The reaction mixture was allowed to stir at rt for 24 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 afford a crude residue. The residue was purified by silica gel chromatography (15-35 % EtOAc in Hexane) to afford product 3.6.1d (1.3 g, 55.2% yield). The product 3.6.1d was further purified by preparative HPLC to afford product 3.6.1 d as desired diastereomer. LCMS (m/z): 468.2 [M-H]. 1H NMR (400 MHz, DMSO) δ 7.85 (d, J=2.6 Hz, 1 H), 7.79 (dd, J =8.9, 3.6 Hz, 1 H), 7.53-7.41 (m, 1 H), 4.80 (d, J =8.8 Hz, 1 H), 4.38 (q, J =7.2 Hz, 1 H), 4.31-4.16 (m, 2H), 3.88-3.78 (m, 1 H), 3.13 (s,3H), 2.67 (d, J=14.9Hz, 1 H), 2.37 (dd, J=14.9, 9.0Hz, 1 H), 1.64 (s,3H), 1.25-1.22 (m, 3H). Step 5. Synthesis of ethyl (R)-3-((S)-3-(3-chloro-4-(prop-1-yn-1-yl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanoate [3.6.1e]. 3.6.1d (desired diastereomer) (0.20 g, 0.43 mmol, 1.0 equiv), but-2-ynoic acid (0.037 g, 0.45 mmol, 1.05 equiv), DBU (0.13 g, 0.85 mmol, 2.0 equiv), PdCI2(PPh3)2 (0.003 g, 0.004 mmol, 0.01 equiv), 1 , 4-bis(diphenylphosphino)butane (0.003 g, 0.0085 mmol, 0.02 equiv) were added in DMSO (7 ml_) in sealed tube and the reaction mixture was stirred at 80 °C for 10 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The residue was purified by silica gel chromatography (20-30 % EtOAc in Hexane) to afford product 3.6.1e (0.152 g, 82.1 % yield). LCMS (m/z): 428.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.74 (d, J = 2.2 Hz, 1 H), 7.54 (d, J = 8.7 Hz, 1 H), 7.45 (dd, J = 8.6, 2.2 Hz, 1 H), 4.80 (d, J = 7.8 Hz, 1 H), 4.33 - 4.17 (m, 3H), 3.87 - 3.78 (m, 1 H), 3.16 (s, 3H), 2.67 (d, J = 12.7 Hz, 1 H), 2.37 (dd, J = 14.9, 8.9 Hz, 1 H), 2.10 (s, 2H), 1.64 (s, 3H), 1.28 - 1.23 (m, 3H). Step 6. Synthesis of (R)-3-((S)-3-(3-chloro-4-(prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-5- yl)-2-methyl-2-(methylsulfonyl)propanoic acid [3.6.1†]. 3.6.1e (0.145 g, 0.3 mmol, 1.0 equiv) was dissolved in THF (6 mL) and MeOH (1 ml_). LiOH (0.016 g, 0.7 mmol, 2.0 equiv) in water (1 mL) was added and the reaction mixture was stirred at rt for 4 hours. The reaction mixture was diluted with water, acidified by 1.0 N HCI aqueous 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 3.6.1f (0.1 15 g, 84.9 % yield), which was used in the next step with no further purification. LCMS (m/z): 400 [M-H]. 1H NMR (400 MHz, DMSO) δ 14.46 - 14.05 (m, 1 H), 7.73 (d, J = 2.2 Hz, 1 H), 7.54 (d, J = 8.6 Hz, 1 H), 7.45 (dd, J = 8.6, 2.1 Hz, 1 H), 4.81 (d, J = 7.8 Hz, 1 H), 4.23 (t, J = 8.8 Hz, 1 H), 3.87-3.78 (m, 1 H), 3.14 (s, 3H), 2.68-2.59 (m,1 H), 2.31 (dd, J = 14.6, 8.6Hz, 1 H), 2.00 (s, 3H), 1.61 (d, J =18.0 Hz, 3H). Step 7. Synthesis of (2R)-3-((S)-3-(3-chloro-4-(prop-1-yn-1-yl)phenyl)-2-oxooxazolidin- 5-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide
[3.6.1g]. 3.6.1f (0.1 1 g, 0.28 mmol, 1.0 equiv) was dissolved in THF (10 mL). Et3N (0.138 g, 1.37 mmol, 5.0 equiv), EDC.HCI (0.093 g, 0.49 mmol, 1.8 equiv) and HOBT (0.055 g, 0.41 mmol, 1.5 equiv) were added and the reaction mixture was stirred at room temperature for 10 minutes. 0-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.063 g, 0.54 mmol, 2.0 equiv) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to dryness. The residue was purified by flash chromatography (1-5 % MeOH in dichloromethane) to afford product 3.6.1 g which was used for next step (0.1g, 72.8 % yield). LCMS (m/z): 518.5 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.71 (dd, J = 8.2, 2.2 Hz, 1 H), 7.54 (d, J = 8.6 Hz, 1 H), 7.49 - 7.42 (m, 1 H), 4.70 (s, 1 H), 4.12 (d, J = 5.3 Hz, 1 H), 3.80 - 3.72 (m, 3H), 3.43 (dd, J = 7.1 , 5.3 Hz, 2H), 3.05 (m, 3H), 2.80 - 2.72 (m, 1 H), 2.25 (m, 1 H), 1.62 (d, J = 8.2 Hz, 3H), 1.48 - 1.40 (m, 9H).
Step 8. Synthesis of (R)-3-((S)-3-(3-chloro-4-(prop-1-yn-1-yl)phenyl)-2-oxooxazolidin-5- yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide [3.6.1]. 3.6.1g (0.095 g, 0.2 mmol, 1.0 equiv) dissolved in methanol (1 ml_), HCI (8 w/w % in MeOH) (2 ml_) was added and the reaction mixture was stirred at rt for 4 hours. The reaction mixture was concentrated to dryness. The crude product was purified by preparative HPLC to afford 3.6.1 as desired diastereomer (0.032 g, 40.5 % yield). LCMS (m/z): 415.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.33 (s, 1 H), 7.74 (d, J = 2.2 Hz, 1 H), 7.54 (d, J = 8.6 Hz, 1 H), 7.44 (dd, J = 8.6, 2.2 Hz, 1 H), 4.64 (d, J = 7.3 Hz, 1 H), 4.20 (t, J = 8.8 Hz, 1 H), 3.88 - 3.74 (m, 1 H), 3.08 (s, 3H), 2.76 (d, J = 1 1.8 Hz, 1 H), 2.22 (dd, J = 14.6, 8.9 Hz, 1 H), 2.09 (d, J = 7.1 Hz, 3H), 1.59 (s, 3H).
III.7. Synthesis of compound 3.7
Step 1. Synthesis of ethyl (R)-3-((S)-3-(4-bromo-2, 3-difluorophenyl)-2-oxooxazolidin-5- yl)-2-methyl-2-(methylsulfonyl) propanoate [3.7a]. (R)-ethyl 2-methyl-2-(methylsulfonyl)- 3-((S)-2-oxooxazolidin-5-yl)propanoate (0.17 g, 0.62 mmol, 1.0 equiv), 1 , 4-dibromo-2, 3- difluorobenzene (0.17 g, 0.62 mmol, 1.0 equiv) were dissolved in 1 , 4-dioxane (10 ml_). Cul (0.14 g, 0.75 mmol, 1.2 equiv), (1 R, 2R)-(-)-1 , 2-diamino cyclohexane (0.099 g, 0.87 mmol, 1.4 equiv), Cs2C03 (0.3 g, 0.94 mmol, 1.5 equiv) were added and the reaction mixture was stirred at 100 °C for 5 hours. The reaction mixture was filtered and filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (30-40 % EtOAc/Hexane) to afford the desired product 3.7a (0.12 g, 41.9 % yield). LCMS (m/z): 470.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.64 (dd, J = 1 1.5, 4.7 Hz, 1 H), 7.42 (dd, J = 1 1.8, 4.7 Hz, 1 H), 4.87 (dd, J = 1 1.2, 5.3 Hz, 1 H), 4.25 (q, J = 7.1 Hz, 2H), 4.16 (t, J = 8.5 Hz, 1 H), 3.86 (t, J = 8.3 Hz, 1 H), 3.17 (t, J = 2.6 Hz, 3H), 2.73 - 2.67 (m, 1 H), 2.38 (dd, J = 14.8, 8.7 Hz, 1 H), 1.65 (s, 3H), 1.27 - 1.23 (m, 3H). Step 2. Synthesis of ethyl (R)-3-((S)-3-(2, 3-difluoro-4-(prop-1-yn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [3.7b]. 3.7a (0.16 g, 0.33 mmol, 1.0 equiv), but-2-ynoic acid (0.041 g, 0.49 mmol, 1.5 equiv), 1, 4-bis (diphenylphosphino) butane (0.003 g, 0.007 mmol, 0.02 equiv), DBU (0.1 g, 0.65 mmol, 2.0 equiv) were dissolved in DMSO (11 ml_) and the reaction mixture was degassed. PdCI2 (PPh3)2 (0.0025 g, 0.0036 mmol, 0.01 equiv) was added and the reaction mixture was stirred at 100 °C for 3 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 afford a crude residue, which was purified by silica gel chromatography (30- 40 % EtOAc/Hexane) to afford the desired product 3.7b (0.13 g, 92.2% yield). LCMS (m/z):
430.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.37 (t, J = 5.2 Hz, 2H), 4.86 (d, J = 8.4 Hz, 1 H), 4.25 (dd, J= 14.2, 7.1 Hz, 2H), 4.17 (t, J= 8.3 Hz, 1H), 3.87 (t, J = 8.0 Hz, 1H), 3.17 (s, 3H), 2.70 (d, J=14.9 Hz,1H), 2.42-2.35 (m, 1H), 2.08 (s, 3H), 1.64 (s, 3H), 1.25 (t, J =7.1 Hz, 3H). Step 3. Synthesis of (R)-3-((S)-3-(2, 3-difluoro-4-(prop-1-yn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl) propanamide [3.7]
3.7 was prepared from 3.7b using the process of example 1.2.. LCMS (m/z): 417.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.31 (s, 1H), 7.36 (dd, J= 12.6, 7.2 Hz, 2H), 4.70 (d, J = 7.2 Hz, 1H), 4.14 (t, J = 8.1 Hz, 1H), 3.84 (t, J = 8.1 Hz, 1H), 3.09 (s, 3H), 2.78 (d, J= 14.0 Hz, 1H), 2.22 (dd, J= 14.5, 8.9 Hz, 1H), 2.13 (s, 3H), 1.59 (s, 3H).
111.8. Synthesis of compound 3.8
Comound 3.8 was synthesized by the process of example 3.4.1. LCMS (m/z): 417.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.32 (s, 1H), 7.55-7.21 (m, 2H), 4.66 (dd, J= 15.1, 6.9 Hz, 1H), 4.19 (t, J = 8.8 Hz, 1H), 3.85-3.67 (m, 1H), 3.17-2.98 (m, 3H), 2.72 (t, J= 15.8 Hz, 1H), 2.30-2.18 (m, 1H), 1.69- 1.47 (m, 3H).
111.9. Synthesis of compound 3.9
Comound 3.8 was synthesized by the process of example 3.4.1. LCMS (m/z): 429.9 [M+18]. 1H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 9.32 (s, 1H), 7.60-7.43 (m, 2H), 7.31 (dd, J= 8.6, 2.0 Hz, 1H), 4.73-4.58 (m, 1H), 4.19 (t, J = 8.8 Hz, 1H), 3.79 (dd, J= 13.6, 5.9 Hz, 1H), 3.18-2.94 (m, 3H), 2.76 (d, J= 12.3 Hz, 1H), 2.45 (t, J = 7.5 Hz, 2H), 2.23 (dd, J = 14.4, 9.0 Hz, 1H), 1.69- 1.50 (m, 3H), 1.23-1.10 (m, 3H).
111.10. Synthesis of compound 3.10
Comound 3.10 was synthesized by the process of example 3.1.48. LCMS (m/z):
469.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 11.26- 10.97 (m, 1H), 9.31 (s, 1H), 7.60-7.43 (m, 2H), 7.32 (d, J = 8.6 Hz, 1H), 4.65 (d, J = 8.0 Hz, 1H), 4.20 (t, J = 8.8 Hz, 1H), 3.76 (dd, J = 16.7, 9.8 Hz, 2H), 3.15 (d, J = 6.4 Hz, 3H), 3.08 (s, 3H), 2.85 (dd, J = 16.6, 8.8 Hz, 1 H), 2.76 (d, J = 17.1 Hz, 1 H), 2.69 - 2.59 (m, 2H), 2.23 (dd, J = 14.4, 9.0 Hz, 1 H), 2.00 - 1.90 (m, 2H), 1.59 (s, 3H).
111.11. Synthesis of compound 3.11
Step 1. Synthesis of ethyl 3-((S)-3-(4-(cyclopropylethynyl)-2-fluorophenyl)-2-oxo oxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanoate [3.11a]. 1.3d (0.27 g, 0.59 mmol, 1.0 equiv), PdCI2(pph3)2 (0.021 g, 0.03 mmol, 0.05 equiv), Cul (0.006 g, 0.03 mmol, 0.05 equiv), triphenyl phosphine (0.031 g, 0.1 1 mmol, 0.2 equiv) were added in diethyl amine (5 mL) and N,N-dimethylformamide (2 mL) and the reaction mixture was degassed for 15 minutes. Ethynylcyclopropane (0.08 g, 1.19 mmol, 2.0 equiv) was added and the reaction mixture was stirred at 120 °C for 4 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 afford a residue that was purified by silica gel chromatography (25-30 % EtOAc in Hexane) to afford product 3.11a (0.18 g, 68.9 % yield). LCMS (m/z): 438.6 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.51 (t, J = 8.4 Hz, 1 H), 7.35 (d, J = 1 1.6 Hz, 1 H), 7.25 (d, J = 8.3 Hz, 1 H), 4.83 (d, J = 6.0 Hz, 1 H), 4.28 - 4.12 (m, 3H), 3.80 (t, J = 8.2 Hz, 1 H), 3.16 (d, J = 10.6 Hz, 3H), 2.67 (s, 1 H), 2.36 (dd, J = 14.8, 8.8 Hz, 1 H), 1.67 - 1.51 (m, 4H), 1.25 (dd, J = 7.0, 4.9 Hz, 3H), 0.91 (dt, J = 6.4, 4.1 Hz, 2H), 0.81 - 0.71 (m, 2H). Step 2. Synthesis of (R)-3-((S)-3-(4-(cyclopropylethynyl)-2-fluorophenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide [3.11]. Compound 3.11 was synthesized by the process of example 1.1. LCMS (m/z): 441.9 [M+18]. 1H NMR (400 MHz, DMSO) δ 1 1.07 (s, 1 H), 9.16 (s, 1 H), 7.51 (t, J = 8.3 Hz, 1 H), 7.35 (dd, J = 1 1.8, 1.7 Hz, 1 H), 7.25 (d, J = 8.1 Hz, 1 H), 4.68 (d, J = 5.2 Hz, 1 H), 4.08 (t, J = 8.4 Hz, 1 H), 3.77 (t, J = 8.3 Hz, 1 H), 3.09 (s, 3H), 2.76 (d, J = 1 1.7 Hz, 1 H), 2.19 (dd, J = 14.3, 8.5 Hz, 1 H), 1.67 - 1.44 (m, 4H), 0.91 (dt, J = 6.3, 4.0 Hz, 2H), 0.76 (td, J = 6.5, 3.9 Hz, 2H).
111.12. Synthesis of compound 3.12
Comound 3.12 was synthesized by the process of example 3.11. LCMS (m/z): 423.3 [M-1]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.32 (s, 1 H), 7.61 - 7.41 (m, 2H), 7.29 (dd, J = 8.7, 2.1 Hz, 1 H), 4.64 (d, J = 6.6 Hz, 1 H), 4.19 (t, J = 8.9 Hz, 1 H), 3.83 - 3.71 (m, 1 H), 3.08 (s, 3H), 2.76 (d, J = 1 1.7 Hz, 1 H), 2.22 (dd, J = 14.4, 9.0 Hz, 1 H), 1.70 - 1.45 (m, 4H), 0.95 - 0.83 (m, 2H), 0.80 - 0.65 (m, 2H).
IV.1. Synthesis of compound 4.1
Figure imgf000154_0001
Reagents: Step 1 : 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane), KOAc, PdCI2(dppf)2, 1 ,4-dioxane, 95°C. Step 2: H202 (30 % in H20), 1 ,4-Dioxane, room
temperature. Step 3: 1-bromobut-2-yne, NaH (60%), Ν,Ν-dimethylformamide, 5°C to room temperature. Step 4: LiOH.H20, THF, MeOH, Water, room temperature. Step 5: NH2OTHP, EDC.HCI, HOBt, TEA, DCM, room temperature. Step 6: 35.5% aq. HCI, EtOH, room temperature.
Step 1. Synthesis of ethyl 2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(4,4,5,5- tetramethyl -1 ,3,2-dioxaborolan-2-yl)phenyl)oxazolidin-5-yl)propanoate [4.1a]. 1.1 d
(1.0 g, 2.3 mmol, 1.0 equiv)(mixture of isomers), potassium acetate (1.0 g, 10.37 mmol, 4.5 equiv), 4,4,4',4', 5, 5, 5', 5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (0.6 g, 2.3 mmol, 1.0 equiv), PdCI2(dppf)2 (0.34 g, 0.46 mmol, 0.2 equiv) were dissolved in 1 ,4-dioxane (15 mL) in a sealed tube. The mixture was stirred at 95°C for 24 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (30-40% EtOAc in Hexane) to afford 4.1a (0.55 g, 49.6% yield). LCMS (m/z): 482.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.68 (t, J=10.0Hz, 2H), 7.61-7.52 (m, 2H), 4.95-4.72 (m, 1 H), 4.25 (dt, J =12.4, 7.8 Hz, 3H), 3.84 (t, J = 8.2 Hz, 1 H), 3.23-3.1 1 (m, 3H), 2.70(d, J =16.0 Hz, 1 H), 2.41-2.30(m, 1 H), 1 .61 (d,J =26.6 Hz, 3H), 1 .36-1.19 (m, 13H). Step 2. Synthesis of ethyl 3-((S)-3-(4-hydroxyphenyl)-2-oxooxazolidin-5-yl)-2-methyl-2- (methylsulfonyl)propanoate [4.1 b]. H2O2 (30 % in H20, 1.0 mL) was added to a mixture of 4.1a (0.55 g, 1.14 mmol, 1.0 equiv) in 1 ,4-dioxane (10 mL) and the resulting mixture was stirred at rt for 24 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (2-3 % MeOH in dichloromethane) to afford product 4.1 b which was used as such for next step (0.19 g, 44.8 % yield). LCMS (m/z): 372.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 9.38 (s, 1 H), 7.35 - 7.28 (m, 2H), 6.81 - 6.74 (m, 2H), 4.90 - 4.66 (m, 1 H), 4.26 (d, J = 7.1 Hz, 2H), 4.12 (t, J = 8.7 Hz, 1 H), 3.74 (t, J = 8.2 Hz, 1 H), 3.15 (d, J = 12.0 Hz, 3H), 2.67 (d, J = 12.8 Hz, 1 H), 2.39 - 2.25 (m, 1 H), 1.69 - 1.51 (m, 3H), 1.25 (d, J = 6.6 Hz, 3H).
Step 3. Synthesis of ethyl 3-((S)-3-(4-(but-2-yn-1-yloxy)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoate [4.1c]. 4.1 b (0.19 g, 0.51 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (4 mL) and cooled the reaction mixture to 5 °C. NaH (0.025 g, 0.62 mmol, 1.2 equiv) was added portion wise and the reaction mixture was stirred at room temperature for 1 hour. A solution of 1-bromobut-2-yne (0.10 g, 0.77 mmol, 1.5 equiv) in N,N-dimethylformamide (3 mL) was added drop wise at 5 °C. The reaction mixture was allowed to stir at room temperature for 3 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. The residue was purified by silica gel chromatography (30-40 % EtOAc in Hexane) to afford product 4.1c (0.19 g, 62.1 % yield). LCMS (m/z): 424.4 [M+H]. 1H NMR (400 MHz, CD3CN) δ 7.46 (qd, J = 5.7, 2.9 Hz, 2H), 7.00 (dt, J = 10.4, 2.5 Hz, 2H), 4.76 (tt, J = 14.3, 4.2 Hz, 1 H), 4.69 (q, J = 2.3 Hz, 2H), 4.34 - 4.24 (m, 2H), 4.22 - 4.1 1 (m, 1 H), 3.81 - 3.69 (m, 1 H), 3.10 - 3.07 (m, 3H), 2.75 - 2.65 (m, 1 H), 2.42 (ddd, J = 11.5, 8.8, 5.9 Hz, 1 H), 2.19 (s, 3H), 1.74 (d, J = 5.7 Hz, 3H), 1.35 - 1.31 (m, 3H).
Step 4. Synthesis of 3-((S)-3-(4-(but-2-yn-1-yloxy)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoic acid [4.1 d]. 4.1c (0.13 g, 0.31 mmol, 1.0 equiv) was dissolved in THF (1 mL), MeOH (2 mL) and LiOH-H20 (0.015 g, 0.37 mmol, 1.2 equiv) in water (1 mL). The resulting mixture was stirred at rt for 2 hours. The reaction mixture was concentrated to dryness and the residue was acidified by addition of 1 N HCI aqueous solution until the pH 4 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was triturated with n- pentane, the solvent was decanted to obtain product 4.1 d (0.10 g, 82.6 % yield). The crude material was used in the next step with no further purification. LCMS (m/z): 396.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 14.26 - 14.06 (m, 1 H), 7.45 (dd, J = 9.2, 2.7 Hz, 2H), 7.05 - 6.97 (m, 2H), 4.74 (t, J = 9.4 Hz, 3H), 4.18 (t, J = 8.8 Hz, 1 H), 3.77 (dd, J = 14.9, 6.2 Hz, 1 H), 3.14 (d, J = 6.9 Hz, 3H), 2.70 - 2.62 (m, 1 H), 2.32 - 2.26 (m, 1 H), 1.83 (t, J = 2.2 Hz, 3H), 1.59 (d, J = 12.4 Hz, 3H). Step 5. Synthesis of 3-((S)-3-(4-(but-2-yn-1-yloxy)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [4.1 e]. 4.1 d
(0.100 g, 0.25 mmol, 1.0 equiv) was dissolved in dichloromethane (5 ml_). TEA (0.128 g, 1.27 mmol, 5.0 equiv), EDC.HCI (0.073 g, 0.38 mmol, 1 .5 equiv), HOBT (0.061 g, 0.46 mmol, 1.8 equiv) and 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.060 g, 0.51 mmol, 2.0 equiv) were added to the solution. The reaction mixture was stirred at rt for 24 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (2-3 % MeOH in dichloromethane) to afford product 4.1 e which was used as such for next step (0.09 g, 71.9 % yield). LCMS (m/z): 512.5 [M+18]. 1H NMR (400 MHz, DMSO) δ 7.44 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 9.0 Hz, 2H), 4.73 (s, 2H), 4.65 (s, 1 H), 4.14 (t, J = 8.5 Hz, 1 H), 3.76 (s, 2H), 3.44 (s, 2H), 3.09 (dd, J = 19.9, 10.4 Hz, 3H), 2.78 (d, J = 15.3 Hz, 1 H), 2.24 (s, 1 H), 1.82 (d, J = 5.0 Hz, 3H), 1.62 (s, 3H), 1.49 (d, J = 38.1 Hz, 6H). Step 6. Synthesis of (R)-3-((S)-3-(4-(but-2-yn-1-yloxy)phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide [4.1]
4.1e (0.085 g, 0.17 mmol, 1.0 equiv) was dissolved in ethanol (5 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 concentrated under reduced pressure. The residue was poured to saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC to afford 4.1 as the desired diastereomer (0.016 g, 22.7 % yield). LCMS (m/z): 41 1.3 [M+H]. 1H NMR (400 MHz, CD3CN) δ 9.67 (s, 1 H), 7.60 - 7.42 (m, 2H), 7.32 (s, 1 H), 7.07 - 6.97 (m, 2H), 4.79 - 4.60 (m, 3H), 4.14 (t, J = 8.8 Hz, 1 H), 3.75 (t, J = 8.1 Hz, 1 H), 3.03 (d, J = 1.5 Hz, 3H), 2.75 (d, J = 14.2 Hz, 1 H), 2.33 (dd, J = 13.7, 8.4 Hz, 2H), 1.92 - 1.79 (m, 3H), 1.70 (s, 3H).
Figure imgf000156_0001
Reagents: Step 1 : K2C03, Ν,Ν-dimethylformamide, 100°C. Step 2: LiOH.H20, THF, MeOH, Water, room temperature. Step 3: NH2OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, room temperature. Step 4: 35.5% aq. HCI, EtOH, room temperature.
Step 1. Synthesis of ethyl 2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(2,2,2- trifluoroethoxy)phenyl)oxazolidin-5-yl)propanoate [4.2a]. 4.1 b (0.2 g, 0.54 mmol, 1.0 equiv), K2CO3 (0.29g, 2.16 mmol, 4.0 equiv) were added in N,N-dimethylformamide (4 mL) in sealed tube. The reaction mixture was stirred at room temperature for 15 minutes. A solution of 1 ,1 ,1-trifluoro-2-iodoethane (0.23 g, 1.07 mmol, 2.0 equiv) in N,N- dimethylformamide (1 mL) was drop wise added and the reaction mixture was stirred at 100 °C for 24 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by silica gel column chromatography (30-35 % EtOAc in Hexane) to afford product 4.2a (0.172 g, 55.7 % yield). LCMS (m/z): 454.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.66 - 7.46 (m, 2H), 7.30 - 7.07 (m, 2H), 5.10 - 4.65 (m, 3H), 4.33 - 4.13 (m, 3H), 3.95 (d, J = 5.5 Hz, 1 H), 3.81 (dd, J = 17.9, 10.2 Hz, 1 H), 3.15 (d, J = 13.2 Hz, 3H), 2.67 (d, J = 3.4 Hz, 1 H), 2.41 - 2.30 (m, 1 H), 1.67 - 1.54 (m, 3H), 1.30 - 1.20 (m, 3H). Step 2. Synthesis of 2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(2,2,2- trifluoroethoxy) phenyl)oxazolidin-5-yl)propanoic acid [4.2b]. 4.2a (0.17 g, 0.3 mmol, 1.0 equiv) was dissolved in THF (4 mL), MeOH (2 mL). LiOH.H20 (0.031 g, 0.7 mmol, 2.0 equiv) in water (2 mL) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, acidified by 1.0 N HCI aqueous solution to the pH 1 to 2 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford the crude product. The crude product was triturated with n-pentane, decanted the solvent and dried to afford product 4.2b (0.14 g, 87.5 % yield). The product was used in the next step with no further purification. LCMS (m/z): 426.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.58 - 7.47 (m, 2H), 7.25 - 7.08 (m, 2H), 5.03 - 4.55 (m, 3H), 4.19 (t, J = 8.2 Hz, 1 H), 3.81 (d, J = 7.7 Hz, 1 H), 3.15 (s, 3H), 2.64 (d, J = 14.9 Hz, 1 H), 2.32 (d, J = 8.4 Hz, 1 H), 1.61 (s, 3H).
Step 3. Synthesis of 2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(2,2,2- trifluoroethoxy) phenyl)oxazolidin-5-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide
[4.2c]. 4.2b (0.14 g, 0.32 mmol, 1.0 equiv) was dissolved in THF (5 mL). N-methyl morpholine (0.167 g, 1.64 mmol, 5.0 equiv), EDC.HCI (0.059 g, 0.49 mmol, 1.5 equiv), HOBT (0.053 g, 0.40 mmol, 1.2 equiv), 0-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.077 g, 0.65 mmol, 2.0 equiv) were added to the solution and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford the crude product. The crude product was purified by column chromatography (1-2 % MeOH in dichloromethane) to afford product 4.2c which was carry forwarded for next step. (0.1g, 58 % yield). LCMS (m/z): 542.4 [M+18].
Step 4. Synthesis of (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4- (2,2,2-trifluoroethoxy)phenyl)oxazolidin-5-yl)propanamide [4.2]. 4.2c (0.1 g, 0.19 mmol, 1.0 equiv) was dissolved in ethanol (5 ml_). 35.5% aq. HCI (1 ml_) was added and the reaction mixture was stirred at rt for 2 hours. The reaction mixture was diluted with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford crude product. The crude product was purified by preparative HPLC to afford 4.2 as desired diastereomer (0.02 g, 23.8 % yield). LCMS (m/z): 443.3 [M+18]. 1H NMR (400 MHz, DMSO) 5 10.96 (s, 1 H), 9.26 (s, 1 H), 7.48 (d, J = 9.1 Hz, 2H), 7.10 (d, J = 9.1 Hz, 2H), 4.75 (q, J = 8.9 Hz, 2H), 4.63 (d, J = 6.5 Hz, 1 H), 4.14 (t, J = 8.8 Hz, 1 H), 3.83 - 3.73 (m, 1 H), 3.08 (s, 3H), 2.75 (d, J = 1 1.8 Hz, 1 H), 2.18 (dd, J = 14.3, 8.7 Hz, 1 H), 1.58 (s, 3H).
Figure imgf000158_0001
Reagents: Step 1 : Pd(OAc)2, P(Cy)3,K3P04, Toluene, Water, 100°C. Step 2: LiOH, THF, MeOH, Water, room temperature. Step 3: NH2OTHP, EDC.HCI, HOBt, N-Methyl morpholine, THF, room temperature. Step 4: Methanolic-HCI (8%w/w), MeOH, 0°C to room temperature.
Step 1. Synthesis of ethyl 3-((S)-3-(4-cyclopropylphenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoate [5.1.1a]. 1.1 d (0.35 g, 0.8 mmol, 1.0 equiv), cyclopropyl boron ic acid (0.21 g, 2.4 mmol, 3.0 equiv) and K3P04 (0.51 g, 2.4 mmol, 3.0 equiv) were added in toluene: water (10:1 , 5.5 ml_) and degassed for 15 min. Pd(OAc)2 (0.009 g, 0.04 mmol, 0.05 equiv) and P(Cy)3 (0.002 g, 0.08 mmol, 0.1 equiv) were added to the reaction mixture and the reaction mixture was stirred at 100 °C under microwave irradiation for 1 hour. The reaction mixture was filtered through Celite bed and concentrated. The residue was purified by silica gel column chromatography (10-35 % EtOAc in Hexane) to afford product 5.1.1a (0.25 g, 78.4 % yield). LCMS (m/z): 396.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.40 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H), 4.76 (d, J = 8.0 Hz, 1 H), 4.26 (q, J = 7.1 Hz, 2H), 4.17 (t, J = 8.8 Hz, 1 H), 3.82 - 3.76 (m, 1 H), 2.72 - 2.65 (m, 1 H), 2.34 (dd, J = 14.8, 9.0 Hz, 1 H), 1.89 (td, J = 8.3, 4.3 Hz, 1 H), 1.64 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H), 0.96 - 0.89 (m, 2H), 0.67 - 0.61 (m, 2H).
Step 2. Synthesis of 3-((S)-3-(4-cyclopropylphenyl)-2-oxooxazolidin-5-yl)-2-methyl-2- (methylsulfonyl)propanoic acid [5.1.1 b]. 5.1.1a (0.25 g, 0.63 mmol, 1.0 equiv) was dissolved in THF (10 ml_), MeOH (2 ml_). LiOH (0.04 g, 0.94 mmol, 1 .5 equiv) in water (1 ml_) was added. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness and the residue was diluted with water, acidified by 1.0 N HCI aqueous solution to the pH 4 to 5 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 5.1.1 b (0.18 g, 77.5 % yield). LCMS (m/z): 368.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.40 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H), 4.77 (d, J = 7.4 Hz, 1 H), 4.18 (t, J = 8.8 Hz, 1 H), 3.82 - 3.75 (m, 1 H), 3.15 (s, 3H), 2.64 (d, J = 14.8 Hz, 1 H), 2.30 (dd, J = 14.7, 8.7 Hz, 1 H), 1.91 - 1.85 (m, 1 H), 1.61 (s, 3H), 0.93 (td, J = 6.3, 4.1 Hz, 2H), 0.69 - 0.59 (m, 2H). Step 3. Synthesis of 3-((S)-3-(4-cyclopropylphenyl)-2-oxooxazolidin-5-yl)-2-methyl-2- (methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [5.1.1 c]
5.1.1 b (0.14 g, 0.36 mmol, 1.0 equiv) was dissolved in THF (7 ml_). N-methyl morpholine (0.19 g, 1.8 mmol, 5.0 equiv), EDC.HCI (0.07 g, 0.55 mmol, 1.5 equiv), HOBT (0.06 g, 0.44 mmol, 1.2 equiv) and 0-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.09 g, 0.73 mmol, 2.0 equiv) were added to the solution. The reaction mixture was stirred at room temperature for 10 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. The residue was purified by silica gel column chromatography (30-50 % EtOAc in Hexane) to afford product 5.1.1c which was used as such for next step (0.09 g, 52.5 % yield). LCMS (m/z): 484.5 [M+18]. 1H NMR (400 MHz, DMSO) δ 11.55 - 1 1.43 (m, 1 H), 7.48 - 7.35 (m, 2H), 7.10 (d, J = 8.5 Hz, 2H), 4.97 (d, J = 9.4 Hz, 1 H), 4.63 (s, 1 H), 4.24 - 4.01 (m, 2H), 3.82 - 3.70 (m, 1 H), 3.51 (s, 1 H), 3.07 (t, J = 7.9 Hz, 3H), 2.78 (d, J = 1 1.9 Hz, 1 H), 2.26 - 2.16 (m, 1 H), 1.89 (dd, J = 9.2, 4.1 Hz, 1 H), 1.64 - 1.49 (m, 6H), 1.25 (d, J =
11.3 Hz, 3H), 1.00 - 0.87 (m, 2H), 0.79 - 0.56 (m, 2H).
Step 4. Synthesis of (R)-3-((S)-3-(4-cyclopropylphenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)propanamide [5.1.1]. 5.1.1g (0.12 g, 0.24 mmol, 1.0 equiv) was dissolved in methanol (1 ml_) and cooled the solution at 0 °C. Methanolic-HCI solution (8% w/w, 2.1 ml_) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness and the crude product was purified by preparative HPLC to afford 5.1.1 as desired diastereomer (0.04 g,
42.4 % yield). LCMS (m/z): 383.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.07 (s, 1 H), 9.30 (s, 1 H), 7.40 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.3 Hz, 2H), 4.60 (s, 1 H), 4.14 (t, J = 8.9 Hz, 1 H), 3.76 (d, J = 8.1 Hz, 1 H), 3.14 (d, J = 43.9 Hz, 3H), 2.77 (d, J = 14.9 Hz, 1 H), 2.19 (dd, J = 14.0, 8.9 Hz, 1 H), 1.90 (s, 1 H), 1.60 (s, 3H), 1.01 - 0.89 (m, 2H), 0.64 (d, J = 4.6 Hz, 2H).
Figure imgf000160_0001
Reagents: Step 1 : lodomethane, NaH (60%), THF, 0°C to room temperature. Step 2: NH4OH, Cul, acetyl acetone, Cs2C03, N,N-dimethylformamide, 100 °C. Step 3: CBZ-CI, NaHC03, Acetone: Water, 0°C to room temperature. Step 4: n-BuLi (23% in Hexane), THF, - 78 °C to room temperature. Step 5: Iodine, triphenylphosphine, imidazole, dichloromethane, room temperature. Step 6: NaH (60%), Ν,Ν-dimethylformamide, 0°C to room temperature. Step 7: LiOH.H20, THF, MeOH, Water, room temperature. Step 8: NH2OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, rt. Step 9: 35.5% aq. HCI, EtOH, room temperature. Step 1. Synthesis of 1-bromo-4-(methoxymethyl)benzene [5.3a]. NaH (60%) (0.51 g, 21.4 mmol, 2.0 equiv) was dissolved in THF (50 mL) and cooled to 0 °C. (4-bromophenyl) methanol (2 g, 10.7 mmol, 1.0 equiv) in THF (5 mL) was added drop wise and the reaction mixture was stirred at room temperature for 1 hour. A solution lodomethane (1.82 g, 12.8 mmol, 1.2 equiv) in THF (5 mL) was added at 0 °C and the reaction mixture was stirred at room temperature for 3 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 afford product 5.3a (1.9 g, 88.4 % yield). 1H NMR (400 MHz, DMSO) δ 7.60 - 7.50 (m, 2H), 7.28 (d, J = 8.4 Hz, 2H), 4.44 - 4.32 (m, 2H), 3.29 (s, 3H).
Step 2. Synthesis of 4-(methoxymethyl) aniline [5.3b]. 5.3a (1.9 g, 9.45 mmol, 1.0 equiv), Cul (0.180 g, 0.94 mmol, 0.1 equiv), acetyl acetone (0.95 g, 9.45 mmol, 1.0 equiv) and Cs2C03 (6.15 g, 18.9 mmol, 2.0 equiv) were suspended in N,N-dimethylformamide (28 ml_) in sealed tube and ammonium hydroxide (2.18 ml_, 5.67 mmol, 6.0 equiv) was added and the reaction mixture was stirred at 100 °C for 5 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 afford a residue. The residue was purified by silica gel column chromatography (0.7 % MeOH in dichloromethane) to afford product 5.3b (1.1 g, 85 % yield). LCMS (m/z): 138.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 6.96 (d, J = 8.1 Hz, 2H), 6.52 (d, J = 8.1 Hz, 2H), 5.06 (s, 2H), 4.18 (s, 2H), 3.19 (s, 3H).
Step 3. Synthesis of benzyl (4-(methoxymethyl)phenyl)carbamate [5.3c]
5.3b (1.1 g, 8.02 mmol, 1.0 equiv) was dissolved in acetone: water (2:1 , 9 ml_) and cooled to 0 °C. NaHC03 (1.42 g, 16.86 mmol, 2.1 equiv) and CBZ-CI (1.78 g, 10.44 mmol, 1.3 equiv) were added and the reaction mixture was stirred at room temperature for 7 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 afford a residue. The residue was purified by silica gel column chromatography (2-5 % EtOAc in Hexane) to afford product 5.3c (1.56 g, 72 % yield). 1H NMR (400 MHz, DMSO) δ 9.80 (s, 1 H), 7.49 - 7.38 (m, 6H), 7.23 (t, J = 6.5 Hz, 2H), 5.15 (s, 2H), 4.32 (s, 2H), 3.25 (s, 3H).
Step 4. Synthesis of (R)-5-(hydroxymethyl)-3-(4-(methoxymethyl)phenyl)oxazolidin-2- one [5.3d]. 5.3c (1.56 g, 5.76 mmol, 1.0 equiv) was dissolved in THF (55 ml_) and cooled to -78 °C. n-BuLi (23% in Hexane) (2.36 ml_, 8.63 mmol, 1.5 equiv) was gradually added and the reaction mixture was stirred at -70 °C for 1 hour. (R)-oxiran-2-ylmethyl butyrate (0.99 g, 6.90 mmol, 1.2 equiv) in THF (5 ml_) was added drop wise and the reaction mixture was allowed to stir at room temperature for 24 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by silica gel chromatography (70 % EtOAc in Hexane) to afford product 5.3d (0.91 g, 67 % yield). LCMS (m/z): 238.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.54 (dd, J = 14.9, 8.6 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 5.33 - 5.15 (m, 1 H), 4.80 - 4.64 (m, 1 H), 4.35 (d, J = 19.6 Hz, 2H), 4.06 (dt, J = 16.3, 8.1 Hz, 1 H), 3.83 (dd, J = 8.8, 6.3 Hz, 1 H), 3.68 (ddd, J = 12.3, 5.5, 3.4 Hz, 1 H), 3.61 - 3.48 (m, 1 H), 3.28 (d, J = 7.5 Hz, 3H).
Step 5. Synthesis of (R)-5-(iodomethyl)-3-(4-(methoxymethyl)phenyl)oxazolidin-2-one
[5.3e]. Triphenylphosphine (1.16 g, 4.44 mmol, 1.3 equiv) was dissolved in dichloromethane (30 ml_), imidazole (0.30 g, 4.44 mmol, 1.3 equiv) was added and the reaction mixture was stirred at room temperature for 5 minutes. Iodine (1.27 g, 4.44 mmol, 1.3 equiv) was added and the reaction mixture was stirred at room temperature for 10 minutes. 5.3d (0.81 g, 3.41 mmol, 1.0 equiv) in dichloromethane (10 ml_) was added drop wise and the reaction mixture was stirred at rt for 24 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by silica gel chromatography (25 % EtOAc in Hexane) to afford product 5.3e (0.83 g, 70 % yield). LCMS (m/z): 348.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.53 (t, J = 12.7 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 4.73 (dd, J = 8.5, 5.1 Hz, 1 H), 4.38 (s, 2H), 4.20 (t, J = 9.0 Hz, 1 H), 3.73 - 3.51 (m, 3H), 3.29 (s, 3H). Step 6. Synthesis of ethyl 3-((S)-3-(4-(methoxymethyl)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoate [5.3f]. Ethyl 2-(methylsulfonyl)propanoate (1.62 g, 8.99 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (15 mL) and cooled to 0 °C. NaH (60%) (0.108 g, 4.49 mmol, 2.0 equiv) was added and the reaction mixture was stirred at room temperature for 2 hours. 5.3d (0.780 g, 2.24 mmol, 1.0 equiv) in N,N- dimethylformamide (6 mL) was added drop wise at 0 °C. The reaction mixture was stirred at room temperature for 24 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude product. The crude product was purified by silica gel column chromatography (28-30 % EtOAc in Hexane) to afford product 5.3f (0.55 g, 61.3 % yield). LCMS (m/z): 400.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.64 - 7.49 (m, 2H), 7.35 (t, J = 5.8 Hz, 2H), 5.00 - 4.72 (m, 1 H), 4.38 (s, 2H), 4.32 - 4.17 (m, 3H), 3.81 (dd, J = 17.1 , 8.3 Hz, 1 H), 3.34 (s, 3H), 3.21 - 3.10 (m, 3H), 2.75 - 2.66 (m, 1 H), 2.41 - 2.24 (m, 1 H), 1.70 - 1.55 (m, 3H), 1.26 (dd, J = 10.0, 4.2 Hz, 3H).
Step 7. Synthesis of 3-((S)-3-(4-(methoxymethyl)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoic acid [5.3g]. 5.3f (0.55 g, 1.37 mmol, 1.0 equiv) was dissolved in THF (10 mL), methanol (2.5 mL) and water (2.5 mL). LiOH.H20 (0.17g, 4.13 mmol, 3.0 equiv) was added and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness; the residue was diluted in 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 a crude product. The crude product was triturated with n-pentane, decanted the solvent and dried to afford product 5.3g (0.36 g, 70.5 % yield). LCMS (m/z): 372.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.52 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 4.80 (d, J = 8.1 Hz, 1 H), 4.38 (s, 2H), 4.22 (t, J = 8.7 Hz, 1 H), 3.87 - 3.78 (m, 1 H), 3.27 (s, 3H), 3.15 (s, 3H), 2.65 (d, J = 12.3 Hz, 1 H), 2.32 (dd, J = 14.7, 8.8 Hz, 1 H), 1.61 (s, 3H).
Step 8. Synthesis of 3-((S)-3-(4-(methoxymethyl)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [5.3h]. 5.3g
(0.3 g, 0.8 mmol, 1.0 equiv) was dissolved in THF (20 mL). N-methyl morpholine (0.40 g, 4.0 mmol, 5.0 equiv), HOBT (0.131 g, 0.97 mmol, 1.2 equiv), 0-(tetrahydro-2H-pyran-2-yl) hydroxylamine (0.19 g, 1.61 mmol, 2.0 equiv) were added and the reaction mixture was stirred at room temperature for 5 minutes. EDC.HCI (0.23 g, 1.21 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by silica gel column chromatography (2 % MeOH in dichloromethane) to afford product 5.3h which was carry forwarded for next step. (0.27 g, 72 % yield). LCMS (m/z): 387.4 [M+18]. 1H NMR (400 MHz, DMSO) δ 11 .48 (d, J = 17.4 Hz, 1 H), 7.58 - 7.48 (m, 2H), 7.34 (d, J = 8.5 Hz, 2H), 4.67 (d, J = 7.9 Hz, 1 H), 4.38 (s, 2H), 4.18 (t, J = 8.5 Hz, 1 H), 3.55 - 3.48 (m, 1 H), 3.46 - 3.40 (m, 1 H), 3.27 (s, 3H), 3.08 (t, J = 8.2 Hz, 3H), 2.84 - 2.72 (m, 1 H), 2.23 (dd, J = 13.3, 7.7 Hz, 1 H), 1.63 (s, 3H), 1.56 - 1.43 (m, 6H).
Step 9. Synthesis of (R)-N-hydroxy-3-((S)-3-(4-(methoxymethyl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide [5.3]. 5.3h (0.274 g, 0.58 mmol, 1.0 equiv) was dissolved in ethanol (10 ml_). 35.5% aq. HCI (0.27 ml_) was added and reaction mixture was stirred at rt for 1 hour. The reaction mixture was diluted with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude product. The crude product was purified by preparative HPLC to afford product 5.3 (0.055 g, 24.4 % yield). LCMS (m/z): 404.3 [M+18]. 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1 H), 9.32 (s, 1 H), 7.52 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 4.63 (d, J = 6.5 Hz, 1 H), 4.40 (d, J = 13.4 Hz, 2H), 4.18 (t, J = 8.7 Hz, 1 H), 3.79 (t, J = 8.2 Hz, 1 H), 3.27 (s, 3H), 3.09 (s, 3H), 2.78 (d, J = 12.3 Hz, 1 H), 2.21 (dd, J = 14.3, 8.8 Hz, 1 H), 1.60 (s, 3H).
Figure imgf000163_0001
Reagents: Step A: ethyl 2-cyanoacetate, KOtBu, EtOH:Water, room temperature. Step 1 : Pd(ll)(Allyl)CI, S-phos, Mesitylene, 140°C. Step 2: LiOH.H20, THF, MeOH, Water, room temperature. Step 3: NH2OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, room temperature. Step 4: 35.5% aq. HCI, EtOH, room temperature.
Step A. Synthesis of potassium 2-cyanoacetate. Ethyl 2-cyanoacetate (1.0 g, 8.9 mmol, 1.0 equiv) was dissolved in EtOH: Water (1 :1 , 10 ml_). Potassium f-butoxide (1.19 g, 10.6 mmol, 1.2 equiv) was added portion wises and the reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated to afford a crude product. The crude product was triturated in diethyl ether, solvent was decanted and dried to afford product which was used as such for next step. (0.78 g, 71.6 % yield).
Step 1. Synthesis of ethyl 3-((S)-3-(4-(cyanomethyl)phenyl)-2-oxooxazolidin-5-yl)-2- methyl -2-(methylsulfonyl)propanoate [5.4a]. 1.1 d (0.7 g, 1.61 mmol, 1.0 equiv), potassium 2-cyanoacetate (0.24 g, 1.93 mmol, 1.2 equiv) were added in mesitylene (6 ml_) and the reaction mixture was degassed for 10 minutes. Pd(ll)(Allyl)CI (0.029 g, 0.08 mmol, 0.5 equiv), S-phos (0.066 g, 0.16 mmol, 0.1 equiv) were added and the reaction mixture was stirred at 140°C for 6 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 afford a residue that was purified by silica gel chromatography (40-50 % EtOAc in Hexane) to afford product 5.4a (0.24 g, 37.7 % yield). LCMS (m/z): 395.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.61 - 7.54 (m, 2H), 7.38 (d, J = 8.7 Hz, 2H), 4.79 (d, J = 8.5 Hz, 1 H), 4.33 - 4.16 (m, 3H), 4.03 (d, J = 9.4 Hz, 2H), 3.87 - 3.76 (m, 1 H), 3.17 (s, 3H), 2.70 (d, J = 15.0 Hz, 1 H), 2.36 (dd, J = 14.8, 8.9 Hz, 1 H), 1.65 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). Step 2. Synthesis of 3-((S)-3-(4-(cyanomethyl)phenyl)-2-oxooxazolidin-5-yl)-2-methyl- 2-(methylsulfonyl)propanoic acid [5.4b]. 5.4a (0.24 g, 0.60 mmol, 1.0 equiv) was dissolved in THF (2 ml_), MeOH (1 ml_). LiOH.H20 (0.076 g, 1.82 mmol, 3.0 equiv) in water (1 ml_) was added and the reaction mixture was stirred at rt for 3 hours. The reaction mixture was concentrated to dryness, the residue was diluted with water, acidified by 1 N HCI aqueous solution to pH 4 to 5 and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 5.4b (0.2 g, 89.7 % yield). 1H NMR (400 MHz, DMSO) δ 14.10 (s, 1 H), 7.56 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 4.80 (d, J = 8.8 Hz, 1 H), 4.22 (t, J = 8.5 Hz, 1 H), 4.02 (s, 2H), 3.85 - 3.79 (m, 1 H), 3.15 (s, 3H), 2.65 (d, J = 15.3 Hz, 1 H), 2.37 - 2.30 (m, 1 H), 1.62 (s, 3H).
Step 3. Synthesis of 3-((S)-3-(4-(cyanomethyl)phenyl)-2-oxooxazolidin-5-yl)-2-methyl- 2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)propanamide [5.4c]. 5.4b (0.15 g, 0.41 mmol, 1.0 equiv) was dissolved in THF (6 ml_). N-methyl morpholine (0.20 g, 2.0 mmol, 5.0 equiv), EDC.HCI (0.1 1 g, 0.61 mmol, 1.5 equiv), HOBT (0.066 g, 0.49 mmol, 1.2 equiv), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.096 g, 0.82 mmol, 2.0 equiv) were added and the reaction mixture was stirred at rt for 12 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by silica gel column chromatography (0-30 % EtOAc in Hexane) to afford product 5.4c which was used for next step. (0.18 g, 70.7 % yield). LCMS (m/z): 464.3 [M-H]. 1H NMR (400 MHz, DMSO) δ 7.55 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 4.67 (s, 1 H), 4.57 (d, J = 4.8 Hz, 1 H), 4.19 (d, J = 8.9 Hz, 1 H), 4.02 (s, 2H), 3.77 (dd, J = 1 1.2, 7.9 Hz, 2H), 3.43 (d, J = 1 1.7 Hz, 2H), 3.08 (t, J = 8.1 Hz, 3H), 2.79 (d, J = 15.4 Hz, 1 H), 2.24 (m, 1 H), 1.63 (s, 3H), 1.50 (m, 6H). Step 4. Synthesis of 3-((S)-3-(4-(cyanomethyl)phenyl)-2-oxooxazolidin-5-yl)-N-hydroxy- 2-methyl-2-(methylsulfonyl)propanamide [5.4]. 5.4c (0.18 g, 0.38 mmol, 1.0 equiv) was dissolved in ethanol (5 mL), 35.5% aq. HCI (0.27 mL) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford crude product 5.4. The crude product was purified by preparative HPLC purification to afford 5.4 as desired diastereomer (0.05 g, 33.9 % yield). LCMS (m/z): 382.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.32 (s, 1 H), 7.56 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 4.64 (d, J = 7.7 Hz, 1 H), 4.18 (t, J = 8.8 Hz, 1 H), 4.02 (s, 2H), 3.85 - 3.74 (m, 1 H), 3.09 (s, 3H), 2.78 (d, J = 13.8 Hz, 1 H), 2.22 (dd, J = 14.1 , 9.0 Hz, 1 H), 1.61 (s, 3H).
Figure imgf000165_0001
Reagents: Step 1 : Cone. H2S04, MeOH, room temperature. Step 2: LiBH4 (2M in THF), THF, 0°C to room temperature. Step 3: NaH (60%), iodomethane, N,N-dimethylformamide, 0°C to room temperature. Step 4: Liq. NH3, Cul, acetyl acetone, Cs2C03, N,N- dimethylformamide, 100°C. Step 5: CBZ-CI, NaHC03, Acetone: Water, 0°C to room temperature. Step 6: n-BuLi (2.5M in hexane), THF, -78°C to room temperature. Step 7: Iodine, triphenylphosphine, imidazole, THF, room temperature. Step 8: NaH (60%), N,N- dimethylformamide, 0°C to room temperature. Step 9: LiOH.H20, THF, Water, room temperature. Step 10: NH2OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, room temperature. Step 1 1 : 35.5% aq. HCI, EtOH, room temperature. Step 1. Synthesis of methyl 2-(4-bromophenyl)acetate [5.5a]. 2-(4-Bromophenyl) acetic acid (10.0 g, 46.5 mmol, 1.0 equiv) was dissolved in methanol (30 ml_). Concentrated H2S04 (7 ml_) was added drop wise at room temperature and the reaction mixture was stirred at room temperature for 2 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 afford product 5.5a (10 g, 94 % yield). 1H NMR (400 MHz, DMSO) δ 7.52 (d, J = 8.4 Hz, 2H), 7.26 (t, J = 14.0 Hz, 2H), 3.69 (s, 2H), 3.62 (s, 3H).
Step 2. Synthesis of 2-(4-bromophenyl)ethan-1-ol [5.5b]. 5.5a (6 g, 26.2 mmol, 1.0 equiv) was dissolved in THF (100 mL) and cooled to 0 °C. LiBH4 (2M in THF) (1.41 g, 52.4 mmol, 2.0 equiv) was added drop wise at 0 °C and the reaction mixture was stirred at room temperature for 2 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 afford product 5.5b (4.5 g, 85.5 % yield). LCMS (m/z): 204.8 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.56 - 7.35 (m, 2H), 7.27 - 7.07 (m, 2H), 4.67 (t, J = 5.2 Hz, 1 H), 3.58 (td, J = 6.8, 5.4 Hz, 2H), 2.69 (t, J = 6.9 Hz, 2H).
Step 3. Synthesis of 1-bromo-4-(2-methoxyethyl)benzene [5.5c]. 5.5b (4.5 g, 22.4 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (50 ml_)and cooled to 0 °C. NaH (60%) (2.23 g, 55.9 mmol, 2.5 equiv) was added in portion wise and the reaction mixture was stirred at rt for 1 hour. Cooled the reaction mixture to 0°C, iodomethane (4.76 g, 33.4 mmol, 1.5 equiv) was added dropwise and the reaction mixture was stirred at rt for 24 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 afford a residue. The residue was purified by silica gel column chromatography (5 % EtOAc in Hexane) to afford product 5.5c (4 g, 83 % yield). 1H NMR (400 MHz, DMSO) δ 7.50 - 7.44 (m, 2H), 7.25 - 7.16 (m, 2H), 3.51 (t, J = 6.7 Hz, 2H), 3.23 (d, J = 4.4 Hz, 3H), 2.82 - 2.75 (m, 2H).
Step 4. Synthesis of 4-(2-methoxyethyl)aniline [5.5d]. 5.5c (4.0 g, 18.6 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (60 mL) and Cul (0.35 g, 18.6 mmol, 0.1 equiv), acetyl acetone (1.86 g, 18.6 mmol, 1.0 equiv), Cs2C03 (12.09 g, 37.2 mmol, 2.0 equiv), ammonium hydroxide (3.9 g, 1 1 1.6 mmol, 6.0 equiv) were added in sealed tube and the reaction was stirred at 100 °C for 24 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude product. The crude product was purified by silica gel column chromatography (25 % EtOAc in Hexane) to afford product 5.5d (2 g, 71.4 % yield). LCMS (m/z): 152.1 [M+H]. 1H NMR (400 MHz, DMSO) δ 6.86 (d, J = 8.1 Hz, 2H), 6.47 (d, J = 8.0 Hz, 2H), 4.83 (s, 2H), 3.42 (q, J = 7.2 Hz, 2H), 3.22 (s, 3H), 2.61 (t, J = 7.1 Hz, 2H). Step 5. Synthesis of benzyl (4-(2-methoxyethyl)phenyl)carbamate [5.5e]. 5.5d (2.0 g, 13.2 mmol, 1.0 equiv) was dissolved in acetone:water (2:1 , 45 mL), NaHC03 (2.2 g, 26.5 mmol, 2.0 equiv) was added and cooled the reaction mixture to 0-5 °C. CBZ-CI (3.38 g, 19.8 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 4 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 afford a residue. The residue was purified by silica gel column chromatography (10 % EtOAc in Hexane) to afford product 5.5e (2 g, 53 % yield). LCMS (m/z): 286 [M+H]. 1H NMR (400 MHz, DMSO) δ 9.70 (s, 1 H), 7.48 - 7.30 (m, 7H), 7.14 (t, J = 7.8 Hz, 2H), 5.22 - 5.07 (m, 2H), 3.52 - 3.44 (m, 2H), 3.23 (d, J = 3.3 Hz, 3H), 2.73 (t, J = 6.9 Hz, 2H).
Step 6. Synthesis of (R)-5-(hydroxymethyl)-3-(4-(2-methoxyethyl)phenyl)oxazolidin-2- one [5.5f]. 5.5e (1.2 g, 4.21 mmol, 1.0 equiv) was dissolved in THF (35 mL) and cooled to - 78 °C. n-BuLi (2.5M in hexane) (0.40 g, 6.31 mmol, 1.5 equiv) was gradually added and the reaction mixture was stirred at -78 °C for 2.5 hours. (R)-oxiran-2-ylmethyl butyrate (0.60 g, 4.21 mmol, 1.0 equiv) was added drop-wise and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by silica gel column chromatography (50 % EtOAc in Hexane) to afford product 5.5f (0.8 g, 79.2 % yield). LCMS (m/z): 252.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.48 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 5.22 (t, J = 5.7 Hz, 1 H), 4.75 - 4.63 (m, 1 H), 4.06 (t, J = 9.0 Hz, 1 H), 3.80 (dt, J = 13.7, 6.8 Hz, 1 H), 3.73 - 3.63 (m, 1 H), 3.62 - 3.55 (m, 1 H), 3.52 (dd, J = 13.4, 6.5 Hz, 2H), 3.23 (s, 3H), 2.78 (t, J = 6.8 Hz, 2H).
Step 7. Synthesis of (R)-5-(iodomethyl)-3-(4-(2-methoxyethyl)phenyl)oxazolidin-2-one
[5.5g]. Triphenylphosphine (1.08 g, 4.14 mmol, 1.3 equiv) was dissolved in THF (25 mL), imidazole (0.28 g, 4.14 mmol, 1.3 equiv) and iodine (1.05 g, 4.14 mmol, 1.3 equiv) were added and the reaction mixture was stirred at room temperature for 10 minutes. 5.5f (0.8 g, 3.18 mmol, 1.0 equiv) in THF (5 mL) was added drop wise and the reaction mixture was stirred at room temperature for 4 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 afford a residue. The residue was purified by silica gel column chromatography (10 % EtOAc in Hexane) to afford product 5.5g (0.6 g, 52.2 % yield). LCMS (m/z): 362.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.47 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 4.72 (td, J = 10.6, 5.0 Hz, 1 H), 4.18 (t, J = 9.1 Hz, 1 H), 3.68 - 3.54 (m, 3H), 3.51 (t, J = 6.8 Hz, 2H), 3.23 (s, 3H), 2.78 (t, J = 6.8 Hz, 2H).
Step 8. Synthesis of ethyl 3-((S)-3-(4-(2-methoxyethyl)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoate [5.5h]. Ethyl 2-(methylsulfonyl) propanoate (1.2 g, 6.64 mmol, 4.0 equiv) was dissolved in N,N-dimethylformamide (15 mL) and cooled to 0-5 °C. NaH (60%) (0.13 g, 3.32 mmol, 2.0 equiv) was added in portion wise and the reaction mixture was stirred at room temperature for 2 hours. A solution of 5.5g (0.6 g, 1.66 mmol, 1.0 equiv) in DMF (5 mL) was added drop-wise at 0-5°C. The reaction mixture was stirred at room temperature for 24 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 afford a residue. The residue was purified by silica gel column chromatography (40 % EtOAc in Hexane) to afford product 5.5h (0.3 g, 38.2 % yield). LCMS (m/z): 414.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.56 - 7.40 (m, 2H), 7.30 - 7.17 (m, 2H), 4.85 - 4.54 (m, 1 H), 4.34 - 4.09 (m, 3H), 3.88 (ddd, J = 26.2, 16.2, 8.3 Hz, 1 H), 3.76 - 3.46 (m, 3H), 3.21 (d, J = 17.2 Hz, 2H), 3.19 - 3.07 (m, 3H), 2.83 - 2.72 (m, 1 H), 2.34 (dd, J = 14.8, 8.8 Hz, 1 H), 1.71 - 1.51 (m, 3H), 1.26 - 1.20 (m, 3H).
Step 9. Synthesis of 3-((S)-3-(4-(2-methoxyethyl)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoic acid [5.5i]. 5.5h (0.3 g, 0.73 mmol, 1.0 equiv) was dissolved in THF (12 mL) and water (4 mL). LiOH.H20 (0.091g, 2.18 mmol, 3.0 equiv) was added and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water, acidified by 1.0 N HCI aqueous solution to the pH 3 to 4 and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 5.5i (0.2 g, 71.7 % yield). LCMS (m/z): 386.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 14.02 (s, 1 H), 7.55 - 7.38 (m, 2H), 7.30 - 7.21 (m, 2H), 4.78 (ddd, J = 16.5, 8.6, 2.8 Hz, 1 H), 4.24 - 4.15 (m, 1 H), 3.79 (dt, J = 12.0, 6.0 Hz, 1 H), 3.56 - 3.48 (m, 2H), 3.23 (s, 3H), 3.16 - 3.1 1 (m, 3H), 2.78 (t, J = 6.8 Hz, 2H), 2.65 (dd, J = 14.7, 2.6 Hz, 1 H), 2.34 - 2.27 (m, 1 H), 1.63 - 1.52 (m, 3H).
Step 10. Synthesis of 3-((S)-3-(4-(2-methoxyethyl)phenyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [5.5j]
5.5i (0.18 g, 0.47 mmol, 1.0 equiv) was dissolved in THF (10 mL). N-methyl morpholine (024 g, 2.33 mmol, 5.0 equiv) was added to afford a clear solution. EDC.HCI (0.12 g, 0.84 mmol, 1.8 equiv), HOBT (0.094 g, 0.70 mmol, 1.5 equiv), 0-(tetrahydro-2H- pyran-2-yl) hydroxylamine (0.109 g, 0.93 mmol, 2.0 equiv) were added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by silica gel column chromatography (2 % MeOH in dichloromethane) to afford product 5.5j which was carry forwarded for next step. (0.18 g, 72 % yield). LCMS (m/z): 483.5 [M-H]. 1H NMR (400 MHz, DMSO) δ 7.44 (dd, J = 8.1 , 5.8 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 4.66 (d, J = 8.2 Hz, 1 H), 4.57 (d, J = 4.9 Hz, 2H), 4.20 - 4.13 (m, 1 H), 3.77 (m, 2H), 3.51 (t, J = 6.8 Hz, 3H), 3.46 - 3.38 (m, 3H), 3.23 (s, 3H), 3.17 (d, J = 5.2 Hz, 2H), 3.07 (t, J = 8.0 Hz, 3H), 2.78 (t, J = 6.8 Hz, 3H), 2.22 (dd, J = 13.8, 10.0 Hz, 1 H), 1.68 - 1.59 (m, 9H). Step 11. Synthesis of (R)-N-hydroxy-3-((S)-3-(4-(2-methoxyethyl)phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide [5.5]. 5.5j (0.17 g, 0.35 mmol, 1.0 equiv) was dissolved in ethanol (10 mL). 35.5% aq. HCI (0.3 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and neutralized by saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by preparative HPLC purification to afford 5.5 (0.063 g, 42.6 % yield). LCMS (m/z): 401.5 [M+H]. 1H NMR (400 MHz, DMSO) δ 9.43 (s, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 4.63 (dd, J = 13.8, 7.9 Hz, 1 H), 4.15 (t, J = 8.8 Hz, 1 H), 3.83 - 3.72 (m, 1 H), 3.51 (t, J = 6.8 Hz, 2H), 3.23 (d, J = 3.9 Hz, 3H), 3.08 (s, 3H), 2.81 - 2.72 (m, 3H), 2.19 (dd, J = 14.3, 8.8 Hz, 1 H), 1.59 (s, 3H).
V.6. Synthesis of compound 5.6
Step 1. Synthesis of (3-methoxypropyl)triphenylphosphonium bromide [5.6a]. 1-
Bromo-3-methoxypropane (3.5 g, 22.87 mmol, 1.0 equiv) was dissolved in toluene (7 mL). Triphenylphosphine (6.3 g, 24.01 mmol, 1.05 equiv) was added and the reaction mixture was stirred at 150 °C for 24 hours. The reaction mixture was diluted with n-hexane and the precipitated solid was filtered to afford the desired product 5.6a (9.2 g, 96.9 % yield). 1H NMR (400 MHz, DMSO) δ 7.94 - 7.88 (m, 3H), 7.85 - 7.76 (m, 1 1 H), 3.58 (ddd, J = 14.3, 12.6, 7.1 Hz, 2H), 3.44 (t, J = 5.9 Hz, 2H), 3.20 (d, J = 12.7 Hz, 3H), 1.83 - 1.70 (m, 2H). Step 2. Synthesis of (E)-1-bromo-4-(4-methoxybut-1-en-1-yl) benzene [5.6b]. 5.6a (8.7 g, 20.9 mmol, 1.0 equiv) was dissolved in THF (80 mL) and cooled to -20 °C. LiHMDS (1 M in THF) (21 mL, 20.9 mmol, 1.0 equiv) was added and the reaction mixture was stirred at -20 for 1 hour. 4-Bromobenzaldehyde (3.1 g, 16.75 mmol, 0.8 equiv) in THF (10 mL) was added and the reaction mixture was stirred at rt for 24 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (0-3 % EtOAc/Hexane) to afford the desired product 5.6b (1 g, 25 % yield). 1H NMR (400 MHz, CDCI3) δ 7.46 - 7.39 (m, 2H), 7.23 (d, J = 8.4 Hz, 2H), 6.42 (d, J = 15.9 Hz, 1 H), 6.25 (dt, J = 15.9, 6.9 Hz, 1 H), 3.59 - 3.47 (m, 2H), 3.46 - 3.32 (m, 3H), 2.50 (qd, J = 6.7, 1.3 Hz, 2H). Step 3. Synthesis of 1-bromo-4-(2-(2-methoxyethyl)cyclopropyl)benzene (5.6c]. 5.6b (0.65 g, 2.69 mmol, 1.0 equiv) was dissolved in toluene (13 mL) and cooled to 0 °C. Et2Zn (1 M in Hexane) (13.48 g, 13.48 mmol, 5.0 equiv), Diiodomethane (7.2 g, 26.9 mmol, 10.0 equiv) was added dropwise and the reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was stirred at 50 °C for 24 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (0-3 % EtOAc in Hexane) to afford the desired product 5.6c (0.55 g, 79.9 % yield). 1H NMR (400 MHz, CDCI3) δ 7.40 - 7.31 (m, 2H), 7.03 - 6.71 (m, 2H), 3.51 (dt, J = 1 1.3, 6.6 Hz, 2H), 3.38 (d, J = 9.3 Hz, 3H), 1.77 - 1.50 (m, 3H), 1.15 - 1.04 (m, 1 H), 0.93 - 0.81 (m, 2H).
Step 4. Synthesis of (2R)-N-hydroxy-3-((5S)-3-(4-(2-(2-methoxyethyl)cyclopropyl) phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanamide [5.6]. 5.6c (0.27 g, 0.51 mmol, 1.0 equiv) was dissolved in dichloromethane (5 ml_). HCI (in IPA) (0.25 ml_) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was triturated with n- pentane, the solvent was decanted to afford the desired product 5.6 (0.185 g, 81.9 % yield). LCMS (m/z): 441.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.07 (s, 1 H), 9.29 (s, 1 H), 7.38 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 4.61 (d, J = 6.0 Hz, 1 H), 4.14 (t, J = 8.6 Hz, 1 H), 3.75 (t, J = 8.0 Hz, 1 H), 3.41 (t, J = 6.6 Hz, 2H), 3.23 (s, 3H), 3.08 (s, 3H), 2.77 (d, J = 12.0 Hz, 1 H), 2.19 (dd, J = 14.4, 8.7 Hz, 1 H), 1.68 (d, J = 4.3 Hz, 1 H), 1.57 (dd, J = 12.9, 6.2 Hz, 5H), 0.99 (s, 1 H), 0.86 (d, J = 4.9 Hz, 1 H), 0.78 (dd, J = 8.8, 5.2 Hz, 1 H).
V.7. Synthesis of compound 5.7
5.7 was synthesized by the process of example 2.4 from 1-bromo-4-propylbenzene. LCMS (m/z): 385.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 9.31 (s, 1 H), 7.43 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 4.62 (dd, J = 13.7, 7.7 Hz, 1 H), 4.16 (t, J = 8.8 Hz, 1 H), 3.82 - 3.72 (m, 1 H), 3.09 (s, 3H), 2.78 (dd, J = 14.4, 2.5 Hz, 1 H), 2.57-2.51 (m, 2H), 2.20 (dd, J = 14.4, 8.9 Hz, 1 H), 1.64-1.49 (m, 5H), 0.88 (t, J = 7.3 Hz, 3H).
V.8. Synthesis of compound 5.8
Step 1. Synthesis of ethyl (R)-3-((S)-3-(4-(2-(3-ethoxycyclobutyl) ethyl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [5.8a]. (R)-ethyl 3-((S)-3-(4- ((3-ethoxycyclobutyl)ethynyl)phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2- (methylsulfonyl)propanoate (0.35 g, 0.73 mmol, 1.0 equiv) was dissolved in methanol (15 ml_). Pd-catalyst (10% on carbon) (0.05 g) was added and H2 (gas) was purged at rt for 12 hours. The reaction mixture was filtered through celite bed and the filtrate was concentrated to afford a crude residue. The crude residue was purified by silica gel chromatography (50 % EtOAc in Hexane) to afford the desired product 5.8a (0.42 g, 92.7 % yield). LCMS (m/z): 482.5 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.47 - 7.39 (m, 2H), 7.20 (d, J = 8.4 Hz, 2H), 4.77 (dd, J = 14.0, 8.1 Hz, 1 H), 4.26 (q, J = 7.0 Hz, 2H), 4.18 (t, J = 8.8 Hz, 1 H), 3.84 - 3.76 (m, 1 H), 3.77 - 3.57 (m, 1 H), 3.29 (q, J = 7.0 Hz, 2H), 3.17 (s, 3H), 2.69 (dd, J = 14.7, 2.4 Hz, 1 H), 2.46 (d, J = 7.5 Hz, 2H), 2.31 (ddd, J = 15.8, 12.1 , 7.8 Hz, 3H), 1.97 - 1.90 (m, 1 H), 1.73 -1.56 (m, 6H), 1.45-1.38 (m, 1 H), 1.26 (t, J = 7.1 Hz, 3H), 1.08 (td, J = 7.0, 5.1 Hz, 3H). Step 2. Synthesis of (R)-3-((S)-3-(4-(2-(3-ethoxycyclobutyl)ethyl)phenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide [5.8 & 5.10]
5.8 & 5.10 were synthesized from 5.8a using the process of example 1.2. Isomer I: LCMS (m/z): 469.5 [M+H]. 1H NMR (400 MHz, DMSO) δ 9.47 - 9.10 (m, 1 H), 7.42 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 4.63 (d, J = 7.8 Hz, 1 H), 4.15 (t, J = 8.6 Hz, 1 H), 3.81 - 3.67 (m, 2H), 3.29 (q, J = 7.0 Hz, 2H), 3.08 (s, 3H), 2.77 (d, J = 14.4 Hz, 1 H), 2.47 (s, 2H), 2.29 (d, J = 6.2 Hz, 2H), 2.18 (dd, J = 14.5, 8.7 Hz, 1 H), 1.72 - 1.62 (m, 3H), 1.59 (s, 3H), 1.41 (d, J = 8.2 Hz, 2H), 1.07 (t, J = 7.0 Hz, 3H). Isomer II: (0.033 g, 9.7 % yield). LCMS (m/z): 469.5 [M+H]. 1H NMR (400 MHz, DMSO) δ 9.33 (s, 1 H), 7.42 (d, J = 7.1 Hz, 2H), 7.21 (d, J = 7.1 Hz, 2H), 4.62 (m, 1 H), 4.15 (m, 1 H), 4.01 (s, 1 H), 3.76 (m, 1 H), 3.29 (d, J = 6.5 Hz, 2H), 3.09 (s, 3H), 2.91 (m, 2H), 2.77 (d, J = 14.3 Hz, 1 H), 2.20 (m, 1 H), 2.08 (m, 1 H), 1.92 (m, 4H), 1.66 (m, 2H), 1.60 (s, 3H), 1.08 (m, 3H).
V.9. Synthesis of compound 5.9
Step 1. Synthesis of (E)-1-bromo-4-(but-2-en-2-yl) benzene [5.9a]. Ethyl phosphonium bromide (3.73 g, 10.0 mmol, 2.0 equiv) was suspended in THF (20 mL) and cooled to -5 °C. n-BuLi (2.5 M in hexane) (4 mL, 10.0 mmol, 2.0 equiv) was gradually added and the reaction mixture was stirred at -5 °C for 30 minutes. 1-(4-bromophenyl) ethan-1-one (1 g, 5.1 mmol,
I .0 equiv) in THF (8 mL) was added drop wise and the reaction mixture was stirred at rt for 24 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (100 % n-Hexane) to afford the desired product 5.9a as mixture of E:Z (-66:33 by NMR) (0.82 g, 76.9 % yield). 1H NMR (400 MHz, CDCI3) δ 7.50 - 7.41 (m, 2H), 7.28 - 7.22 (m, 1.5H), 7.12 - 7.07 (m, 0.5H), 5.93 - 5.83 (m, 0.7H), 5.64 - 5.56 (m, 0.3H), 2.02 (dd, J = 2.4, 1.2 Hz, 3H), 1.81 (dd, J = 6.9, 1.0 Hz, 2H), 1.62 - 1.59 (m, 1 H).
Step 2. Synthesis of (R)-3-((S)-3-(4-((E)-but-2-en-2-yl) phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl) propanamide [5.9]. 5.9 was synthesized from 5.9a using the process of example 2.4. LCMS (m/z): 414.3 [M+18]. 1H NMR (400 MHz, DMSO) δ
I I .08 (s, 1 H), 9.31 (s, 1 H), 7.48 (d, J = 9.0 Hz, 2H), 7.42 (d, J = 8.9 Hz, 2H), 5.94 - 5.83 (m, 1 H), 4.63 (d, J = 8.2 Hz, 1 H), 4.18 (t, J = 8.8 Hz, 1 H), 3.83 - 3.75 (m, 1 H), 3.09 (s, 3H), 2.78 (d, J = 12.7 Hz, 1 H), 2.20 (dd, J = 14.4, 8.9 Hz, 1 H), 1.97 (s, 3H), 1.77 (d, J = 6.8 Hz, 3H), 1.60 (s, 3H). V.11. Synthesis of compound 5.11
5.11 was synthesized from (E)-1-bromo-4-(prop-1-en-1-yl)benzene using the process of example 2.4. LCMS (m/z): 383.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 9.30 (s, 1 H), 7.50 (dd, J = 24.2, 8.6 Hz, 2H), 7.37 (dd, J = 21.3, 8.7 Hz, 2H), 6.39 (d, J = 16.3 Hz, 1 H), 6.25 (dd, J = 15.8, 6.5 Hz, 1 H), 4.63 (d, J = 6.2 Hz, 1 H), 4.17 (t, J = 8.8 Hz, 1 H), 3.83 - 3.73 (m, 1 H), 3.09 (s, 3H), 2.77 (d, J = 14.4 Hz, 1 H), 2.20 (dd, J = 14.2, 8.7 Hz, 1 H), 1.85 (t, J = 7.8 Hz, 3H), 1.59 (s, 3H).
V.13. Synthesis of compound 5.13
3.1.2 (0.1 g, 0.2 mmol, 1.0 equiv) was dissolved in methanol (10 ml_). Pd/C (0.02 g) was added to the solution and the reaction mixture was stirred at room temperature for 2 hours under H2 (1 atm) pressure. The reaction mixture was filtered through celite bed under nitrogen atmosphere and the filtrate was concentrated to afford a crude product. The crude product was purified by preparative HPLC purification to afford the desired product 5.13 (0.047 g, 34 % yield). LCMS (m/z): 41 1.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 9.28 (s, 1 H), 7.43 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 4.62 (d, J = 7.7 Hz, 1 H), 4.15 (t, J = 8.7 Hz, 1 H), 3.80 - 3.73 (m, 1 H), 3.09 (s, 3H), 2.77 (d, J = 12.4 Hz, 1 H), 2.67 - 2.59 (m, 2H), 2.19 (dd, J = 14.1 , 8.8 Hz, 1 H), 1.60 (s, 3H), 1.45 (dd, J = 14.7, 7.3 Hz, 2H), 0.67 (s, 1 H), 0.39 (d, J = 7.7 Hz, 2H), 0.04 (d, J = 4.4 Hz, 2H).
V.14. Synthesis of compound 5.14
Step 1. Synthesis of ethyl (R)-3-((S)-3-(4-(3-hydroxyprop-1-yn-1-yl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [5.14a]. 1.1 d (2 g, 4.6 mmol, 1.0 equiv) was suspended into diethyl amine (30 ml_) and N, N-dimethylformamide (6 ml_). Cul (0.087 g, 0.46 mmol, 0.1 equiv), triphenylphosphine (0.24 g, 0.92 mmol, 0.2 equiv) were added and the reaction mixture was degassed for 15 minutes. Prop-2-yn-1-ol (0.39 g, 6.91 mmol, 1.5 equiv), PdCI2(pph3)2 (0.16 g, 0.23 mmol, 0.05 equiv) were added and the reaction mixture was stirred at 100 °C for 24 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 afford a crude residue. The crude residue was purified by silica gel column chromatography (62-65 % EtOAc/Hexane) to afford the desired product 5.14a (1.2 g, 64.9 % yield). LCMS (m/z): 410.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.55 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 5.34 (t, J = 6.0 Hz, 1 H), 4.79 (d, J = 7.5 Hz, 1 H), 4.25 (ddd, J = 17.5, 13.6, 7.4 Hz, 5H), 3.88 - 3.78 (m, 1 H), 3.17 (s, 3H), 2.68 (d, J = 12.9 Hz, 1 H), 2.40 - 2.34 (m, 1 H), 1.64 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). Step 2. Synthesis of ethyl (R)-3-((S)-3-(4-(3-hydroxypropyl) phenyl)-2-oxooxazolidin-5- yl)-2-methyl-2-(methylsulfonyl) propanoate [5.14b]. 5.14a (1.2 g, 2.98 mmol, 1.0 equiv) was dissolved in methanol (40 ml_). Pd/C (50% moisture) (0.48 g) was added and the reaction mixture was stirred at room temperature for 3 hours under H2 atmosphere. The reaction mixture was filtered through celite bed under N2 atmosphere, washed with methanol and the filtrate was concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (75-80 % EtOAc/Hexane) to afford the desired product 5.14b (0.84 g, 68.2 % yield). LCMS (m/z): 414.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.43 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 4.77 (d, J = 6.2 Hz, 1 H), 4.47 (t, J = 5.1 Hz, 1 H), 4.26 (dd, J = 14.0, 6.9 Hz, 2H), 4.18 (t, J = 8.8 Hz, 1 H), 3.84 - 3.77 (m, 1 H), 3.40 (dd, J = 11.7, 6.3 Hz, 2H), 3.17 (d, J = 5.1 Hz, 3H), 2.69 (d, J = 14.9 Hz, 1 H), 2.62 - 2.54 (m, 2H), 2.38 - 2.32 (m, 1 H), 1.75 - 1.59 (m, 5H), 1.26 (t, J = 7.1 Hz, 3H).
Step 3. Synthesis of ethyl (R)-3-((S)-3-(4-(3-fluoropropyl) phenyl)-2-oxooxazolidin-5-yl)- 2-methyl-2-(methylsulfonyl) propanoate [5.14c]. 5.14b (0.32 g, 0.77 mmol, 1.0 equiv) was suspended in dichloromethane (30 ml_) and cooled to -78 °C. DAST (0.25 g, 1.55 mmol, 2.0 equiv) was added drop wise and the reaction mixture was stirred at -78 °C for 10 minutes. The reaction mixture was stirred at rt for 2 hours. The reaction mixture was quenched with water, basified with solid sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (35-40 % EtOAc/Hexane) to afford the desired product 5.14c (0.23 g, 71.7 % yield). LCMS (m/z): 416.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.46 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 4.83 - 4.73 (m, 1 H), 4.50 (t, J = 6.0 Hz, 1 H), 4.38 (t, J = 6.0 Hz, 1 H), 4.31 - 4.24 (m, 2H), 4.19 (t, J = 8.8 Hz, 1 H), 3.86 - 3.76 (m, 1 H), 3.17 (s, 3H), 2.69 (dd, J = 16.4, 6.1 Hz, 3H), 2.35 (dd, J = 14.8, 8.9 Hz, 1 H), 2.03 - 1.87 (m, 2H), 1.65 (s, 3H), 1.29 - 1.22 (m, 3H). Step 4. Synthesis of (R)-3-((S)-3-(4-(3-fluoropropyl) phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl) propanamide [5.14]
5.14 was synthesized from 5.14c using the process of example 1.2. LCMS (m/z): 403.1 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.32 (s, 1 H), 7.45 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 4.62 (d, J = 6.1 Hz, 1 H), 4.50 (t, J = 6.0 Hz, 1 H), 4.38 (t, J = 6.0 Hz, 1 H), 4.16 (t, J = 8.7 Hz, 1 H), 3.81 - 3.72 (m, 1 H), 3.09 (s, 3H), 2.78 (d, J = 14.4 Hz, 1 H), 2.69 - 2.62 (m, 2H), 2.20 (dd, J = 14.4, 8.9 Hz, 1 H), 2.00 - 1.89 (m, 2H), 1.60 (s, 3H).
V.15. Synthesis of compound 5.15
Step 1. Synthesis of 1-bromo-4-(2, 2-difluoropropyl) benzene [5.15a]. 1-(4- Bromophenyl) propan-2-one (1 g, 4.6 mmol, 1.0 equiv) was dissolved in dichloromethane (17 mL) and cooled to -70 °C. DAST (3.78 g, 23.46 mmol, 5.0 equiv) was added drop wise and the reaction mixture was stirred at rt for 24 hours. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue, which was purified by silica gel column chromatography (0-5 % EtOAc/Hexane) to afford the desired product 5.15a (0.8 g, 72.5 % yield). 1H NMR (400 MHz, DMSO) δ 7.59 - 7.52 (m, 2H), 7.26 (d, J = 8.2 Hz, 2H), 3.22 (t, J = 16.4 Hz, 2H), 1.56 (t, J = 18.8 Hz, 3H). Step 2. Synthesis of (R)-3-((S)-3-(4-(2, 2-difluoropropyl) phenyl)-2-oxooxazolidin-5-yl)- N-hydroxy-2-methyl-2-(methylsulfonyl) propanamide [5.15]. 5.15 was synthesized from 5.15a using the process of example 2.4. LCMS (m/z): 421.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 10.93 (s, 1 H), 9.30 (s, 1 H), 7.50 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 4.63 (d, J = 6.0 Hz, 1 H), 4.18 (t, J = 8.7 Hz, 1 H), 3.83 - 3.75 (m, 1 H), 3.20 (t, J = 16.3 Hz, 2H), 3.09 (s, 3H), 2.78 (d, J = 14.4 Hz, 1 H), 2.20 (dd, J = 14.4, 8.9 Hz, 1 H), 1.72 - 1.44 (m, 6H).
V.16. Synthesis of compound 5.16
Step 1. Synthesis of (4-bromophenyl) (2, 2, 2-trifluoroethyl) sulfane [5.16a]
4-Bromobenzenethiol (0.5 g, 2.64 mmol, 1.0 equiv) was dissolved in N, N- dimethylformamide (5 mL). Cs2C03 (1.2 g, 3.96 mmol, 1.5 equiv), 2-Bromo-1 , 1 , 1- trifluoroethane (0.28 mL, 3.17 mmol, 1.2 equiv) were added and the reaction mixture was stirred at room temperature for 24 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 afford the desired product 5.16a (0.065 g, 90 % yield). The product was used in the next step with no further purification. LCMS (m/z): 289.9 [M+H]. 1H NMR (400 MHz, CDCI3) δ 7.52 - 7.44 (m, 1 H), 7.41 - 7.35 (m, 1 H), 3.44 (q, J = 9.6 Hz, 1 H). Step 2. Synthesis of (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-((2, 2, 2-trifluoroethyl) thio) phenyl) oxazolidin-5-yl) propanamide [5.16]
5.16 was synthesized from 5.16a using the process of example 2.4. LCMS (m/z): 457.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 9.31 (s, 1 H), 7.55 (d, J = 3.6 Hz, 4H), 4.63 (s, 1 H), 4.18 (t, J = 8.5 Hz, 1 H), 3.95 (dd, J = 20.3, 10.3 Hz, 2H), 3.80 (d, J = 7.7 Hz, 1 H), 3.08 (s, 3H), 2.78 (d, J = 14.3 Hz, 1 H), 2.25 - 2.18 (m, 1 H), 1.60 (s, 3H).
V.17. Synthesis of compound 5.17
Step 1. Synthesis of ethyl (R)-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(3- oxopropyl) phenyl) oxazolidin-5-yl) propanoate [5.17a]. (R)-ethyl 3-((S)-3-(4-(3- hydroxypropyl)phenyl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanoate (0.32 g, 0.77 mmol, 1.0 equiv) was added in dichloromethane (60 mL) and cooled to 0 °C. Dess- Martin periodinane (0.49 g, 1.16 mmol, 1.5 equiv) was added in portions and the reaction mixture was stirred at rt for 4 hours. The reaction mixture was added to mixture of saturated aqueous sodium bicarbonate solution, sodium thiosulphate solution and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated to afford the desired product 5.17a (0.29 g, 81.6 % yield). LCMS (m/z): 412.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 9.71 (s, 1 H), 7.44 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 4.78 (m, 1 H), 4.26 (m, 2H), 4.18 (m, 1 H), 3.80 (m, 1 H), 3.17 (s, 3H), 2.84 (d, J = 6.4 Hz, 2H), 2.77 (d, J = 7.0 Hz, 2H), 2.68 (m, 1 H), 2.33 (s, 1 H), 1.65 (s, 3H), 1.29 - 1.24 (m, 3H).
Step 2. Synthesis of ethyl (R)-3-((S)-3-(4-(3, 3-difluoropropyl) phenyl)-2-oxooxazolidin- 5-yl)-2-methyl-2-(methylsulfonyl) propanoate [5.17b]. 5.17a (0.28 g, 0.69 mmol, 1.0 equiv) was dissolved in dichloromethane (40 ml_) and cooled to -78 °C. DAST (0.56 g, 3.47 mmol, 5.0 equiv) was added drop wise and the reaction mixture was stirred at -78 °C for 10 minutes. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water, basified with solid sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel chromatography (40-45 % EtOAc/Hexane) to afford the product 5.17b (0.22 g, 73 % yield). LCMS (m/z): 434.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.46 (d, J = 8.6 Hz, 2H), 7.26 (dd, J = 19.3, 8.2 Hz, 2H), 6.08 (tt, J = 56.7, 4.4 Hz, 1 H), 4.77 (dd, J = 14.3, 7.7 Hz, 1 H), 4.26 (q, J = 7.1 Hz, 2H), 4.19 (t, J = 8.8 Hz, 1 H), 3.85 - 3.74 (m, 1 H), 3.17 (s, 3H), 2.74 - 2.64 (m, 3H), 2.39 - 2.32 (m, 1 H), 2.19 - 2.05 (m, 2H), 1.65 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 3. Synthesis of (R)-3-((S)-3-(4-(3, 3-difluoropropyl) phenyl)-2-oxooxazolidin-5-yl)- N-hydroxy-2-methyl-2-(methylsulfonyl) propanamide [5.17]
5.17 was synthesized from 5.17b using the process of example 1.2. LCMS (m/z): 421.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.31 (s, 1 H), 7.46 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 6.08 (tt, J = 56.7, 4.3 Hz, 1 H), 4.63 (d, J = 8.5 Hz, 1 H), 4.16 (t, J = 8.7 Hz, 1 H), 3.82 - 3.74 (m, 1 H), 3.09 (s, 3H), 2.78 (d, J = 14.4 Hz, 1 H), 2.73 - 2.67 (m, 2H), 2.24 - 2.18 (m, 1 H), 2.16 - 1.97 (m, 2H), 1.60 (s, 3H).
V.18. Synthesis of compound 5.18
Step 1. Synthesis of (4-bromophenyl) (ethyl) sulfane [5.18a]. 4-Bromobenzenethiol (0.3 g, 1.59 mmol, 1.0 equiv) was dissolved in N, N-dimethylformamide (6 mL). Cs2C03 (1.55 g, 4.76 mmol, 3.0 equiv), lodoethane (0.15 mL, 1.9 mmol, 1.2 equiv) were added and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (0-5 % EtOAc/Hexane) to afford the desired product 5.18a (0.32 g, 93 % yield). 1H NMR (400 MHz, DMSO) δ 7.50 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 2.99 (q, J = 7.3 Hz, 2H), 1.23 (t, J = 7.3 Hz, 3H).
Step 2. Synthesis of (R)-3-((S)-3-(4-(ethylthio) phenyl)-2-oxooxazolidin-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl) propanamide [5.18]
5.18 was syntheized from 5.18a using the process of example 2.4. LCMS (m/z): 402.7 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.23 - 10.69 (m, 1 H), 9.34 (s, 1 H), 7.50 (d, J = 8.9 Hz, 2H), 7.42 - 7.35 (m, 2H), 4.63 (dd, J = 13.3, 7.8 Hz, 1 H), 4.16 (t, J = 8.8 Hz, 1 H), 3.81 - 3.74 (m, 1 H), 3.08 (s, 3H), 2.94 (q, J = 7.3 Hz, 2H), 2.76 (dd, J = 14.4, 2.7 Hz, 1 H), 2.19 (dd, J = 14.4, 8.8 Hz, 1 H), 1.59 (s, 3H), 1.20 (t, J = 7.3 Hz, 3H).
V.19. Synthesis of compound 5.19
Step 1. Synthesis of 3-(4-bromophenyl)-2, 2-dichlorocyclobutan-1-one [5.19a]
1-Bromo-4-vinylbenzene (1 g, 5.46 mmol, 1.0 equiv) and Zn-Cu couple (1.07 g, 16.4 mmol, 3.0 equiv) was added to diethyl ether (10 mL). Trichloroacetyl chloride (1.99 g, 10.9 mmol, 2.0 equiv), POCI3 (0.92 g, 6.0 mmol, 1.1 equiv) in diethyl ether (5 mL) were added and the reaction mixture was stirred at 40 °C for 2 hours and at room temperature for 24 hours. The reaction mixture was filtered through celite bed and washed with diethyl ether. Filtrate was washed with saturated aqueous ammonium chloride solution. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (0-10 % EtOAc/Hexane) to afford the desired product 5.19a (1 g, 62.2 % yield). 1H NMR (400 MHz, DMSO) δ 7.66 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 4.51 (t, J = 10.5 Hz, 1 H), 4.06 (dd, J = 18.2, 10.7 Hz, 1 H), 3.69 (dd, J = 18.2, 10.4 Hz, 1 H).
Step 2. Synthesis of 3-(4-bromophenyl) cyclobutan-1-one [5.19b]. 5.19a (1 g, 3.40 mmol, 1.0 equiv) was dissolved in acetic acid (10 mL). Zn-dust (1.1 g, 17.0 mmol, 5.0 equiv) was added and the reaction mixture was stirred at rt for 2 hours. The reaction mixture was stirred at reflux temperature for 4 hours. The reaction mixture was diluted with water, neutralized with solid sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue that was purified by silica gel chromatography (0-5 % EtOAc/Hexane) to afford the desired product 5.19b (0.66 g, 86.2 % yield). 1H NMR (400 MHz, DMSO) δ 7.54 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 3.70 - 3.60 (m, 1 H), 3.51 - 3.38 (m, 2H), 3.28 - 3.12 (m, 2H).
Step 3. Synthesis of 1-bromo-4-(3, 3-difluorocyclobutyl) benzene [5.19c]
5.19b (0.66 g, 2.93 mmol, 1.0 equiv) was dissolved in dichloromethane (15 mL) and cooled to -70 °C. DAST (1.18 g, 7.33 mmol, 2.5 equiv) was added drop wise and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (0-2 % EtOAc/Hexane) to afford the desired product 5.19c (0.6 g, 82.8 % yield). 1H NMR (400 MHz, DMSO) δ 7.53 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 3.47 - 3.36 (m, 1 H), 3.08 - 2.91 (m, 2H), 2.67 (dddd, J = 18.4, 14.4, 10.5, 6.2 Hz, 2H).
Step 4. Synthesis of (R)-3-((S)-3-(4-(3, 3-difluorocyclobutyl) phenyl)-2-oxooxazolidin-5- yl)-N-hydroxy-2-methyl-2-(methylsulfonyl) propanamide [5.19]
5.19 was synthesized from 5.19c using the process of example 2.4. LCMS (m/z): 432.3
[M+H]. 1H NMR (400 MHz, DMSO) δ 11.08 (s, 1 H), 9.30 (s, 1 H), 7.50 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 4.63 (d, J = 5.8 Hz, 1 H), 4.17 (t, J = 8.7 Hz, 1 H), 3.82 - 3.74 (m, 1 H), 3.44 - 3.36 (m, 1 H), 3.09 (s, 3H), 2.99 (tdd, J = 14.2, 8.9, 5.5 Hz, 2H), 2.78 (d, J = 12.3 Hz, 1 H), 2.72 - 2.60 (m, 2H), 2.20 (dd, J = 14.5, 8.8 Hz, 1 H), 1.60 (s, 3H)
V.20. Synthesis of compound 5.20
Step 1. Synthesis of 1-bromo-4-(1, 1-difluoropropyl) benzene [5.20a]. 1-(4- Bromophenyl) propan-1-one (0.5 g, 2.3 mmol, 1.0 equiv) was dissolved in dichloromethane (10 mL) and cooled to -70 °C. DAST (1.89 g, 1 1.7 mmol, 5.0 equiv) was added drop wise and the reaction mixture was stirred at rt for 24 hours. The reaction mixture was stirred at 50 °C for 48 hours. The reaction mixture was quenched with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel chromatography (100 % hexane) to afford the desired product 5.20a (0.3 g, 54.5 % yield). 1H NMR (400 MHz, CDCI3) δ 7.59 (t, J = 9.5 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 2.12 (ddd, J = 16.5, 12.5, 4.5 Hz, 2H), 1.00 (t, J = 7.5 Hz, 3H). Step 2. Synthesis of (R)-3-((S)-3-(4-(1, 1-difluoropropyl) phenyl)-2-oxooxazolidin-5-yl)- N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide [5.20]
5.20 was synthesized from 5.20a using the process of example 2.4. LCMS (m/z): 421.1 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.32 (s, 1 H), 7.64 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 4.66 (d, J = 7.0 Hz, 1 H), 4.22 (t, J = 8.7 Hz, 1 H), 3.87 - 3.79 (m, 1 H), 3.09 (s, 3H), 2.79 (d, J = 12.4 Hz, 1 H), 2.29 - 2.13 (m, 3H), 1.61 (s, 3H), 0.90 (t, J = 7.4 Hz, 3H).
V.21. Synthesis of compound 5.21
Step 1. Synthesis of 3-(4-bromophenyl) propanal [5.21a]. 3-(4-Bromophenyl) propan-1- ol (4 g, 18.5 mmol, 1.0 equiv) was dissolved into dichloromethane (60 mL) and cooled to 0 °C. PCC (5.21 g, 24.1 mmol, 1.5 equiv) was added in portions and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through celite bed and the filtrate was concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (10-20 % diethyl ether/n-pentane) to afford the desired product 5.21a (3.05 g, 76.9 % yield). 1H NMR (400 MHz, CDCI3) δ 9.83 (s, 1 H), 7.43 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H), 2.94 (t, J = 7.3 Hz, 2H), 2.79 (t, J = 7.4 Hz, 2H).
Step 2. Synthesis of 1-bromo-4-(but-3-yn-1-yl) benzene [5.21 b]. 5.21a (3 g, 14.0 mmol, 1.0 equiv) was dissolved in methanol (30 ml_). K2C03 (5.83 g, 42.2 mmol, 3.0 equiv), Ohira bestmann reagent (3.24 g, 16.8 mmol, 1.2 equiv) was added and the reaction mixture was stirred at rt for 8 hours. The reaction mixture was concentrated, diluted with water and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford crude residue. The crude residue was purified by silica gel column chromatography (5-10 % diethyl ether/n-pentane) to afford the desired product 5.21 b (1.7 g, 57.7 % yield). 1H NMR (400 MHz, CDCI3) δ 7.44 (d, J = 8.3 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 2.49 (td, J = 7.3, 2.5 Hz, 2H), 2.00 (t, J = 2.6 Hz, 1 H). Step 3. Synthesis of 1-bromo-4-(pent-3-yn-1 -yl) benzene [5.21c]. 5.21 b (0.5 g, 2.39 mmol, 1.0 equiv) was dissolved into THF (10 mL) and cooled to -78 °C. NaHMDS (1 M in THF) (1.75 g, 9.56 mmol, 4.0 equiv) was added drop wise and the reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was cooled to -78 °C, iodomethane (1.01 g, 7.17 mmol, 3.0 equiv) was added and the reaction mixture was stirred at rt for 24 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford the crude product 5.21c (0.75 g). The product was crude having SM and product. 1H NMR (400 MHz, CDCI3) δ 7.43 (dd, J = 8.2, 5.4 Hz, 2H), 7.12 (t, J = 7.7 Hz, 2H), 2.78 (dt, J = 22.4, 7.4 Hz, 2H), 2.53 - 2.36 (m, 2H), 1.87 (s, 3H).
Step 4. Synthesis of (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-(pent- 3-yn-1-yl) phenyl) oxazolidin-5-yl) propanamide [5.21]
5.21 was synthesized from 5.21c using the process of example 2.4. LCMS (m/z): 409.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 9.31 (s, 1 H), 7.44 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 4.67 - 4.56 (m, 1 H), 4.16 (t, J = 8.8 Hz, 1 H), 3.84 - 3.73 (m, 1 H), 3.09 (s, 3H), 2.78 (dd, J = 14.5, 2.5 Hz, 1 H), 2.70 (t, J = 7.4 Hz, 2H), 2.38 (td, J = 7.3, 2.5 Hz, 2H), 2.22 - 2.14 (m, 1 H), 1.71 (t, J = 2.5 Hz, 3H), 1.60 (s, 3H).
V.22. Synthesis of compound 5.22
Step 1. Synthesis of ethyl (R)-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-((E)-prop-1- en-1-yl) phenyl) oxazolidin-5-yl) propanoate [5.22a]. (E)-1-bromo-4-(prop-1-en-1- yl)benzene (0.29 g, 1.28 mmol, 1.2 equiv) and (R)-ethyl 2-methyl-2-(methylsulfonyl)-3-((S)- 2-oxooxazolidin-5-yl)propanoate (0.3 g, 1.07 mmol, 1.0 equiv) were added in 1 , 4-dioxane (12 mL) in sealed tube. Cs2C03 (0.52 g, 1.6 mmol, 1.5 equiv), Cul (0.24 g, 1.3 mmol, 1.2 equiv), (1 R, 2R)-(-)-1 , 2-diamino cyclohexane (0.17 g, 1.5 mmol, 1.4 equiv) were added and the reaction mixture was stirred at 125 °C for 4 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 afford a crude residue. The crude residue was purified by silica gel column chromatography (25-30 % EtOAc/Hexane) to afford product as E/Z isomer mixture. The E/Z isomers were further separated by preparative HPLC purification to afford product 5.22a. LCMS (m/z): 396.1 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.57 - 7.49 (m, 2H), 7.35 (d, J = 8.7 Hz, 2H), 6.40 (dd, J = 1 1.6, 1.8 Hz, 1 H), 5.81 - 5.71 (m, 1 H), 4.79 (dd, J = 15.0, 7.2 Hz, 1 H), 4.25 (dt, J = 16.8, 7.9 Hz, 3H), 3.83 (dd, J = 9.0, 7.6 Hz, 1 H), 3.17 (s, 3H), 2.70 (dd, J = 15.0, 2.6 Hz, 1 H), 2.36 (dd, J = 14.8, 8.9 Hz, 1 H), 1.87 (dd, J = 7.2, 1.8 Hz, 3H), 1.65 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).
Step 2. Synthesis of ethyl (R)-2-methyl-3-((S)-3-(4-((1 R, 2R)-2-methylcyclopropyl) phenyl)-2-oxooxazolidin-5-yl)-2-(methylsulfonyl) propanoate [5.22b]. 5.22a (0.1 g, 0.25 mmol, 1.0 equiv) was added to toluene (1.26 ml_) and cooled to 0 °C. Et2Zn (1 M in Hexane) (0.16 g, 1.26 mmol, 5.0 equiv), Diiodomethane (0.68 g, 2.52 mmol, 10.0 equiv) was added drop wise and the reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was stirred at 50 °C for 30 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated (Repeated the process three times) to afford product 5.22b (0.1 g, 96.6 % yield). LCMS (m/z): 410.3 [M+H]. 1H NMR (400 MHz, CDCI3) δ 7.40 (dt, J = 24.0, 9.1 Hz, 4H), 4.90 - 4.80 (m, 1 H), 4.37 (dtd, J = 7.1 , 5.4, 1.7 Hz, 2H), 4.27 - 4.15 (m, 2H), 3.76 (dd, J = 17.3, 9.7 Hz, 1 H), 3.21 (t, J = 7.1 Hz, 1 H), 3.10 (d, J = 1.9 Hz, 3H), 2.70 (dd, J = 10.5, 7.3 Hz, 1 H), 2.55 - 2.47 (m, 1 H), 1.94 - 1.80 (m, 5H), 1.38 (td, J = 7.1 , 1.5 Hz, 3H), 0.94 - 0.89 (m, 3H).
Step. Synthesis of (2R)-N-hydroxy-2-methyl-3-((5S)-3-(4-(2-methylcyclopropyl)phenyl)- 2-oxooxazolidin-5-yl)-2-(methylsulfonyl)propanamide [5.22]
5.22 was synthesized from 5.22a using the process of example 2.4. LCMS (m/z): 397.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 9.30 (s, 1 H), 7.38 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 4.61 (d, J = 5.6 Hz, 1 H), 4.14 (t, J = 8.7 Hz, 1 H), 3.79 - 3.71 (m, 1 H), 3.08 (s, 3H), 2.77 (d, J = 14.6 Hz, 1 H), 2.25 - 2.16 (m, 1 H), 1.60 (s, 3H), 1.14 (d, J = 5.9 Hz, 3H), 1.00 (s, 1 H), 0.86 - 0.80 (m, 1 H), 0.75 - 0.69 (m, 1 H).
V.23. Synthesis of compound 5.23
Step 1. Synthesis of 4-hydroxycyclopent-2-en-1-one [5.23a]. Furan-2-ylmethanol (20 g, 203.8 mmol, 1.0 equiv) was suspended in water (400 mL). K2HP04 (1.86 g, 8.15 mmol, 0.04 equiv), H3P04 (0.46 mL) was added drop wise to adjust pH 4.5 to 4.8 and the reaction mixture was stirred at 99 °C for 24 hours. The reaction mixture was washed with dichloromethane. The aqueous layer was concentrated to afford a crude residue. The crude residue was dissolved in dichloromethane, dried over sodium sulfate and concentrated to afford the desired product 5.23a (4.7 g, 23.5 % yield). 1H NMR (400 MHz, CDCI3) δ 7.60 (dd, J = 5.7, 2.3 Hz, 1 H), 6.27 (dd, J = 5.7, 1.2 Hz, 1 H), 5.09 (d, J = 5.8 Hz, 1 H), 2.82 (dd, J = 18.5, 6.1 Hz, 1 H), 2.31 (dd, J = 18.5, 2.2 Hz, 1 H), 2.09 (d, J = 17.8 Hz, 1 H).
Step 2. Synthesis of 4-((tert-butyldimethylsilyl) oxy) cyclopent-2-en-1-one [5.23b] 5.23a (4.7 g, 47.9 mmol, 1.0 equiv), DMAP (0.58 g, 4.79 mmol, 0.1 equiv), TEA (17 mL, 122.6 mmol, 2.56 equiv) were suspended in dichloromethane (90 mL) and cooled to 0 °C. TBDMS-CI (8.66 g, 57.5 mmol, 1.2 equiv) in dichloromethane (30 mL) was added and the reaction mixture was stirred at 0 °C for 10 minutes. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (5 % EtOAc/n-pentane) to afford the desired product 5.23b (7 g, 68.9 % yield). 1H NMR (400 MHz, CDCI3) δ 7.48 (dd, J = 5.7, 2.3 Hz, 1 H), 6.21 (dd, J = 5.7, 1.2 Hz, 1 H), 5.09 - 4.94 (m, 1 H), 2.73 (dd, J = 18.2, 6.0 Hz, 1 H), 2.27 (dd, J = 18.2, 2.2 Hz, 1 H), 0.95 (d, J = 13.8 Hz, 9H), 0.18 - 0.10 (m, 6H).
Step 3. Synthesis of 4-((tert-butyldimethylsilyl) oxy) cyclopent-1-en-1-yl trifluoromethanesulfonate [5.23c]. L-selectride (1 M in THF) (9.4 g, 9.43 mmol, 1.0 equiv) was suspended in THF (80 mL) and cooled to -78 °C. 5.23b (2 g, 9.43 mmol, 1.0 equiv), TEA (0.39 g, 2.83 mmol, 0.3 equiv) in THF (40 mL) was added drop wise within 30 minutes and the reaction mixture was stirred at -78 °C for 30 minutes. N-phenyl bis trifluoro methanesulfonimide (2.93 g, 8.21 mmol, 0.87 equiv) was added in two portions and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, the residue was added to saturated aqueous sodium bicarbonate solution and extracted with hexane. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (2-5 % EtOAc/Hexane) to afford the desired product 5.23c (1.8 g, 55.2 % yield). 1H NMR (400 MHz, CDCI3) δ 5.61 - 5.55 (m, 1 H), 4.58 (ddd, J = 1 1.0, 7.3, 3.8 Hz, 1 H), 2.84 (dd, J = 16.3, 6.1 Hz, 1 H), 2.77 - 2.67 (m, 1 H), 2.54 (ddd, J = 16.3, 4.0, 2.1 Hz, 1 H), 2.39 - 2.33 (m, 1 H), 0.90 (s, 9H), 0.09 (s, 6H).
Step 4. Synthesis of ((3-(4-bromophenyl) cyclopent-3-en-1 -yl) oxy) (tert-butyl) dimethylsilane [5.23d]. 5.23c (1.7 g, 4.91 mmol, 1.0 equiv), (4-bromophenyl)boronic acid (1.48 g, 7.37 mmol, 1.5 equiv), K3P04 (3.13 g, 14.74 mmol, 3.0 equiv) were suspended in 1 , 4-dioxane (40 mL) in sealed tube and the reaction mixture was degassed for 10 minutes. PdCI2(dppf) (0.18 g, 0.25 mmol, 0.05 equiv) was added and the reaction mixture was stirred at reflux for 5 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (5-10 % EtOAc/Hexane) to afford the desired product 5.23d (0.8 g, 46.2 % yield). 1H NMR (400 MHz, DMSO) δ 7.52 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 6.26 (s, 1 H), 4.68 - 4.60 (m, 1 H), 3.00 - 2.89 (m, 1 H), 2.79 (d, J = 1 1.6 Hz, 1 H), 2.35 (d, J = 16.5 Hz, 2H), 0.87 (s, 9H), 0.07 (s, 6H).
Step 5. Synthesis of 3-(4-bromophenyl) cyclopent-3-en-1-ol [5.23e]. 5.23d (0.5 g, 1.41 mmol, 1.0 equiv) was suspended in THF (30 ml_). TEA (0.03 ml_, 0.22 mmol, 0.15 equiv) was added drop wise. TBAF (1 M in THF) (1.41 g, 1.41 mmol, 1.0 equiv) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (30 % EtOAc/Hexane) to afford the desired product 5.23e (0.27 g, 80.1 % yield).
Step 6. Synthesis of 1-bromo-4-(4-fluorocyclopent-1-en-1-yl) benzene [5.23f]. 5.23e (0.27 g, 1.13 mmol, 1.0 equiv) was suspended in dichloromethane (30 ml_) and cooled to -78 °C. DAST (0.36 g, 2.26 mmol, 2.0 equiv) was added drop wise and the reaction mixture was stirred at -78 °C for 10 minutes. The reaction mixture was stirred at rt for 4 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (8-10 % EtOAc/Hexane) to afford the desired product 5.23f (0.23 g, 84.9 % yield). 1H NMR (400 MHz, CDCI3) δ 7.56 - 7.45 (m, 4H), 6.20 (d, J = 19.8 Hz, 1 H), 5.46 (d, J = 54.0 Hz, 1 H), 5.03 (d, J = 54.9 Hz, 1 H), 3.15 - 2.80 (m, 4H).
Step 7. Synthesis of (2R)-3-((5S)-3-(4-(4-fluorocyclopent-1-en-1-yl) phenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl) propanamide [5.23]. 5.23 was synthesized from 5.23f using the process of example 2.4. LCMS (m/z): 444.3 [M+18]. 1H NMR (400 MHz, DMSO) δ 11.06 (s, 1 H), 9.30 (s, 1 H), 7.53 (s, 4H), 6.23 (s, 1 H), 5.46 (d, J = 54.4 Hz, 1 H), 4.64 (d, J = 8.0 Hz, 1 H), 4.19 (t, J = 8.7 Hz, 1 H), 3.86 - 3.75 (m, 1 H), 3.09 (s, 3H), 2.82 (ddd, J = 50.6, 32.6, 17.5 Hz, 5H), 2.25 - 2.20 (m, 1 H), 1.60 (s, 3H).
V.24. Synthesis of compound 5.24
Step 1. Synthesis of ethyl (R)-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(4-((Z)-prop-1- en-1-yl) phenyl) oxazolidin-5-yl) propanoate [5.24a]. 1.1d (0.3 g, 0.69 mmol, 1.0 equiv), (Z)-prop-1-en-1-ylboronic acid (0.078 g, 0.89 mmol, 1.3 equiv) were suspended in 1 , 4- dioxane (18 ml_) in sealed tube. Cs2CO3 (0.67 g, 2.07 mmol, 3.0 equiv) was added and the reaction mixture was degassed for 10 minutes. PdCI2(dppf) (0.036 g, 0.048 mmol, 0.07 equiv) was added and the reaction mixture was stirred at 120 °C for 24 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 afford a crude residue. The crude residue was purified by silica gel column chromatography (35-38 % EtOAc/Hexane) to afford the desired product 5.24a (0.23 g, 85 % yield). LCMS (m/z): 396.5 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.50 (dd, J = 23.6, 8.8 Hz, 2H), 7.37 (dd, J = 21.1 , 8.8 Hz, 2H), 6.40 (d, J = 9.9 Hz, 1 H), 5.76 (td, J = 14.4, 7.2 Hz, 1 H), 4.83 - 4.75 (m, 1 H), 4.25 (dt, J = 16.4, 7.9 Hz, 3H), 3.86 - 3.79 (m, 1 H), 3.17 (s, 3H), 2.70 (d, J = 14.8 Hz, 1 H), 2.40 - 2.34 (m, 1 H), 1.86 (dt, J = 9.5, 4.7 Hz, 3H), 1.65 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 2. Synthesis of ethyl (R)-3-((S)-3-(4-((1S, 2S)-2-bromo-1-fluoropropyl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [5.24b]. 5.24a (0.23 g, 0.58 mmol, 1.0 equiv) was suspended in dichloromethane (20 ml_) and cooled to 0 °C. NEt3.3HF (0.14 g, 0.88 mmol, 1.5 equiv), NBS (0.12 g, 0.65 mmol, 1.1 equiv) were added and the reaction mixture was stirred at 0 °C for 10 minutes. The reaction mixture was stirred at rt for 24 hours. The reaction was quenched with water (slightly basic, adjusted with NH4OH) and extracted with dichloromethane. The organic layer was washed with 1.0 N HCI and 1.0 N sodium bicarbonate solution, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel chromatography (30-35 % EtOAc/Hexane) to afford 5.24b (0.23 g, 80 % yield). LCMS (m/z): 495 [M+H].
Step 3. Synthesis of ethyl (R)-3-((S)-3-(4-((Z)-1-fluoroprop-1-en-1-yl) phenyl)-2- oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl) propanoate [5.24c]
5.24b (0.2 g, 0.4 mmol, 1.0 equiv) was suspended in DBU (0.06 ml_, 0.4 mmol, 1.0 equiv). The reaction mixture was stirred at 85 °C for 45 minutes. 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 afford the desired product 5.24c (0.16 g, 95.8 % yield). LCMS (m/z): 414.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.76 - 7.61 (m, 2H), 7.54 (t, J = 1 1.0 Hz, 2H), 5.50 (dq, J = 22.6, 7.5 Hz, 1 H), 4.86 - 4.75 (m, 1 H), 4.24 (dq, J = 15.2, 7.1 Hz, 3H), 3.90 - 3.82 (m, 1 H), 3.17 (s, 3H), 2.70 (d, J = 15.2 Hz, 1 H), 2.38 (dd, J = 14.8, 8.9 Hz, 1 H), 1.76 (dd, J = 7.5, 2.3 Hz, 2H), 1.65 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).
Step 4. Synthesis of (R)-3-((S)-3-(4-((Z)-1-fluoroprop-1-en-1-yl) phenyl)-2- oxooxazolidin-5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl) propanamide [5.24]
5.24 was synthesized from 5.24c using the process of example 1.2. LCMS (m/z): 401.3 [M+H]. 1H NMR (400 MHz, DMSO) 5 1 1.06 - 10.45 (m, 1 H), 9.82 - 9.21 (m, 1 H), 7.63 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 5.49 (dq, J = 22.6, 7.5 Hz, 1 H), 4.67 (dd, J = 13.7, 7.9 Hz, 1 H), 4.22 (t, J = 8.8 Hz, 1 H), 3.88 - 3.78 (m, 1 H), 3.09 (s, 3H), 2.78 (dd, J = 14.4, 2.6 Hz, 1 H), 2.22 (dd, J = 14.4, 8.8 Hz, 1 H), 1.76 (dd, J = 7.5, 2.3 Hz, 3H), 1.60 (s, 3H). V.25. Synthesis of compound 5.25
Compound 5.25 was synthesized by the process of example of 2.1. LCMS (m/z): 532.6 [M+H].1H NMR (400 MHz, DMSO) δ 7.44 (m, 8H), 4.58 (m, 1H), 4.30 - 4.06 (m, 1H), 3.94 - 3.67 (m, 1H), 3.59 (m, 2H), 3.49 (m, 2H), 3.39 (m, 4H), 3.10 (m, 2H), 2.77 (m, 2H), 2.56 (m, 1 H), 2.03 - 1.92 (m, 1 H), 1.60 (s, 3H).
V.26. Synthesis of compound 5.26
Compound 5.26 was synthesized by the example of 2.1. LCMS (m/z): 547.5 [M-H]. 1H NMR (400 MHz, DMSO) δ 8.24 (s, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 5.7 Hz, 4H), 7.03 (d, J = 8.8 Hz, 2H), 4.67 (s, 1H), 4.24 - 4.19 (m, 1H), 4.13 (s, 2H), 3.83 (s, 1H), 3.59 (s, 4H), 3.10 (s, 3H), 2.82-2.76 (m, 1H), 2.70 (d, J= 5.5 Hz, 2H), 2.26-2.21 (m, 1H), 1.61 (s, 3H).
V.27. Synthesis of compound 5.27
Compound 5.27 was synthesized by the example of 2.1. LCMS (m/z): 463.5 [M+H]. 1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.31 (s, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.59 (dd, J = 13.1, 8.4 Hz, 4H), 7.30 (d, J = 7.9 Hz, 2H), 4.67 (s, 2H), 4.22 (t, J = 8.8 Hz, 1H), 3.83 (t, J = 8.1 Hz, 1H), 3.70-3.56 (m, 2H), 3.10 (s, 3H), 2.77 (dd, J= 18.3, 11.1 Hz, 3H), 2.22 (dd, J = 14.3, 8.6 Hz, 1H), 1.61 (s, 3H).
V.28. Synthesis of compound 5.28
Compound 5.28 was synthesized by the process of example of 2.4. LCMS (m/z): 425.5 [M+H]. 1H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 9.31 (s, 1H), 7.50 (q, J= 8.8 Hz, 4H), 6.25 (s, 1H), 4.64 (d, J = 7.7 Hz, 1H), 4.20 (dd, J = 18.2, 5.4 Hz, 3H), 3.81 (dt, J = 14.0, 6.9 Hz, 3H), 3.09 (s, 3H), 2.79 (d, J= 14.6 Hz, 1H), 2.44 (s, 2H), 2.21 (dd, J= 14.4, 8.9 Hz, 1H), 1.61 (s, 3H).
V.29. Synthesis of compound 5.29
Compound 5.29 was synthesized by the process of example 2.4. LCMS (m/z): 426.6 [M+H]. 1H NMR (400 MHz, DMSO) δ 11.07 (s, 1 H), 9.29 (s, 1 H), 7.50 - 7.39 (m, 2H), 7.28 (d, J = 8.6 Hz, 2H), 4.62 (d, J = 5.8 Hz, 1H), 4.16 (t, J = 8.8 Hz, 1H), 3.94 (d, J= 10.8 Hz, 2H), 3.81 -3.71 (m, 1H), 3.47-3.39 (m, 2H), 3.06 (d, J= 19.9 Hz, 3H), 2.75 (t, J= 15.4 Hz, 2H), 2.19 (dd, J= 14.4, 8.8 Hz, 1H), 1.78- 1.62 (m, 4H), 1.60 (s, 3H).
VI.1. Synthesis of compound 6.1
Figure imgf000184_0001
Figure imgf000184_0002
Reagents: Step 1 : CBZ-CI, 2M NaOH 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: CAN, CH3CN:Water, room temperature. Step 6: Cul, Cs2C03, trans-cyclohexane-1 ,2-diamine, 1 ,4-dioxane, 125 °C. Step 7: DBU, dppb, PdCI2(PPh3)2, DMSO, 100°C. Step 8: LiOH.H20, THF, MeOH, Water, room temperature. Step 9: NH2OTHP, EDC.HCI, HOBt, N-methyl morpholine, THF, room temperature. Step 10: 35.5% aq. HCI, EtOH, room temperature.
Step 1. Synthesis of benzyl (4-methoxybenzyl)carbamate [6.1a]. (4-methoxyphenyl) methanamine (2 g, 14.6 mmol, 1.0 equiv) was dissolved in THF (20 ml_). NaOH (2M solution) (1.16 g, 29.2 mmol, 2.0 equiv) was added and the reaction mixture was cooled to 0- 5 °C. CBZ-CI (2.74 g, 16.0 mmol, 1.1 equiv) was added and the reaction mixture was stirred at rt for 3 hours. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford product 6.1a (3.7 g, 92.5 % yield). 1H NMR (400 MHz, DMSO) δ 7.76 (t, J = 5.8 Hz, 1 H), 7.41 - 7.30 (m, 5H), 7.18 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 5.04 (s, 2H), 4.13 (d, J = 6.2 Hz, 2H), 3.73 (s, 3H).
Step 2. Synthesis of (R)-5-(hydroxymethyl)-3-(4-methoxybenzyl)oxazolidin-2-one [6.1 b] 6.1a (3.7 g, 13.6 mmol, 1.0 equiv) was dissolved in THF (40 mL) and cooled to - 70°C. n-BuLi (2.5M in hexane) (0.96 g, 15.0 mmol, 1.1 equiv) was gradually added and the reaction mixture was stirred at -70 °C for 1 hour. (R)-oxiran-2-ylmethyl butyrate (2.16 g, 15.0 mmol, 1.1 equiv) was added drop wise and the reaction mixture was stirred at -70 °C for 1 hour. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The residue was purified by silica gel column chromatography (50-60 % EtOAc in Hexane) to afford product 6.1 b (2.54 g, 79.4 % yield). LCMS (m/z): 238.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.20 (d, J = 8.6 Hz, 2H), 7.01 - 6.86 (m, 2H), 5.1 1 (t, J = 5.7 Hz, 1 H), 4.50 (d, J = 8.9 Hz, 1 H), 4.35 - 4.17 (m, 2H), 3.74 (d, J = 5.1 Hz, 3H), 3.60 - 3.49 (m, 1 H), 3.47 - 3.37 (m, 2H), 3.18 (dd, J = 8.5, 6.6 Hz, 1 H).
Step 3. Synthesis of (R)-5-(iodomethyl)-3-(4-methoxybenzyl)oxazolidin-2-one [6.1c]
Triphenylphosphine (3.65 g, 13.9 mmol, 1.3 equiv) was dissolved in dichloromethane (30 mL). imidazole (1.02 g, 15.0 mmol, 1.4 equiv) and iodine (3.53 g, 13.9 mmol, 1.3 equiv) were added and the reaction mixture was stirred at room temperature for 15 minutes. 6.1 b (2.54 g, 10.7 mmol, 1.0 equiv) was added and the reaction mixture was stirred at room temperature for 7 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 afford a crude residue. The residue was purified by silica gel column chromatography (40-70 % EtOAc in Hexane) to afford product 6.1c (2.6 g, 70.2 % yield). LCMS (m/z): 348.1 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.32 - 7.13 (m, 2H), 6.91 (t, J = 10.1 Hz, 2H), 4.52 (dt, J = 1 1.1 , 5.0 Hz, 1 H), 4.38 - 4.17 (m, 2H), 3.81 - 3.66 (m, 3H), 3.64 - 3.37 (m, 3H), 3.02 (dd, J = 9.1 , 6.2 Hz, 1 H).
Step 4. Synthesis of ethyl (R)-3-((S)-3-(4-methoxybenzyl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoate [6.1 d]. Ethyl 2-(methylsulfonyl)propanoate (5.45 g, 30.1 mmol, 4.0 equiv) was dissolved in N,N-dimethylformamide (20 mL) and cooled to 0-5 °C. NaH (60%) (0.45 g, 1 1.2 mmol, 1.5 equiv) was added in portion wise and the reaction mixture was stirred at room temperature for 1 hour. A solution of 6.1c (2.61g, 7.5 mmol, 1.0 equiv) in N,N-dimethylformamide (10 mL) was added drop wise at 0-5 °C, stirred at the same temperature for 30 minutes and the reaction mixture was allowed to stir at room temperature for 2 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 afford a crude residue. The residue was purified by silica gel column chromatography (20-30 % EtOAc in Hexane) to afford product 6.1d as mixture of diastereomers (1.9 g, 63.3 % yield). 6.1d was further purified by the preparative HPLC to afford 6.1d as desired diastereomer. LCMS (m/z): 400.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 7.21 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 4.59 (tt, J = 8.4, 4.2 Hz, 1 H), 4.28 (t, J = 8.3 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.75 (s, 3H), 3.53 (t, J = 8.7 Hz, 1 H), 3.13 (s, 3H), 3.1 1 - 3.06 (m, 1 H), 2.54 (dd, J = 15.2, 3.3 Hz, 1 H), 2.15 (dd, J = 14.6, 8.6 Hz, 1 H), 1.58 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H).
Step 5. Synthesis of ethyl (R)-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxooxazolidin-5-yl) propanoate [6.1 e]. 6.1d (0.8 g, 2.0 mmol, 1.0 equiv) was dissolved in acetonitrile: water (9:1 , 30 ml_), eerie ammonium nitrate (4.39 g, 8.0 mmol, 4.0 equiv) was added and the reaction mixture was stirred at room temperature for 24 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 afford a crude residue. The residue was purified by silica gel column chromatography (70-90 % EtOAc in Hexane) to afford product 6.1e (0.41 g, 84 % yield). LCMS (m/z): 280.2 [M+H].
Step 6. Synthesis of ethyl (R)-3-((S)-3-(5-bromopyridin-2-yl)-2-oxooxazolidin-5-yl)-2- methyl-2-(methylsulfonyl)propanoate [6.1f]. 6.1e (0.3 g, 1.1 mmol, 1.0 equiv), 2,5- dibromopyridine (0.28 g, 1.2 mmol, 1.1 equiv) were dissolved in 1 ,4-dioxane (5 ml_). Cul (0.24 g, 1.3 mmol, 1.2 equiv), trans-cyclohexane-1 ,2-diamine (0.17 g, 1.5 mmol, 1.4 equiv), Cs2C03 (0.52 g, 1.6 mmol, 1.5 equiv) were added and the reaction mixture was stirred at 125 °C for 4 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 afford a residue. The residue was purified by silica gel column chromatography (30-50 % EtOAc in Hexane) to afford product 6.1f (0.31 g, 66.4 % yield). LCMS (m/z): 437.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 8.52 (dd, J = 3.5, 2.7 Hz, 3H), 8.1 1 - 8.04 (m, 6H), 4.88 - 4.75 (m, 4H), 4.33 - 4.24 (m, 10H), 3.87 (dd, J = 10.3, 7.5 Hz, 4H), 3.17 (s, 9H), 2.78 - 2.66 (m, 4H), 2.42 - 2.32 (m, 5H), 1.64 (s, 10H), 1.28 - 1.25 (m, 9H). Step 7. Synthesis of ethyl (R)-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(5-(prop-1-yn- 1-yl)pyridin-2-yl)oxazolidin-5-yl)propanoate [6.1g]. 6.1f (0.15 g, 0.3 mmol, 1.0 equiv), but-2-ynoic acid (0.032 g, 0.4 mmol, 1.1 equiv), 1 ,4-bis(diphenylphosphino)butane (0.003 g, 0.007 mmol, 0.02 equiv) and DBU(0.10 g, 0.7 mmol, 2.0 equiv) were dissolved in DMSO (2 ml_). The reaction mixture was degassed for 10 minutes, PdCI2 (PPh3)2 (0.002 g, 0.003 mmol, 0.01 equiv) was added and the reaction mixture was stirred at 100 °C for 3 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 afford a residue. The residue was purified by silica gel chromatography (30-50 % EtOAc in Hexane) to afford 6.1 g (0.1 1 g, 80.9 % yield). 1H NMR (400 MHz, DMSO) δ 8.41 (t, J = 3.1 Hz, 1 H), 8.04 (d, J = 8.8 Hz, 1 H), 7.86 (dt, J = 8.8, 2.8 Hz, 1 H), 4.90 - 4.74 (m, 1 H), 4.39 - 4.31 (m, 1 H), 4.30 - 4.21 (m, 2H), 3.95 - 3.84 (m, 1 H), 3.21 - 3.10 (m, 3H), 2.71 (dd, J = 14.8, 2.9 Hz, 1 H), 2.42 - 2.33 (m, 1 H), 2.07 (s, 3H), 1.61 (d, J = 19.9 Hz, 3H), 1.26 (dd, J = 9.1 , 5.1 Hz, 3H). Step 8. Synthesis of (R)-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(5-(prop-1-yn-1- yl)pyridin-2-yl)oxazolidin-5-yl)propanoic acid [6.1 h]. 6.1 g (0.1 1 g, 0.3 mmol, 1.0 equiv) was dissolved in THF (2 mL), MeOH (1 mL). LiOH.H20 (0.012 g, 0.3 mmol, 1.0 equiv) in water (1 mL) was added and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was acidified by 1 N HCI aqueous solution to pH 4 to 5 and concentrated under reduced pressure to afford product 6.1 h as HCI salt which was used as such for next step (0.14 g, 100 % yield as crude product). LCMS (m/z): 367.4 [M+H].
Step 9. Synthesis of (2R)-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(5-(prop-1-yn-1-yl) pyridin-2-yl)oxazolidin-5-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide [6.1 i]. 6.1 h (0.14 g, 0.4 mmol, 1.0 equiv) was dissolved in THF (5 mL). N-methyl morpholine (0.19 g, 2.0 mmol, 5.0 equiv), EDC.HCI (0.1 1 g, 0.6 mmol, 1.5 equiv), HOBT (0.093 g, 0.7 mmol, 1.8 equiv), 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.089 g, 0.8 mmol, 2.0 equiv) were added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated to afford a residue. The residue was purified by silica gel column chromatography (1-2 % MeOH in dichloromethane) to afford product 6.1 i (0.09 g, 70 % yield). Which was used as such for next step LCMS (m/z): 466.5 [M+H].
Step 10. Synthesis of (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(5- (prop-1-yn-1-yl)pyridin-2-yl)oxazolidin-5-yl)propanamide [6.1]. 6.1 i (0.09 g, 0.2 mmol, 1.0 equiv) was dissolved in ethanol (5 mL). 35.5% aq. HCI (0.2 mL) was added and the reaction mixture was stirred at rt for 1 hour. The reaction mixture was quenched with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford crude product. The crude product was purified by preparative HPLC purification to afford 6.1 as desired diastereomer (0.022 g, 30.1 % yield). LCMS (m/z): 382.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.33 (s, 1 H), 8.40 (s, 1 H), 8.04 (d, J = 8.6 Hz, 1 H), 7.85 (d, J = 8.3 Hz, 1 H), 4.68 (d, J = 6.4 Hz, 1 H), 4.29 (t, J = 9.1 Hz, 1 H), 3.93 - 3.74 (m, 1 H), 3.08 (s, 3H), 2.79 (d, J = 13.5 Hz, 1 H), 2.27 - 2.15 (m, 1 H), 2.07 (s, 3H), 1.59 (s, 3H).
VI.2. Synthesis of compound 6.2
Step 1. Synthesis of 5-bromo-2-(cyclopropylethynyl) pyridine [6.2a]. 2,5- Dibromopyridine (0.4 g, 1.7 mmol, 1.0 equiv), PdCI2(PPh3)2 (0.07 g, 0.1 mmol, 0.05 equiv), Cul (0.032 g, 0.2 mmol, 0.1 equiv), triphenyl phosphine (0.088 g, 0.3 mmol, 0.2 equiv) were added in diethyl amine (5 mL), N,N-dimethylformamide (1 mL) and the reaction mixture was degassed for 10 minutes. Ethynylcyclopropane (0.13 g, 2.0 mmol, 1.2 equiv) was added and the reaction mixture was stirred at 100 °C for 24 hours in sealed tube. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (1-2 % EtOAc in Hexane) to afford product 6.2a (0.15 g, 32.1 % yield). LCMS (m/z): 222.1 [M+H]. 1H NMR (400 MHz, DMSO) δ 8.63 (d, J = 1.8 Hz, 1 H), 8.01 (dd, J = 8.4, 2.4 Hz, 1 H), 7.39 (t, J = 10.3 Hz, 1 H), 1.59 (ddd, J = 13.2, 8.3, 5.0 Hz, 1 H), 0.94 (dt, J = 6.3, 4.0 Hz, 2H), 0.80 (dt, J = 6.9, 4.0 Hz, 2H).
Step 2. Synthesis of (R)-3-((S)-3-(6-(cyclopropylethynyl)pyridin-3-yl)-2-oxooxazolidin- 5-yl) -N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide [6.2]
Compound 6.2 was synthesized from 6.2a by the process of example 2.4. LCMS (m/z): 408.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.09 (s, 1 H), 9.31 (s, 1 H), 8.64 (d, J = 2.4 Hz, 1 H), 7.95 (dd, J = 8.7, 2.7 Hz, 1 H), 7.47 (d, J = 8.7 Hz, 1 H), 4.68 (d, J = 8.3 Hz, 1 H), 4.23 (t, J = 8.7 Hz, 1 H), 3.86 - 3.76 (m, 1 H), 3.08 (s, 3H), 2.77 (d, J = 12.2 Hz, 1 H), 2.24 (dd, J = 14.5, 9.1 Hz, 1 H), 1.66 - 1.52 (m, 4H), 0.92 (dt, J = 6.3, 4.0 Hz, 2H), 0.77 (td, J = 6.6, 4.0 Hz, 2H).
VI.3. Synthesis of compound 6.3
Compound 6.3 was synthesized by the process of example 6.4. LCMS (m/z): 436.6 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 8.38 (d, J = 1.6 Hz, 1 H), 8.04 (d, J = 8.8 Hz, 1 H), 7.83 (dd, J = 8.8, 2.2 Hz, 1 H), 4.67 (d, J = 5.9 Hz, 1 H), 4.34 - 4.26 (m, 1 H), 3.86 (dd, J = 10.3, 7.5 Hz, 1 H), 3.1 1 (d, J = 24.1 Hz, 3H), 2.87 (dd, J = 15.0, 7.5 Hz, 1 H), 2.85 - 2.75 (m, 1 H), 2.22 (dd, J = 14.5, 8.7 Hz, 1 H), 2.10 - 1.85 (m, 2H), 1.72 (s, 2H), 1.59 (s, 6H).
VI.4. Synthesis of compound 6.4
Step 1. Synthesis of ethynylcyclobutane [6.4a]. Cyclobutanecarbaldehyde (1 g, 1 1.8 mmol, 1.0 equiv) was dissolved in EtOH (15 mL) and cooled to 0 °C. Ohira-Bestmann reagent (2.23 g, 1 1.8 mmol, 1.0 equiv), K2C03 (3.27 g, 23.9 mmol, 2.0 equiv) was added and the reaction mixture was stirred at rt for 24 hours. The crude reaction mass was subjected to fractional distillation at 70-75 °C at atmospheric pressure to afford the desired product 6.4a with EtOH (2 mL). The solution of product was directly used in next step as such. 1H NMR (400 MHz, CDCI3) δ 2.98 - 2.85 (m, 1 H), 2.23 - 2.13 (m, 2H), 2.1 1 (t, J = 3.6 Hz, 1 H), 2.09 - 1.98 (m, 2H), 1.91 - 1.75 (m, 2H). NMR shows Ethanol peaks as product was distilled out along with ethanol.
Step 2. Synthesis of ethyl 3-((S)-3-(5-(cyclobutylethynyl) pyridin-2-yl)-2-oxooxazolidin- 5-yl)-2-methyl-2-(methylsulfonyl) propanoate [6.4b]. (R)-ethyl 3-((S)-3-(5-bromopyridin- 2-yl)-2-oxooxazolidin-5-yl)-2-methyl-2-(methylsulfonyl)propanoate (0.2 g, 0.4 mmol, 1.0 equiv), PdCI2(pph3)2 (0.016 g, 0.02 mmol, 0.05 equiv), Cul (0.008 g, 0.04 mmol, 0.1 equiv) and triphenylphosphine (0.023 g, 0.08 mmol, 0.2 equiv) were added in diethyl amine (5 mL) and N, N-dimethylformamide (1 mL). The reaction mixture was degassed for 10 minutes. Ethynylcyclobutane (2 mL with ethanol) was added and the reaction mixture was stirred at 130 °C for 3 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 afford a crude residue. The crude residue was purified by silica gel chromatography (1 % EtOAc in dichloromethane) to afford 6.4b (0.16 g, 53.3% yield). LCMS (m/z): 435.8 [M+H]. 1H NMR (400 MHz, DMSO) δ 8.08 - 8.03 (m, 1 H), 7.98 (d, J = 15.3 Hz, 1 H), 7.90 - 7.82 (m, 1 H), 4.82 (ddd, J = 16.6, 8.6, 3.1 Hz, 1 H), 4.37 - 4.20 (m, 3H), 3.88 (dd, J = 10.4, 7.5 Hz, 1 H), 3.30 - 3.21 (m, 1 H), 3.17 (d, J = 3.4 Hz, 3H), 2.70 (d, J = 2.8 Hz, 1 H), 2.40 - 2.26 (m, 3H), 2.20 - 2.09 (m, 2H), 1.98 - 1.83 (m, 2H), 1.65 (d, J = 9.4 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H).
Step 3. Synthesis of (R)-3-((S)-3-(5-(cyclobutylethynyl) pyridin-2-yl)-2-oxooxazolidin-5- yl)-N-hydroxy-2-methyl-2-(methylsulfonyl) propanamide [6.4]
6.4 was synthesized from 6.4b using the process of example 6.1. LCMS (m/z): 422.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1 H), 9.33 (s, 1 H), 8.40 (s, 1 H), 8.06 (s, 1 H), 7.86 (s, 1 H), 4.68 (m, 1 H), 4.30 (m, 1 H), 3.87 (m, 1 H), 3.56 (m, 1 H), 3.09 (s, 3H), 2.80 (d, J = 12.1 Hz, 1 H), 2.30 (m, 2H), 2.15 (m, 3H), 1.92 (m, 2H), 1.59 (s, 3H)
VI.5. Synthesis of compound 6.5
6.5 was synthesized by the process of 6.1. LCMS (m/z): 396.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 8.40 (d, J = 1.8 Hz, 1 H), 8.05 (d, J = 8.7 Hz, 1 H), 7.85 (dd, J = 8.8, 2.3 Hz, 1 H), 4.67 (d, J = 7.8 Hz, 1 H), 4.31 (d, J = 10.2 Hz, 1 H), 3.90 - 3.84 (m, 1 H), 3.08 (s, 3H), 2.80 (d, J = 14.9 Hz, 1 H), 2.48 - 2.42 (m, 2H), 2.22 (dd, J = 14.5, 8.8 Hz, 1 H), 1.17 (t, J = 7.5 Hz, 3H).
VI.6. Synthesis of compound 6.6
6.6 was synthesized by the process of 6.4. LCMS (m/z): 410.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 8.38 (d, J = 1.6 Hz, 1 H), 8.05 (d, J = 8.8 Hz, 1 H), 7.84 (dd, J = 8.8, 2.3 Hz, 1 H), 4.67 (d, J = 5.6 Hz, 1 H), 4.30 (dd, J = 10.2, 8.6 Hz, 1 H), 3.86 (dd, J = 10.3, 7.4 Hz, 1 H), 3.08 (s, 3H), 2.88 - 2.77 (m, 2H), 2.22 (dd, J = 14.5, 8.8 Hz, 1 H), 1.59 (s, 3H), 1.22 (d, J = 6.9 Hz, 6H).
VI.7. Synthesis of compound 6.7
6.7 was synthesized by the process of 6.4. LCMS (m/z): 414.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 8.20 (s, 1 H), 7.97 (d, J = 8.5 Hz, 1 H), 7.69 (d, J = 8.5 Hz, 1 H), 4.65 (d, J = 6.1 Hz, 1 H), 4.29 (t, J = 9.5 Hz, 1 H), 3.92 - 3.79 (m, 1 H), 3.09 (s, 3H), 2.81 (d, J = 14.3 Hz, 1 H), 2.59 - 2.53 (m, 2H), 2.20 (dd, J = 14.3, 8.8 Hz, 1 H), 1.67 - 1.50 (m, 5H), 1.32 - 1.22 (m, 4H), 0.86 (t, J = 7.0 Hz, 3H). VI.8. Synthesis of compound 6.8
Compound 6.8 was synthesized from 6.1f by the process of example 6.1. LCMS (m/z): 424.2 [M+H]. 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1 H), 9.31 (s, 1 H), 8.51 (s, 1 H), 8.06 (s, 2H), 4.67 (d, J = 6.5 Hz, 1 H), 4.27 (t, J = 9.1 Hz, 1 H), 3.94 - 3.76 (m, 1 H), 3.08 (s, 3H), 2.80 (d, J = 13.6 Hz, 1 H), 2.21 (dd, J = 14.0, 8.9 Hz, 1 H), 1.59 (s, 3H).
VI.9. Synthesis of compound 6.9
Step 1. Synthesis of ethyl (R)-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3-(5- phenylpyridin-2-yl)oxazolidin-5-yl)propanoate [6.9a]
6.1f (0.21 g, 0.5 mmol, 1 .0 equiv), phenylboronic acid (0.071 g, 0.6 mmol, 1.2 equiv), Cs2CC>3 (0.47 g, 1.4 mmol, 3.0 equiv) were added in 1 , 4-dioxane (5 mL) and degassed for 10 minutes. PdCI2(dppf) (0.035 g, 0.05 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 90 °C for 3 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. The residue was purified by silica gel column chromatography (20-30 % EtOAc in Hexane) to afford product 6.9a (0.17 g, 66 % yield). LCMS (m/z): 433.6 [M+H].
Step 2. Synthesis of (R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-3-((S)-2-oxo-3- (5-phenyl pyridin-2-yl)oxazolidin-5-yl)propanamide [6.9]. Compound 6.9 was synthesized from 6.9a by the example of 6.1. LCMS (m/z): 420.4 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.08 (s, 1 H), 9.36 (s, 1 H), 8.78 - 8.62 (m, 1 H), 8.26 - 8.05 (m, 2H), 7.71 (t, J = 13.7 Hz, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.41 (t, J = 7.3 Hz, 1 H), 4.71 (d, J = 5.1 Hz, 1 H), 4.43 - 4.29 (m, 1 H), 3.93 (dd, J = 10.3, 7.5 Hz, 1 H), 3.20 - 2.97 (m, 3H), 2.88 - 2.77 (m, 1 H), 2.24 (dd, J = 14.5, 8.7 Hz, 1 H), 1.72 - 1.46 (m, 3H).
VI.10. Synthesis of compound 6.10
Step 1. Synthesis of ethyl 3-((S)-3-(5-(cyclopropylethynyl)pyridin-2-yl)-2-oxooxazolidin -5-yl)-2-methyl-2-(methylsulfonyl)propanoate [6.10a]. 6.1f (0.25 g, 0.6 mmol, 1.0 equiv), 3-cyclopropylpropiolic acid (0.076 g, 0.7 mmol, 1.0 equiv), 1 ,4-bis(diphenylphosphino) butane (0.005 g, 0.013 mmol, 0.02 equiv) and DBU (0.18 g, 1.1 mmol, 2.0 equiv) were added in DMSO (5 mL). The reaction mixture was degassed for 10 minutes, PdCI2(PPh3)2 (0.004 g, 0.006 mmol, 0.01 equiv) was added and the reaction mixture was stirred at 125 °C for 5 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a residue. The residue was purified by silica gel column chromatography (20-30 % ethyl acetate in Hexane) to afford product 6.10a which was carry forwarded in next step (0.18 g, 72.6 % yield). LCMS (m/z): 421.4 [M+H]. Step 2. Synthesis of (R)-3-((S)-3-(5-(cyclopropylethynyl)pyridin-2-yl)-2-oxooxazolidin- 5-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)propanamide [6.10]. 6.10a (0.14 g, 0.3 mmol, 1.0 equiv) was dissolved in ethanol (5 ml_). 35.5% aq. HCI (0.2 ml_) was added and the reaction mixture was stirred at rt for 1 hour. The reaction was quenched with water, neutralized by saturated aqueous sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford crude product. The crude product was purified by preparative HPLC purification to afford 6.10 as desired diastereomer (0.040 g, 34.5 % yield). LCMS (m/z): 408.3 [M+H]. 1H NMR (400 MHz, DMSO) δ 1 1.06 (s, 1 H), 9.30 (s, 1 H), 8.38 (d, J = 1.5 Hz, 1 H), 8.1 1 - 7.97 (m, 1 H), 7.82 (dd, J = 8.8, 2.3 Hz, 1 H), 4.67 (d, J = 8.3 Hz, 1 H), 4.29 (t, J = 9.4 Hz, 1 H), 3.86 (dd, J = 10.3, 7.5 Hz, 1 H), 3.13 - 3.01 (m, 3H), 2.79 (d, J = 14.7 Hz, 1 H), 2.21 (dd, J = 14.5, 8.7 Hz, 1 H), 1.62 - 1.46 (m, 4H), 0.90 (dt, J = 6.4, 4.0 Hz, 2H), 0.79 - 0.70 (m, 2H).
Vl.11. Synthesis of compound 6.11
Compound 6.11 was synthesized by the process of example 6.9. LCMS (m/z): 452.4 [M-1]. 1H NMR (400 MHz, DMSO) δ 1 1.06 (s, 1 H), 9.33 (s, 1 H), 8.73 (d, J = 1.5 Hz, 1 H), 8.18 (dt, J = 15.2, 5.5 Hz, 2H), 7.77 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 4.70 (d, J = 5.6 Hz, 1 H), 4.36 (t, J = 9.4 Hz, 1 H), 3.92 (dd, J = 10.3, 7.4 Hz, 1 H), 3.16 - 3.00 (m, 3H), 2.83 (d, J = 12.0 Hz, 1 H), 2.24 (dd, J = 14.5, 8.8 Hz, 1 H), 1.61 (s, 3H).
Table 1. Compound Structures and LCMS
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Pharmaceutical Activity
Example P. aeruginosa LpxC Inhibition Assay
The P. aeruginosa LpxC protein is produced according to the general method of Hyland et al (Journal of Bacteriology 1997 179, 2029-2037: Cloning, expression and purification of UDP-3-O-acyl-GlcNAc deacetylase from Pseudomonas aeruginosa: a metalloamidase of the lipid A biosynthesis pathway). The LC-MS/MS method for quantitation of LpxC product was developed using an Agilent 1200 Capillary HPLC system coupled to an Applied Biosystems MDS Sciex 4000QTRAP mass spectrometer. Both instruments are controlled using the Applied Biosystems MDS Sciex Analyst software. LpxC reaction product (UDP-3-0-(R-3-hydroxyacyl)-glucosamine) was produced by hydrolysis of LpxC substrate catalyzed by P. a. LpxC and purified using reversed phase chromatography on a
Phenomenex Luna C18(2) 4.6 x 50 mm column. An LpxC product calibration curve was generated to evaluate the sensitivity and dynamic range of the LC-MS/MS method. Briefly, compounds are pre-incubated with 1 nM P. aeruginosa LpxC for 30 min. at room
temperature. Reactions are initiated by the addition of 2 μΜ UDP-3-0-(R-3- hydroxydecanoyl)-GlcNAc. Reactions are conducted in a 384-well plate with a total volume of 50 \}L in each well containing 50 mM Sodium phosphate pH 7.5, 0.005% Trition X-100 for 20 min at room temperature. After quenching with 1.8% HOAc (5 μί of a 20% HOAc added to each well), reaction mixtures are analyzed using the LC-MS/MS method and peak areas are transformed into product concentration using a LpxC product calibration curve. Total activity (0% inhibition control) is obtained from reactions with no inhibitors and 100% inhibition control is the background using quenched samples before reaction starts. For IC50 determinations, peak areas are converted to percent inhibition in Microsoft Excel. Percent inhibition values are plotted vs. log compound concentration using XLfit. Data is fit to the four-parameter logistic equation using the non-linear regression algorithm in XLfit to return the IC5o and hill slope values.
Bacterial Screens and Cultures
Bacterial isolates were cultivated from -70°C frozen stocks by two consecutive overnight passages at 35°C in ambient air on 5% blood agar (Remel, Lenexa, Kans.). Quality control and P. aeruginosa ATCC 27853) is from the American Type Culture Collection (ATCC; Rockville, Md.) and PA01 was received from Dr. K. Poole.
Susceptibility Testing
Minimal Inhibitory Concentrations (MICs) were determined by the broth microdilution method in accordance with Clinical and Laboratories Institute (CLSI) guidelines. In brief, fresh bacterial overnight cultures were resuspended in sterile saline, adjusted to a 0.5 McFarland turbidity standard and then diluted 20010-fold in cation adjusted Mueller-Hinton Broth II (MHB; Remel BBL) to yield a final inoculum of approximately 5x105 colony-forming units (CFU)/mL. Two-fold serial dilutions of compounds were prepared in 100% dimethyl sulfoxide (DMSO) at 100-fold the highest final assay concentration; the resulting dilution series of compounds were diluted 1 :10 with sterile water. Ten μΙ of the drug dilution series in 10% DMSO was transferred to microtiter wells and 90 μΙ of bacterial suspension was inoculated into the wells. All inoculated microdilution trays were incubated in ambient air at 37 35°C for 20 hours. Following incubation, assay plates were read in a microtiter plate reader at 600 nm and visually inspected to confirm the MIC endpoint well with the OD value. The lowest concentration of the compound that prevented visible growth was recorded as the MIC. Performance of the assay was monitored by testing ciprofloxacin against laboratory quality control strains in accordance with guidelines of the
CLSI. Compounds of Examples 1-6, 8-19, 21 , 23-26 and 28-53 exhibit an MIC of 64 μg mL against at least one P. aeruginosa strain selected from PA01 and ATCC27853.
The LpxC inhibitory activity for compounds of the Examples is shown in Table A.
Table A: Biological data
Figure imgf000215_0001
P.A. LpxC P.A. PA01 WT
Cmpd number
IC50 [umol 1-1] NB52019 MIC ( g ml)
1.4 0.0076 32
2.1 0.0005 0.125
2.2 0.0007 2
2.3 0.0008 1
2.4 0.0029 16
2.5 0.0025 32
2.6 0.0019 1
2.7 0.0008 0.5
2.8 0.5
3.1.1 0.0005 0.21
3.1.2 0.0009 0.125
3.1.3 0.0005 0.2
3.1.4 0.0006 8
3.1.5 0.0005 4
3.1.6 0.0023 16
3.1.7 0.0005 1
3.1.8 0.0005 4
3.1.9 0.0005 2
3.1.10 0.0005 4
3.1.1 1 0.0005 1
3.1.12 0.0009 1.4
3.1.13 0.0005 4
3.1.14 0.0013 8
3.1.15 0.0005 2
3.1.16a 0.0005 8
3.1.17 0.0005 8
3.1.18 0.0007 2
3.1.19 0.0005 1
3.1.20 0.0006 0.5
3.1.21 0.0005 0.5
3.1.22 0.0007 1
3.1.23 0.0007 0.5
3.1.24 0.0005 1 P.A. LpxC P.A. PA01 WT
Cmpd number
IC50 [umol 1-1] NB52019 MIC (jig/ml)
3.1.25 2
3.1.26 0.5
3.1.27 0.0005 0.5
3.1.28 0.0008 1
3.1.29 0.0005 0.25
3.1.30 0.0005 1
3.1.31 0.0005 4
3.1.32 0.0005 0.5
3.1.33 0.0005 4
3.1.34 0.0005 1
3.1.35 0.0005 0.25
3.1.36 0.0006 0.5
3.1.37 0.0007 1
3.1.38 0.0012 0.25
3.1.39 0.0010 1
3.1.40 0.0005 1
3.1.41 0.0010 0.5
3.1.42 0.0036 8
3.1.43 8
3.1.44 0.0005 4
3.1.45 0.0005 2
3.1.46 0.0005 1
3.1.47 0.0005 0.71
3.1.48 0.0005 0.71
3.1.49 0.0005 0.5
3.1.50 0.0005 0.5
3.1.51 0.0005 2
3.1.52 0.0005 0.71
3.1.53 0.0005 0.5
3.1.54 0.0005 8
3.1.55 0.0005 1
3.1.56 0.0005 2
3.1.57 0.0007 0.125 P.A. LpxC P.A. PA01 WT
Cmpd number
IC50 [umol 1-1] NB52019 MIC ( g ml)
3.1.58 0.0005 0.5
3.1.59 0.0014 0.25
3.1.60 0.0007 0.5
3.2.1 0.0014 2
3.3.1 0.0005 0.25
3.3.3 0.0007 0.5
3.4.1 0.0006 0.25
3.5.1 0.0010 1
3.6.1 0.0004 0.4
3.7 0.0005 0.35
3.8 0.0005 1
3.9 0.0021 0.25
3.10 0.0005 1
3.1 1 0.0005 0.5
3.12 0.0005 0.5
4.1 0.0013 2
4.2 0.0018 8
5.1.1 0.0005 1
5.3 0.0017 4
5.4 0.0024 32
5.5 0.0018 4
5.6 0.0005 2
5.7 0.0004 0.125
5.8 0.0005 1
5.9 0.0006 0.06
5.10 0.0007 0.5
5.1 1 0.0005 0.125
5.12 0.0005 1
5.13 0.0008 0.125
5.14 0.0005 1.4
5.15 0.0005 1
5.16 0.0005 2
5.17 0.0013 1 P.A. LpxC P.A. PA01 WT
Cmpd number
IC50 [umol 1-1] NB52019 MIC (jig/ml)
5.18 0.25
5.19 2
5.20 0.5
5.21 0.0005 0.25
5.22 0.0005 0.25
5.23 0.0005 0.5
5.24 0.0005 0.125
5.25 0.0006 2
5.26 0.0005 2
5.27 0.0005 0.71
5.28 0.0008 4
5.29 0.0005 4
6.1 0.0021 1
6.2 0.001 1 8
6.3 0.0012 8
6.4 0.0006 4
6.5 0.0008 0.25
6.6 0.0017 2
6.7 0.0005 2
6.8 0.0016 4
6.9 0.0005 0.35
6.10 0.0006 1
6.1 1 0.5
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the following claims.

Claims

CLAIMS We Claim:
1. A compound of the formula (I):
Figure imgf000220_0001
or a pharmaceutically acceptable salt thereof, wherein: X is N or C, wherein when X is N, R4 is absent; Y is N or C, wherein when Y is N, R5 is absent;
R1, R2, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, -CH3, and -Cihaloalkyl;
R3 is L-R;
L is a divalent bond, or -CH2-;
R is selected from group consisting of
halogen,
-CrC4alkyl optionally substituted with one or more groups selected from halogen, d- C4alkoxy, -CN and -OH;
-CN,
-CrC4alkoxy optionally substituted with one or more groups selected from halogen, C C4alkoxy, -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-C6alkenyl optionally substituted with one or more groups selected from halogen, - CN, -OH and C C4alkoxy;
-C2-C6alkynyl optionally substituted with one or more groups selected from halogen, C C4alkoxy, -CN and -OH;
-C3-C7cycloalkyl optionally substituted with one or more groups selected from halogen, CrC4alkyl, -Ci-C4alkylCrC4alkoxy, CrC4alkoxy, CrC4haloalkyl, nitrile, -S(0)2C C4alkyl and -OH;
-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl and C C alkyl;
-CrC alkyl-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more groups selected from halogen, Ci-C4alkoxy, Ci-C4haloalkoxy, CrC4haloalkyl and Ci-C4 alkyl;
-CrC alkyl-C3-C7cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more groups selected from halogen, Ci-C alkoxy, C C haloalkoxy, CrC haloalkyl and Ci-C4 alkyl;
-C5-C6cycloalkenyl optionally substituted with one or more groups selected from halogen, C C alkoxy, CrC haloalkoxy, Ci-C haloalkyl and C C alkyl;
4 to 7 membered 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)2CrC alkyl and -OH, and said heterocyclyl may contain one unsaturated bond;
-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 groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, - S(0)2C C4alkyl and -OH;
-C3-C5cycloalkyl-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 groups selected from halogen, C C alkoxy, Ci-C haloalkoxy, CrC haloalkyl, Ci-C alkyl, nitrile, -S(0)2C C4alkyl and -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 groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, -S(0)2C C alkyl and -OH;
-C C alkyl-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 groups selected from halogen, C C alkoxy, Ci-C haloalkoxy, CrC haloalkyl, Ci-C alkyl, nitrile, - S(0)2C C4alkyl and -OH; and
-C3-C5cycloalkyl-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 groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, - S(0)2C C4alkyl and -OH; or
Figure imgf000222_0001
R is selected from group consisting of
-CrCealkyl optionally substituted with one or more groups selected from halogen, Ci- 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;
-C2-C6alkenyl optionally substituted with one or more groups selected from halogen, - CN, -OH and C C4alkoxy;
-C2-C4alkynyl optionally substituted with one or more groups selected from halogen, C C4alkoxy, -CN and -OH ;
-C3-C7cycloalkyl 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)2C C alkyl, -OH , and C C3 alkyl substituted with a group selected from CN, OH, -S02R', - 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;
-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl and C C alkyl;
-CrC alkyl-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more groups selected from halogen, C C alkoxy, C C haloalkoxy, CrC haloalkyl and C C alkyl;
4 to 7 membered 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)2C C alkyl and -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 groups selected from halogen, C C alkoxy, Ci-C haloalkoxy, CrC haloalkyl, Ci-C alkyl, nitrile, - S(0)2C C4alkyl and -OH;
-C3-C5cycloalkyl-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 groups selected from halogen, C C alkoxy, C C haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, -S(0)2C C4alkyl and -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 groups selected from halogen, CrC4alkoxy, CrC4haloalkoxy, CrC4haloalkyl, C1-C4 alkyl, nitrile, -S(0)2CrC4alkyl and -OH;
-CrC4alkyl-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 groups selected from halogen, C C4alkoxy, CrC4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, - S(0)2C C4alkyl and -OH; and
-C3-C5cycloalkyl-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 groups selected from halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, - S(0)2CrC4alkyl and -OH; or
R2 and R3 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 C4 alkyl.
2. The compound of claim 1 , wherein X is N and Y is C, and R4 is absent.
3. The compound of claim 1 , wherein X is C and Y is N, and R5 is absent.
4. The compound of claim 1 , wherein X is C and Y is C. '
5. The compound of any of the preceding claims, wherein L is
6. The compound of any of claims 1-4, wherein L is a bond.
Figure imgf000223_0001
7. The compound of any of claims 1-4, wherein L is
8. The compound of any of the preceding claims, wherein R is -C3- C7cycloalkyl optionally substituted with one to three groups selected from halogen, d- C alkyl, -Ci-C alkylCrC alkoxy, CrC alkoxy, CrC haloalkyl, nitrile, -S(0)2CrC alkyl, and - OH.
9. The compound of any of claims 1-7, wherein R is phenyl optionally substituted with one to three groups selected from halogen, Ci-C alkoxy, Ci-C haloalkoxy, CrC haloalkyl and C C alkyl.
10. The compound of any of the preceding claims, wherein Z is H.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: X is N or C, wherein when X is N, R4 is absent; Y is N or C, wherein when Y is N, R5 is absent;
R1, R2, R4 or R5 are independently selected from the group consisting of hydrogen, halogen, -CH3, and -Cihaloalkyl;
R3 is L-R;
L is a divalent bond, or -CH2-;
R is selected from group consisting of
halogen,
-CrC4alkyl optionally substituted with halogen, CrC4alkoxy, -CN or -OH,
-CN,
-CrC4alkoxy optionally substituted with halogen or CrC4alkoxy,
-C2-C6alkenyl optionally substituted with halogen, -CN, -OH or C C alkoxy,
-C2-C alkynyl optionally substituted with halogen, C C alkoxy, -CN or -OH,
-C3-C7cycloalkyl optionally substituted with halogen, Ci-C alkyl, -d-C alkylCr
C4alkoxy, C C4alkoxy, C C4haloalkyl, nitrile, -S(0)2C C4alkyl or -OH,
-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, C
C alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl,
-CrC4alkyl-C6-Cioaryl, wherein the aryl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl or Ci-C alkyl,
4 to 7 membered 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 C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl 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)2C C alkyl or -OH,
-C3-C5cycloalkyl-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, Ci-C alkoxy, C C haloalkoxy, CrC haloalkyl, Ci-C alkyl, nitrile, -S(0)2Cr C4alkyl 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-C4alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2CrC4alkyl or -OH,
-CrC4alkyl-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 alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, -S(0)2CrC alkyl or -OH, and
-C3-C5cycloalkyl-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, C C4alkoxy, d-C4haloalkoxy, d-C4haloalkyl, d-d alkyl, nitrile, -S(0)2d-dalkyl or -OH; or '
L is ;
R is selected from group consisting of
-CrC4alkyl optionally substituted with halogen, Ci-C4alkoxy, -CN or -OH,
-C2-C6alkenyl optionally substituted with halogen, -CN, -OH or d-dalkoxy,
-C2-C alkynyl optionally substituted with halogen, d-dalkoxy, -CN or -OH,
-C3-C7cycloalkyl optionally substituted with halogen, CrC4alkyl, -d-dalkyld-
C4alkoxy, d-dalkoxy, C C4haloalkyl, nitrile, -S(0)2C C4alkyl or -OH,
-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, d-
C alkoxy, CrC haloalkoxy, CrC haloalkyl or d-d alkyl,
-CrC alkyl-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, d-dalkoxy, CrC haloalkoxy, CrC haloalkyl or Ci-C alkyl,
4 to 7 membered heterocyclyl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, d-dalkoxy, CrC4haloalkoxy, Ci-C4haloalkyl, d-C4 alkyl, nitrile, -S(0)2Ci-C4alkyl 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, d-dalkoxy, CrC haloalkoxy, CrC haloalkyl, d-d alkyl, nitrile, -S(0)2C C alkyl or -OH,
-C3-C5cycloalkyl-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, Ci-C alkoxy, d-dhaloalkoxy, CrC haloalkyl, Ci-C alkyl, nitrile, -S(0)2d- C4alkyl 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, Ci-C alkoxy, C C4haloalkoxy, d-C4haloalkyl, d-d alkyl, nitrile, -S(0)2C C4alkyl or -OH, -CrC4alkyl-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- C4alkoxy, CrC4haloalkoxy, CrC4haloalkyl, C C alkyl, nitrile, -S(0)2CrC alkyl or -OH, and
-C3-C5cycloalkyl-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, C C4alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl or -OH; or
R2 and R3 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.
12. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or claim 1 1 , which is represented by formula II:
Figure imgf000226_0001
II wherein X, Y, R1 , R2, R3, R4 and R5 are as defined in claim 1 or claim 1 1
13. The compound or a pharmaceutically acceptable salt thereof according to claim 12, which is represented by formula III:
Figure imgf000226_0002
III
wherein
X is N or C, wherein when X is N, R4 is absent; Y is N or C, wherein when Y is N, R5 is absent;
R1, R2, R4 or R5 are independently selected from the group consisting of hydrogen, halogen, -CH3 , and Cihaloalkyl;
R is selected from group consisting of
-C C4alkyl optionally substituted with halogen, CrC4alkoxy, -CN or -OH,
-C2-C6alkenyl optionally substituted with halogen, -CN, -OH or CrC4alkoxy,
-C2-C4alkynyl optionally substituted with halogen, Ci-C4alkoxy, -CN or -OH,
-C3-C7cycloalkyl optionally substituted with halogen, CrC4alkyl, -CrC alkylCr
C4alkoxy, C C4alkoxy, C C4haloalkyl, nitrile, -S(0)2C C4alkyl or -OH,
-Ce-Cioaryl, wherein the aryl is optionally substituted with one or more halogen, Cr
C alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl,
-CrC alkyl-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, CrC haloalkyl or Ci-C alkyl,
4 to 7 membered 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 C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl 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)2CrC alkyl or -OH,
-C3-C5cycloalkyl-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, Ci-C alkoxy, Ci-C haloalkoxy, Ci-C haloalkyl, Ci-C alkyl, nitrile, -S(0)2Ci- C4alkyl 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, C C alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl or -OH,
-CrC alkyl-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 alkoxy, CrC haloalkoxy, CrC haloalkyl, C C alkyl, nitrile, -S(0)2C C alkyl or -OH, and
-C3-C5cycloalkyl-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, C C4alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl or -OH.
14. The compound or a pharmaceutically acceptable salt thereof according to any preceding claim, wherein X is C,
Y is N or C, wherein when Y is N, R5 is absent;
R1, R2, R4 or R5 are independently selected from the group consisting of hydrogen and halogen;
R is selected from group consisting of
-CrC4alkyl optionally substituted with halogen, CrC4alkoxy, -CN or -OH,
-C2-C6alkene optionally substituted with halogen, CrC4alkoxy, -CN or -OH,
-C3-C7cycloalkyl optionally substituted with halogen, Ci-C4alkyl, -Ci-C4alkylCr
C4alkoxy, C C4alkoxy, C C4haloalkyl, nitrile, -S(0)2C C4alkyl or -OH,
-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, C
C alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl,
-CrC alkyl-C6-Ci0aryl, wherein the aryl is optionally substituted with one or more halogen, C C alkoxy, CrC haloalkoxy, Ci-C haloalkyl or Ci-C alkyl,
4 to 7 membered 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 C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2C C4alkyl 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)2CrC alkyl or -OH,
-C3-C5cycloalkyl-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, Ci-C alkoxy, C C haloalkoxy, CrC haloalkyl, Ci-C alkyl, nitrile, -S(0)2Cr C4alkyl 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, Ci-C alkoxy, CrC haloalkoxy, Ci-C haloalkyl or C C alkyl, and
-CrC alkyl-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, Ci- C alkoxy, CrC haloalkoxy, CrC haloalkyl or C C alkyl.
15. The compound or a pharmaceutically acceptable salt thereof according to any proceeding claim, wherein the compound is formula III
X is C, Y is C,
R1, R2, R4 or R5 are independently selected from the group consisting of hydrogen and halogen;
R is selected from group consisting of
-C C4alkyl optionally substituted with halogen, Ci-C4alkoxy, -CN or -OH,
-C3-C7cycloalkyl optionally substituted with halogen, d-C4alkyl, -CrC4alkylCr C4alkoxy, C C4alkoxy, C C4haloalkyl, nitrile, -S(0)2Ci-C4alkyl or -OH,
-Ce-Cioaryl, wherein the aryl is optionally substituted with one or more halogen, d- C4alkoxy, CrC4haloalkoxy, CrC4haloalkyl or C C4 alkyl,
-CrC4alkyl-C6-Cioaryl, wherein the aryl is optionally substituted with one or more halogen, CrC4alkoxy, CrC4haloalkoxy, CrC4haloalkyl or CrC4 alkyl,
4 to 7 membered heterocyclyl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, CrC4alkoxy, C C4haloalkoxy, C C4haloalkyl, C C4 alkyl, nitrile, -S(0)2CrC4alkyl or -OH,
-CrC4alkyl-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, CrC4alkoxy, CrC4haloalkoxy, CrC4haloalkyl, C C4 alkyl, nitrile, -S(0)2CrC4alkyl or -OH,
-C3-C5cycloalkyl-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, CrC4alkoxy, CrC4haloalkoxy, CrC4haloalkyl, Ci-C4 alkyl, nitrile, -S(0)2Ci- C4alkyl 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, CrC4alkoxy, CrC4haloalkoxy, CrC4haloalkyl or CrC4 alkyl, and
-CrC4alkyl-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- C4alkoxy, CrC4haloalkoxy, CrC4haloalkyl or C C4 alkyl.
16. The compound or a pharmaceutically acceptable salt thereof according to any preceding claim, wherein the compound is formula III,
wherein
X is C,
Y is C, R1 , R2, R4 or R5 are independently selected from the group consisting of hydrogen and halogen;
R is selected from group consisting of
4 to 7 membered heterocyclyl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, CrC4alkoxy, CrC4haloalkoxy, CrC4haloalkyl or CrC4 alkyl,
-CrC alkyl-4 to 7 membered heterocyclyl containing 1 to 3 heteroatom selected from N, S, and O, wherein said heterocyclyl is optionally substituted with one or more halogen, CrC alkoxy, C C haloalkoxy, CrC haloalkyl or C C alkyl,
-C3-C7cycloalkyl optionally substituted with halogen, Ci-C alkyl, -CrC alkylCr C4alkoxy, Ci-C4alkoxy, CrC4haloalkyl or -OH, and
-CrC alkyl optionally substituted with halogen, C C alkoxy, -CN or -OH.
17. The compound or a pharmaceutically acceptable salt thereof according to any preceding claim, wherein the compound is formula III,
wherein
X is C,
Y is C,
R1 , R2, R4 or R5 are independently selected from the group consisting of hydrogen and halogen;
R is selected from group consisting of
Figure imgf000230_0001
Figure imgf000230_0002
HON'" \ Olli"
Figure imgf000231_0001
, and
Figure imgf000231_0002
18. The compound of claim 12, represented by formula III, wherein:
X is C;
Y is C;
R1, R2, R4 or R5 are independently selected from the group consisting of hydrogen, halogen, -CH3 , and Cihaloalkyl;
R3 is L-R;
L is a divalent bond, or -CH2-;
R is halogen,
-CrC4alkyl optionally substituted with halogen, CrC4alkoxy, -CN or -OH, -CN,
-CrC4alkoxy optionally substituted with halogen or CrC4alkoxy, or
R2 and R3 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.
19. The compound according to claim 12, wherein
L is a direct bond;
Figure imgf000231_0003
R is selected from group consisting of , Br, , and
Figure imgf000231_0004
20. A pharmaceutical composition, comprising the compound according to any of claims 1 -19 and a pharmaceutically acceptable carrier.
21 . A pharmaceutical combination composition, comprising:
a compound according to any of claims 1 -19,
an antibacterial effective amount of a second therapeutic agent, and
a pharmaceutically acceptable carrier.
22. The pharmaceutical combination composition according to claim 21 , wherein the second therapeutic agent is selected from the group consisting of Ampicillin, Piperacillin, Penicillin G, Ticarcillin, Imipenem, Meropenem, Azithromycin, erythromycin, Aztreonam, Cefepime, Cefotaxime, Ceftriaxone, Cefatazidime, Ciprofloxacin, Levofloxacin, Clindamycin, Doxycycline, Gentamycin, Amikacin, Tobramycin, Tetracycline, Tegacyclin, Rifampicin, Vancomycin and Polymyxin.
23. A method of inhibiting a deacetylase enzyme in a Gram-negative bacterium, comprising contacting the Gram-negative bacteria with a compound according to any one of claims 1 -19.
24. A method for treating a subject with a Gram-negative bacterial infection, comprising:
administering to the subject in need thereof an antibacterial effective amount of the compound according to any one of claims 1 -19 and a pharmaceutically acceptable carrier.
25. The method of claim 24, wherein the Gram-negative bacterial infection is an infection comprising at least one bacterium selected from the group consisting of
Pseudomonas, Stenotrophomonas maltophila, Burkholderia, Alcaligenes xylosoxidans, Acinetobacter, Enterobacteriaceae, Haemophilus, Moraxella, Bacteroids, Fransicella, Shigella, Proteus, Vibrio, Salmonella, Bordetella, Helicobactor, Legionella, Citrobactor, Serratia, Campylobactor, Yersinia and Neisseria.
26. The method of claim 25, wherein the bacterium is a Enterobacteriaceae which is selected from the group consisting of Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Providencia, Morganella, Cedecea, Yersinia, and Edwardsiella species and Escherichia coli.
27. A compound according to any one of claims 1-19 or a pharmaceutically acceptable salt thereof, for use as a medicament.
28. The compound according to claim 27, for use in treatment of a Gram-negative bacterial infection.
29. The compound according to claims 28 or a pharmaceutically acceptable salt thereof for use in treatment of a Gram-negative bacterial infection, wherein the Gram- negative bacterial infection is caused by a bacterium selected from Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans, Acinetobacter, Enterobacteriaceae, Haemophilus, and Neisseria species.
30. Use of the compound according to any one of claims 1-19, for the preparation of a medicament for the treatment of a Gram-negative bacterial infection in a subject, wherein the bacterial infection is selected from Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans, Acinetobacter,
Enterobacteriaceae, Haemophilus, and Neisseria species.
31. The use of claim 30, wherein the bacterial infection is an Enterobacteriaceae selected from the group consisting of Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Providencia, Morganella, Cedecea, and Edwardsiella species and Escherichia coli.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106045934A (en) * 2015-10-27 2016-10-26 博瑞生物医药（苏州）股份有限公司 Crystal form of intermediate used for synthesis of tedizolid
WO2017037221A1 (en) 2015-09-03 2017-03-09 Actelion Pharmaceuticals Ltd Substituted 1,2-dihydro-3h-pyrrolo[1,2-c]imidazol-3-one antibacterial compounds
JP2018526354A (en) * 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 Substituted 1,2-dihydro-3H-pyrrolo [1,2-c] imidazol-3-one antibacterial agent
WO2019086452A1 (en) 2017-10-31 2019-05-09 Idorsia Pharmaceuticals Ltd Antibacterial heteroaromatic compounds

Citations (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0090505B1 (en) 1982-03-03 1990-08-08 Genentech, Inc. Human antithrombin iii, dna sequences therefor, expression vehicles and cloning vectors containing such sequences and cell cultures transformed thereby, a process for expressing human antithrombin iii, and pharmaceutical compositions comprising it
WO1999020758A1 (en) 1997-10-21 1999-04-29 Human Genome Sciences, Inc. Human tumor necrosis factor receptor-like proteins tr11, tr11sv1, and tr11sv2
WO1999040196A1 (en) 1998-02-09 1999-08-12 Genentech, Inc. Novel tumor necrosis factor receptor homolog and nucleic acids encoding the same
US6111090A (en) 1996-08-16 2000-08-29 Schering Corporation Mammalian cell surface antigens; related reagents
WO2001003720A2 (en) 1999-07-12 2001-01-18 Genentech, Inc. Promotion or inhibition of angiogenesis and cardiovascularization by tumor necrosis factor ligand/receptor homologs
WO2004078163A2 (en) 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen
WO2005007190A1 (en) 2003-07-11 2005-01-27 Schering Corporation Agonists or antagonists of the clucocorticoid-induced tumour necrosis factor receptor (gitr) or its ligand for the treatment of immune disorders, infections and cancer
WO2005054234A2 (en) * 2003-09-08 2005-06-16 Wockhardt Limited Substituted piperidino phenyloxazolidinones having antimicriobial activity with improved in vivo efficacy
WO2005055808A2 (en) 2003-12-02 2005-06-23 Genzyme Corporation Compositions and methods to diagnose and treat lung cancer
WO2005115451A2 (en) 2004-04-30 2005-12-08 Isis Innovation Limited Methods for generating improved immune response
WO2006083289A2 (en) 2004-06-04 2006-08-10 Duke University Methods and compositions for enhancement of immunity by in vivo depletion of immunosuppressive cell activity
WO2006121168A1 (en) 2005-05-09 2006-11-16 Ono Pharmaceutical Co., Ltd. Human monoclonal antibodies to programmed death 1(pd-1) and methods for treating cancer using anti-pd-1 antibodies alone or in combination with other immunotherapeutics
WO2007005874A2 (en) 2005-07-01 2007-01-11 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (pd-l1)
WO2007133822A1 (en) 2006-01-19 2007-11-22 Genzyme Corporation Gitr antibodies for the treatment of cancer
EP1866339A2 (en) 2005-03-25 2007-12-19 TolerRx, Inc Gitr binding molecules and uses therefor
WO2009101611A1 (en) 2008-02-11 2009-08-20 Curetech Ltd. Monoclonal antibodies for tumor treatment
WO2009114335A2 (en) 2008-03-12 2009-09-17 Merck & Co., Inc. Pd-1 binding proteins
US7618632B2 (en) 2003-05-23 2009-11-17 Wyeth Method of treating or ameliorating an immune cell associated pathology using GITR ligand antibodies
WO2010003118A1 (en) 2008-07-02 2010-01-07 Trubion Pharmaceuticals, Inc. Tgf-b antagonist multi-target binding proteins
US20100028330A1 (en) 2002-12-23 2010-02-04 Medimmune Limited Methods of upmodulating adaptive immune response using anti-pd1 antibodies
WO2010019570A2 (en) 2008-08-11 2010-02-18 Medarex, Inc. Human antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
WO2010027827A2 (en) 2008-08-25 2010-03-11 Amplimmune, Inc. Targeted costimulatory polypeptides and methods of use to treat cancer
WO2010077634A1 (en) 2008-12-09 2010-07-08 Genentech, Inc. Anti-pd-l1 antibodies and their use to enhance t-cell function
WO2011028683A1 (en) 2009-09-03 2011-03-10 Schering Corporation Anti-gitr antibodies
WO2011051726A2 (en) 2009-10-30 2011-05-05 Isis Innovation Ltd Treatment of obesity
WO2011066342A2 (en) 2009-11-24 2011-06-03 Amplimmune, Inc. Simultaneous inhibition of pd-l1/pd-l2
WO2011090754A1 (en) 2009-12-29 2011-07-28 Emergent Product Development Seattle, Llc Polypeptide heterodimers and uses thereof
US20120039906A1 (en) 2009-02-09 2012-02-16 INSER (Institut National de la Recherche Medicale) PD-1 Antibodies and PD-L1 Antibodies and Uses Thereof
US20120114649A1 (en) 2008-08-25 2012-05-10 Amplimmune, Inc. Delaware Compositions of pd-1 antagonists and methods of use
US8354509B2 (en) 2007-06-18 2013-01-15 Msd Oss B.V. Antibodies to human programmed death receptor PD-1
WO2013021363A1 (en) * 2011-08-11 2013-02-14 Actelion Pharmaceuticals Ltd Quinazoline-2,4-dione derivatives
WO2013039954A1 (en) 2011-09-14 2013-03-21 Sanofi Anti-gitr antibodies
WO2013079174A1 (en) 2011-11-28 2013-06-06 Merck Patent Gmbh Anti-pd-l1 antibodies and uses thereof
EP1947183B1 (en) 1996-08-16 2013-07-17 Merck Sharp & Dohme Corp. Mammalian cell surface antigens; related reagents
WO2013149136A1 (en) 2012-03-30 2013-10-03 Cubist Pharmaceuticals, Inc. ISOXAZOLE β-LACTAMASE INHIBITORS
US20130281359A1 (en) 2011-12-02 2013-10-24 Naeja Pharmaceutical Inc. New bicyclic compounds and their use as antibacterial agents and beta-lactamase inhibitors
US8586023B2 (en) 2008-09-12 2013-11-19 Mie University Cell capable of expressing exogenous GITR ligand
US8591886B2 (en) 2007-07-12 2013-11-26 Gitr, Inc. Combination therapies employing GITR binding molecules
WO2014008218A1 (en) 2012-07-02 2014-01-09 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
WO2014152996A1 (en) 2013-03-14 2014-09-25 Cubist Pharmaceuticals, Inc. Crystalline form of a beta-lactamase inhibitor
WO2014160649A1 (en) 2013-03-29 2014-10-02 Novartis Ag Hydroxamic acid derivatives as lpxc inhibitors for the treatment of bacterial infections

Patent Citations (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0090505B1 (en) 1982-03-03 1990-08-08 Genentech, Inc. Human antithrombin iii, dna sequences therefor, expression vehicles and cloning vectors containing such sequences and cell cultures transformed thereby, a process for expressing human antithrombin iii, and pharmaceutical compositions comprising it
US6111090A (en) 1996-08-16 2000-08-29 Schering Corporation Mammalian cell surface antigens; related reagents
EP1947183B1 (en) 1996-08-16 2013-07-17 Merck Sharp & Dohme Corp. Mammalian cell surface antigens; related reagents
US7025962B1 (en) 1996-08-16 2006-04-11 Schering Corporation Mammalian cell surface antigens; related reagents
WO1999020758A1 (en) 1997-10-21 1999-04-29 Human Genome Sciences, Inc. Human tumor necrosis factor receptor-like proteins tr11, tr11sv1, and tr11sv2
WO1999040196A1 (en) 1998-02-09 1999-08-12 Genentech, Inc. Novel tumor necrosis factor receptor homolog and nucleic acids encoding the same
WO2001003720A2 (en) 1999-07-12 2001-01-18 Genentech, Inc. Promotion or inhibition of angiogenesis and cardiovascularization by tumor necrosis factor ligand/receptor homologs
US20100028330A1 (en) 2002-12-23 2010-02-04 Medimmune Limited Methods of upmodulating adaptive immune response using anti-pd1 antibodies
WO2004078163A2 (en) 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen
US7618632B2 (en) 2003-05-23 2009-11-17 Wyeth Method of treating or ameliorating an immune cell associated pathology using GITR ligand antibodies
WO2005007190A1 (en) 2003-07-11 2005-01-27 Schering Corporation Agonists or antagonists of the clucocorticoid-induced tumour necrosis factor receptor (gitr) or its ligand for the treatment of immune disorders, infections and cancer
WO2005054234A2 (en) * 2003-09-08 2005-06-16 Wockhardt Limited Substituted piperidino phenyloxazolidinones having antimicriobial activity with improved in vivo efficacy
WO2005055808A2 (en) 2003-12-02 2005-06-23 Genzyme Corporation Compositions and methods to diagnose and treat lung cancer
WO2005115451A2 (en) 2004-04-30 2005-12-08 Isis Innovation Limited Methods for generating improved immune response
WO2006083289A2 (en) 2004-06-04 2006-08-10 Duke University Methods and compositions for enhancement of immunity by in vivo depletion of immunosuppressive cell activity
US8388967B2 (en) 2005-03-25 2013-03-05 Gitr, Inc. Methods for inducing or enhancing an immune response by administering agonistic GITR-binding antibodies
EP1866339A2 (en) 2005-03-25 2007-12-19 TolerRx, Inc Gitr binding molecules and uses therefor
US7812135B2 (en) 2005-03-25 2010-10-12 Tolerrx, Inc. GITR-binding antibodies
EP2161336A1 (en) 2005-05-09 2010-03-10 ONO Pharmaceutical Co., Ltd. Human monoclonal antibodies to programmed death 1(PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
US8008449B2 (en) 2005-05-09 2011-08-30 Medarex, Inc. Human monoclonal antibodies to programmed death 1 (PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
WO2006121168A1 (en) 2005-05-09 2006-11-16 Ono Pharmaceutical Co., Ltd. Human monoclonal antibodies to programmed death 1(pd-1) and methods for treating cancer using anti-pd-1 antibodies alone or in combination with other immunotherapeutics
US7943743B2 (en) 2005-07-01 2011-05-17 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (PD-L1)
WO2007005874A2 (en) 2005-07-01 2007-01-11 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (pd-l1)
WO2007133822A1 (en) 2006-01-19 2007-11-22 Genzyme Corporation Gitr antibodies for the treatment of cancer
US8354509B2 (en) 2007-06-18 2013-01-15 Msd Oss B.V. Antibodies to human programmed death receptor PD-1
US8591886B2 (en) 2007-07-12 2013-11-26 Gitr, Inc. Combination therapies employing GITR binding molecules
WO2009101611A1 (en) 2008-02-11 2009-08-20 Curetech Ltd. Monoclonal antibodies for tumor treatment
WO2009114335A2 (en) 2008-03-12 2009-09-17 Merck & Co., Inc. Pd-1 binding proteins
WO2010003118A1 (en) 2008-07-02 2010-01-07 Trubion Pharmaceuticals, Inc. Tgf-b antagonist multi-target binding proteins
US20110150892A1 (en) 2008-08-11 2011-06-23 Medarex, Inc. Human antibodies that bind lymphocyte activation gene-3 (lag-3) and uses thereof
WO2010019570A2 (en) 2008-08-11 2010-02-18 Medarex, Inc. Human antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
US8609089B2 (en) 2008-08-25 2013-12-17 Amplimmune, Inc. Compositions of PD-1 antagonists and methods of use
WO2010027827A2 (en) 2008-08-25 2010-03-11 Amplimmune, Inc. Targeted costimulatory polypeptides and methods of use to treat cancer
US20120114649A1 (en) 2008-08-25 2012-05-10 Amplimmune, Inc. Delaware Compositions of pd-1 antagonists and methods of use
US8586023B2 (en) 2008-09-12 2013-11-19 Mie University Cell capable of expressing exogenous GITR ligand
WO2010077634A1 (en) 2008-12-09 2010-07-08 Genentech, Inc. Anti-pd-l1 antibodies and their use to enhance t-cell function
US20120039906A1 (en) 2009-02-09 2012-02-16 INSER (Institut National de la Recherche Medicale) PD-1 Antibodies and PD-L1 Antibodies and Uses Thereof
WO2011028683A1 (en) 2009-09-03 2011-03-10 Schering Corporation Anti-gitr antibodies
WO2011051726A2 (en) 2009-10-30 2011-05-05 Isis Innovation Ltd Treatment of obesity
WO2011066342A2 (en) 2009-11-24 2011-06-03 Amplimmune, Inc. Simultaneous inhibition of pd-l1/pd-l2
WO2011090754A1 (en) 2009-12-29 2011-07-28 Emergent Product Development Seattle, Llc Polypeptide heterodimers and uses thereof
WO2013021363A1 (en) * 2011-08-11 2013-02-14 Actelion Pharmaceuticals Ltd Quinazoline-2,4-dione derivatives
WO2013039954A1 (en) 2011-09-14 2013-03-21 Sanofi Anti-gitr antibodies
WO2013079174A1 (en) 2011-11-28 2013-06-06 Merck Patent Gmbh Anti-pd-l1 antibodies and uses thereof
US20130281359A1 (en) 2011-12-02 2013-10-24 Naeja Pharmaceutical Inc. New bicyclic compounds and their use as antibacterial agents and beta-lactamase inhibitors
WO2013149136A1 (en) 2012-03-30 2013-10-03 Cubist Pharmaceuticals, Inc. ISOXAZOLE β-LACTAMASE INHIBITORS
WO2014008218A1 (en) 2012-07-02 2014-01-09 Bristol-Myers Squibb Company Optimization of antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof
WO2014152996A1 (en) 2013-03-14 2014-09-25 Cubist Pharmaceuticals, Inc. Crystalline form of a beta-lactamase inhibitor
WO2014160649A1 (en) 2013-03-29 2014-10-02 Novartis Ag Hydroxamic acid derivatives as lpxc inhibitors for the treatment of bacterial infections

Non-Patent Citations (24)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY
"Science of Synthesis: Houben-Weyl Methods of Molecular Transformation", 2005, GEORG THIEME VERLAG
"Science of Synthesis: Houben-Weyl Methods of Molecular Transformation", vol. 48, 2005, GEORG THIEME VERLAG, pages: 41627
"The Peptides", vol. 3, 1981, ACADEMIC PRESS
BENNETT ET AL., J. IMMUNOL., vol. 170, 2003, pages 711 - 8
BLANK ET AL., CANCER IMMUNOL. IMMUNOTHER., vol. 54, 2005, pages 307 - 314
BLANK, C. ET AL., IMMUNOL. IMMUNOTHER., vol. 56, no. 5, 29 December 2006 (2006-12-29), pages 739 - 745
BROWN ET AL., J. IMMUNOL., vol. 170, 2003, pages 1257 - 66
DONG ET AL., J. MOL. MED., vol. 81, 2003, pages 281 - 7
H.-D. JAKUBKE; H. JESCHKEIT: "Aminosauren, Peptide, Proteine", 1982, VERLAG CHEMIE
HAMID, O. ET AL., NEW ENGLAND JOURNAL OF MEDICINE, vol. 369, no. 2, 2013, pages 134 - 44
HOUBEN WEYL: "Methoden der organischen Chemie", vol. 15, 1974, GEORG THIEME VERLAG
HOUBEN-WEYL: "Methods of Organic Synthesis", vol. 21, 1952, THIEME
HOUBEN-WEYL: "Methods of Organic Synthesis", vol. 21, THIEME
HYLAND ET AL., JOURNAL OF BACTERIOLOGY, vol. 179, 1997, pages 2029 - 2037
ISHIDA, Y. ET AL., EMBO J., vol. 11, 1992, pages 3887 - 3895
IWAI ET AL., PROC. NAT'L. ACAD. SCI. USA, vol. 99, 2002, pages 12293 - 7
J. F. W. MCOMIE: "Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
JOCHEN LEHMANN: "Chemie der Kohlenhydrate: Monosaccharide und Derivate", 1974, GEORG THIEME VERLAG
KONISHI ET AL., CLIN. CANCER RES., vol. 10, 2004, pages 5094 - 100
OKAZAKI ET AL., CURR OPIN IMMUNOL, vol. 14, 2002, pages 391779 - 82
STAHL; WERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH
T. W. GREENE; P. G. M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY
WOO ET AL., CANCER RES., vol. 72, no. 4, 2012, pages 917 - 27

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018526354A (en) * 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 Substituted 1,2-dihydro-3H-pyrrolo [1,2-c] imidazol-3-one antibacterial agent
US10441576B2 (en) 2015-08-11 2019-10-15 Idorsia Pharmaceuticals Ltd. Substituted 1,2-dihydro-3H pyrrolo[1,2-c]imidazol-3 one antibacterials
WO2017037221A1 (en) 2015-09-03 2017-03-09 Actelion Pharmaceuticals Ltd Substituted 1,2-dihydro-3h-pyrrolo[1,2-c]imidazol-3-one antibacterial compounds
US10314823B2 (en) 2015-09-03 2019-06-11 Idorsia Pharmaceuticals Ltd Substituted 1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one antibacterial compounds
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