WO2019086452A1 - Composés hétéroaromatiques antibactériens - Google Patents

Composés hétéroaromatiques antibactériens Download PDF

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Publication number
WO2019086452A1
WO2019086452A1 PCT/EP2018/079707 EP2018079707W WO2019086452A1 WO 2019086452 A1 WO2019086452 A1 WO 2019086452A1 EP 2018079707 W EP2018079707 W EP 2018079707W WO 2019086452 A1 WO2019086452 A1 WO 2019086452A1
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Prior art keywords
methyl
methylsulfonyl
butanamide
hydroxy
oxo
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PCT/EP2018/079707
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English (en)
Inventor
Stefan Diethelm
Jean-Christophe Gauvin
Loïc JACOB
Philippe Panchaud
Christine Schmitt
Jean-Philippe Surivet
Naomi TIDTEN-LUKSCH
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Idorsia Pharmaceuticals Ltd
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Publication of WO2019086452A1 publication Critical patent/WO2019086452A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention concerns heteroaromatic antibacterial compounds, pharmaceutical compositions containing them and uses of these compounds in the manufacture of medicaments for the treatment of bacterial infections.
  • These compounds are useful antimicrobial agents effective against a variety of human and veterinary pathogens, especially Gram-negative aerobic and anaerobic bacteria.
  • the compounds of the present invention can optionally be employed in combination, either sequentially or simultaneously, with one or more therapeutic agents effective against bacterial infections.
  • Another embodiment of the present invention relates to compounds according to embodiment 1 , wherein M represents M2.
  • Another embodiment of the present invention relates to compounds according to any one of
  • Another embodiment of the present invention relates to compounds according to any one of
  • T represents a di-substituted cyclopropyl, wherein both substituents are attached to thesame carbon atom and wherein one substituent is methyl and the other is independently selected from
  • Another embodiment of the present invention relates to compounds according to any one of
  • T represents a mono-substituted cyclobutyl, wherein the substituent is selected from
  • Another embodiment of the present invention relates to compounds according to embodiment 1 , wherein M represents M1 or M2; T represents CP or CB
  • R 2 represents H or methyl
  • a cp and A CB independently represent SC A , SC B , SC C , SC D or SC E as defined below
  • R 1A represents hydrogen or fluorine
  • R 3A represents H, oxetan-3-yl, 2-hyd roxyeth- 1 -yl , 1 ,2-dihydroxyethyl, (3-fluoroazetidin-1 -yl)methyl, 1 - (hydroxymethyl)cycloprop-l -yl, 1 -((3-fluoroazetidin-1 -yl)methyl)cycloprop-1 -yl, 1 -aminocycloprop-1 - yl, (morpholin-4-yl)methyl, hydroxymethyl o;
  • R 1C represents cyclopropyl or 1-(oxetan-3-yl)piperidine-4-yl;
  • n an integer from 2 to 3.
  • Another embodiment of the present invention relates to compounds according to embodiment 8, wherein M represents M1.
  • Another embodiment of the present invention relates to compounds according to any one of embodiments 8 or 9, wherein T represents CP.
  • Another embodiment of the present invention relates to compounds according to any one of embodiments 8 to 10, wherein A cp represents SC A , SC B or SC C .
  • Another embodiment of the present invention relates to compounds according to any one of embodiments 8 or 9, wherein T represents CB.
  • Another embodiment of the present invention relates to compounds according to any one of embdiments 8, 9 or 12, wherein A CB represents SC A or SC D .
  • Another embodiment of the present invention relates to compounds according to embodiment 8, wherein M represents M2.
  • Another embodiment of the present invention relates to compounds according to embodiment 14, wherein T represents CP.
  • a cp represents SC A , SC B or SC C (notably SC A or SC C ).
  • Another embodiment of the present invention relates to compounds according to embdiment 17, wherein A CB represents SC A or SC D .
  • Another embodiment of the present invention relates to compounds according to embodiment 8, wherein M represents M2 and T represents CP.
  • M represents M1 or M2
  • T represents CP or CB
  • a cp or A CB independently represent SC A , SC B or SC c .
  • Another embodiment of the present invention relates to compounds according to embodiment 8, werein M represents M1 ; T represents CP or CB; and A cp or A CB independentnly represent SC A , SC B or SC c .
  • Another embodiment of the present invention relates to compounds according to embodiment 8, werein M represents M1 ; T represents CP; and A cp represents SC A , SC B or SC c .
  • Another embodiment of the present invention relates to compounds according to embodiment 8, werein M represents M1 ; T represents CB; and A CB represents SC A or SC C . 24) Another embodiment of the present invention relates to compounds of embodiment 1 , selected from:
  • R 1 may be selected from -P(0)(0H)2, - S(0)2(0H), phosphonooxymethyl or PM as defined below
  • R PM represents (Ci-C4)alkylamino(Ci-C4)alkyl, [di(Ci-C4)alkylamino](Ci-C4)alkyl, phosphonooxy(Ci-C4)alkyl, phosphonooxymethoxy, 2-(phosphonooxy-(Ci-C4)alkyl)-phenyl,
  • (2-(phosphonooxy)-phenyl)-(CrC4)alkyl especially 2-(2-(phosphonooxy)-phenyl)-ethyl) or [2-(phosphonooxy- (Ci-C 4 )alkyl)-phenyl]-(Ci-C 4 )alkyl.
  • the prodrug comprising the group (di(Ci-C4)alkylamino)-(Ci-C3)alkyl-carbonyloxy (occurring when R PM represents [di(Ci-C4)alkylamino](Ci-C4)alkyl)) notably refers to dimethylaminoacetoxy;
  • the prodrug comprising the group [2-(phosphonooxy-(Ci-C4)alkyl)-phenyl]-carbonyloxy (occurring when R PM represents 2-(phosphonooxy-(Ci-C4)alkyl)-phenyl) notably refers to one of the groups represented below
  • the prodrug comprising the group [(2-phosphonooxy-phenyl)-(Ci-C4)alkyl]-carbonyloxy (occurring when R PM represents (2-(phosphonooxy)-phenyl)-(Ci-C4)alkyl) notably refers to one of the groups represented below
  • prodrugs may be formed by replacing a hydrogen of a hydroxy group, wherein said hydroxy group may be attached to a substituent of the group T by any one of: -P(0)(0H)2 , - S(0)2(0H), phosphonooxymethyl or PM.
  • cyclopropyl as used throughout the present text means a cyclopropyl ring having one or two single bonds to substituents in addition to the bond to M.
  • mono-substituted cyclobutyl as used throughout the present text means a cyclobutyl ring having one single bond to a substituent in addition to the bond to M.
  • mono- or di-substituted cyclopropyl represents the group CP
  • (C x -C y )alkyl refers to a saturated straight or branched hydrocarbon chain with x to y carbon atoms.
  • (Ci-C4)alkyl alone or in combination with other groups, means saturated, branched or straight chain groups with one to four carbon atoms.
  • Examples of "(Ci-C4)alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl and t-butyl. . Preferred is methyl.
  • (C x -C y )alkenyl refers to an unsaturated straight or branched hydrocarbon chain with x to y carbon atoms having one double bond.
  • (C2-C3)alkenyl alone or in combination with other groups, means unsaturated, branched or straight chain groups with one to three carbon atoms having one double bond. Examples thereof are ethenyl, prop-1 - en-1-yl, prop-1 -en-2-yl. Preferred are ethenyl and prop-1 -en-1-yl.
  • (C x -C y )alkynyl refers to an unsaturated straight or branched hydrocarbon chain with x to y carbon atoms having one triple bond.
  • (C2-C3)alkynyl alone or in combination with other groups, means unsaturated, branched or straight chain groups with one to three carbon atoms having one triple bond. Examples thereof are ethynyl, prop-1-yn-
  • an "(jd-hydroxy(Ci-C4)alkyl” group as used as a substituent for the group "T”, is a linear alkyl group which contains from one to four carbon atoms in which one terminal hydrogen atom has been replaced by hydroxy.
  • Examples of oo-hydroxy(Ci-C4)alkyl groups are hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and
  • 5-membered heteroaryl used alone or in combination, means a 5- membered monocyclic aromatic ring containing one to a maximum of four heteroatoms, each independently selected from oxygen, nitrogen and sulfur.
  • Examples of such 5-membered heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl.
  • the term “5-membered heteroaryl” refers to thiazolyl and thiophenyl; in particular thiophen-
  • 5- membered heteroaryl group is unsubstituted thiophen-2-yl.
  • alkylamino refers to an amino group wherein one of the two hydrogen atoms has been replaced by an alkyl group as defined before.
  • (C x -C y )alkylamino (x and y each being an integer) refers to an alkylamino group as defined before wherein the alkyi group contains x to y carbon atoms.
  • a (Ci-C4)alkylamino group is an alkylamino group as defined before wherein the alkyi group contains from one to four carbon atoms.
  • Representative examples of alkylamino groups include methylamino, ethylamino and /so-propyl-amino; notably methylamino and ethylamino; and especially methylamino.
  • dialkylamino refers to an amino group wherein each hydrogen atom has been replaced by an alkyi group as defined before, whereby the alkyi groups may be the same or different.
  • di(C x -C y )alkylamino (x and y each being an integer) refers to a dialkylamino group as defined before wherein each alkyi group independently contains x to y carbon atoms.
  • a di(Ci- C4)alkylamino group is a dialkylamino group as defined before wherein each alkyi group independently contains from one to four carbon atoms.
  • dialkylamino groups include dimethylamino, diethylamino, N-ethyl-N-methyl-amino and N-iso-propyl-N-methyl-amino; notably dimethylamino and diethylamino; especially dimethylamino.
  • (Ci-C4)alkylamino(Ci-C4)alkyl refers to an alkyi group containing from one to four carbon atoms as defined before wherein one of the hydrogen atoms has been replaced by a (Ci-C4)alkylamino group as defined before.
  • Representative examples of (Ci-C4)alkylamino-(Ci-C4)alkyl groups include methylaminomethyl, 2-methylamino-ethyl, 3-methylamino-propyl, 4-methylamino-butyl, ethylaminomethyl, 2-ethylamino-ethyl, 3-ethylamino-propyl, 4-ethylamino-butyl, n-propylaminomethyl, 2-(n-propylamino)-ethyl and 3-(n-propylamino)-propyl; preferred are methylaminomethyl, 2-methylamino-ethyl and 3-methylamino- propyl; most preferred is methylaminomethyl.
  • [di(Ci-C4)alkylamino]-(Ci-C4)alkyl refers to an alkyi group containing from one to four carbon atoms as defined before wherein one of the hydrogen atoms has been replaced by a di(Ci-C4)alkylamino group as defined before.
  • [di(Ci-C4)alkylamino]-(Ci-C4)alkyl groups include dimethylaminomethyl, 2-(dimethylamino)-ethyl, 3-(dimethylamino)-propyl, 4-(dimethylamino)-butyl, diethylaminomethyl, 2-(diethylamino)-ethyl, 3-(diethylamino)-propyl, 4-(diethylamino)-butyl, di(n-propyl)aminomethyl, 2-(di(n-propyl)amino)-ethyl and 3-(di(n-propyl)amino)-propyl; notably dimethylaminomethyl, 2-(dimethylamino)-ethyl and 3-(dimethylamino)-propyl; especially dimethylaminomethyl.
  • quinolone-resistant when used in this text, refers to a bacterial strain against which ciprofloxacin has a Minimal Inhibitory Concentration of at least 16 mg/L (said Minimal Inhibitory Concentration being measured with the standard method described in "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobicallf, Approved standard, 7 th ed., Clinical and Laboratory Standards Institute (CLSI) Document M7-A7, Wayne, PA, USA (2006)).
  • carbapenem-resistant when used in this text, refers to a bacterial strain against which imipenem has a Minimal Inhibitory Concentration of at least 16 mg/L (said Minimal Inhibitory Concentration being measured with the standard method described in "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically", Approved standard, 7th ed., Clinical and Laboratory Standards Institute (CLSI) Document M7-A7, Wayne, PA, USA (2006)).
  • multi-drug resistant refers to a bacterial strain against which at least three antibiotic compounds selected from three distinct antibiotic categories have Minimal Inhibitory Concentrations (MICs) over their respective clinical breakpoints, whereby said three distinct antibiotic categories are chosen among penicillins, combinations of penicillins with beta-lactamase inhibitors, cephalosporins, carbapenems, monobactams, fluoro-quinolones, aminoglycosides, phosphonic acids, tetracyclins and polymixins.
  • Clinical breakpoints are defined according to the latest available list published by Clinical and Laboratory Standards Institute (Wayne, PA, USA). Accordingly, clinical breakpoints are the levels of MIC at which, at a given time, a bacterium is deemed either susceptible or resistant to treatment by the corresponding antibiotic or antibiotic combination.
  • the present invention also includes isotopically labeled, especially 2 H (deuterium) labeled compounds of formula I, which compounds are identical to the compounds of formula I except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • Isotopically labeled, especially 2H (deuterium) labeled compounds of formula I and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2 H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile.
  • the compounds of formula I are not isotopically labeled, or they are labeled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula I are not isotopically labeled at all. Isotopically labeled compounds of formula I may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
  • salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound.
  • pharmaceutically acceptable salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound.
  • the compounds of formula I may encompass compounds with one or more asymmetric centers, such as one or more asymmetric carbon atoms, which are allowed to be present in (R)- as well as (S)-configuration.
  • the compounds of formula I may further encompass compounds with one or more double bonds which are allowed to be present in Z- as well as E-configuration and/or compounds with substituents at a ring system which are allowed to be present, relative to each other, in cis- as well as trans-configuration.
  • the compounds of formula I may thus be present as mixtures of stereoisomers or preferably in stereoisomerically enriched form, especially as essentially pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • enriched when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least 70:30, especially of at least 90:10 (i.e., in a purity of at least 70% by weight, especially of at least 90% by weight), with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.
  • essentially pure when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a purity of at least 95% by weight, especially of at least 99% by weight, with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.
  • prevention or “prevention” or “preventing” used with reference to a disease means either that said disease does not occur in the patient or animal, or that, although the animal or patient is affected by the disease, part or all the symptoms of the disease are either reduced or absent.
  • prevention and “preventing” may be understood to mean “prophylaxis”.
  • treat or “treatment” or “treating” used with reference to a disease means either that said disease is cured in the patient or animal, or that, although the animal or patient remains affected by the disease, part or all the symptoms of the disease are either reduced or eliminated.
  • room temperature refers to a temperature of 25°C.
  • the compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof exhibit antibacterial activity, especially against Gram-negative organisms and are therefore suitable to treat bacterial infections in mammals, especially humans.
  • Said compounds may also be used for veterinary applications, such as treating infections in livestock and companion animals. They may further constitute substances for preserving inorganic and organic materials in particular all types of organic materials for example polymers, lubricants, paints, fibres, leather, paper and wood. Furthermore, they may be used for threating hard surfaces, liquids, or semi-liquids.
  • the compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof may therefore be used for the treatment or prevention of infectious disorders caused by fermentative or non-fermentative gram negative bacteria, especially those caused by susceptible and multi-drug resistant Gram-negative bacteria.
  • Gram-negative bacteria include Acinetobacter spp. such as Acinetobacter baumannii or Acinetobacter haemolyticus, Actinobacillus actinomycetemcomitans, Achromobacter spp. such as Achromobacter xylosoxidans or Achromobacter faecalis, Aeromonas spp. such as Aeromonas hydrophila, Bacteroides spp.
  • Bacteroides fragilis such as Bacteroides fragilis, Bacteroides theataioatamicron, Bacteroides distasonis, Bacteroides ovatus or Bacteroides vulgatus, Bartonella hensenae, Bordetella spp. such as Bordetella pertussis, Borrelia spp. such as Borrelia Burgdorferi, Brucella spp. such as Brucella melitensis, Burkholderia spp. such as Burkholderia cepacia, Burkholderia pseudomallei or Burkholderia mallei, Campylobacter spp.
  • Campylobacter jejuni Campylobacter fetus or Campylobacter coli
  • Cedecea Chlamydia spp. such as Chlamydia pneumoniae, Chlamydia trachomatis
  • Citrobacter spp. such as Citrobacter diversus (koseri) or Citrobacter freundii
  • Coxiella burnetii Edwardsiella spp.
  • Edwarsiella tarda Ehrlichia chafeensis
  • Eikenella corrodens Enterobacter spp.
  • Enterobacter cloacae Enterobacter aerogenes, Enterobacter agglomerans, Escherichia coli, Francisella tularensis, Fusobacterium spp.
  • Haemophilus spp. such as Haemophilus influenzae (beta-lactamase positive and negative) or Haemophilus ducreyi, Helicobacter pylori, Kingella kingae, Klebsiella spp.
  • Klebsiella oxytoca Klebsiella pneumoniae (including those encoding extended-spectrum beta-lactamases (hereinafter "ESBLs"), carbapenemases (KPCs), cefotaximase-Munich (CTX-M), metallo-beta-lactamases, and AmpC-type beta-lactamases that confer resistance to currently available cephalosporins, cephamycins, carbapenems, beta-lactams, and beta-lactam/beta-lactamase inhibitor combinations), Klebsiella rhinoscleromatis or Klebsiella ozaenae, Legionella pneumophila, Mannheimia haemolyticus, Moraxella catarrhalis (beta-lactamase positive and negative), Morganella morganii, Neisseria spp.
  • Providencia spp. such as Providencia stuartii, Providencia rettgeri or Providencia alcalifaciens, Pseudomonas spp. such as Pseudomonas aeruginosa (including ceftazidime-, cefpirome- and cefepime-resistant P. aeruginosa, carbapenem-resistant P. aeruginosa or quinolone-resistant P.
  • aeruginosa or Pseudomonas fluorescens, Ricketsia prowazekii, Salmonella spp. such as Salmonella typhi or Salmonella paratyphi, Serratia marcescens, Shigella spp. such as Shigella flexneri, Shigella boydii, Shigella sonnei or Shigella dysenteriae, Streptobacillus moniliformis, Stenotrophomonas maltophilia, Treponema spp., Vibrio spp.
  • Vibrio cholerae Vibrio parahaemolyticus, Vibrio vulnificus, Vibrio alginolyticus, Yersinia spp. such as Yersinia enterocolitica, Yersinia pestis or Yersinia pseudotuberculosis.
  • the compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof are thus useful for treating a variety of infections caused by fermentative or non-fermentative Gram-negative bacteria, especially infections such as: nosocomial pneumonia (related to infection by Legionella pneumophila, Haemophilus influenzae, or Chlamydia pneumonia); urinary tract infections; systemic infections (bacteraemia and sepsis); skin and soft tissue infections (including burn patients); surgical infections; intraabdominal infections; lung infections (including those in patients with cystic fibrosis); Helicobacter pylori (and relief of associated gastric complications such as peptic ulcer disease, gastric carcinogenesis, etc.); endocarditis; diabetic foot infections; osteomyelitis; otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Haemophilus influenzae or Moraxella catarrhalis; pharynigitis, rheumatic fever, and glomeruloneph
  • the compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof may thus especially be used for the preparation of a medicament, and are suitable, for the prevention or treatment of a bacterial infection selected from urinary tract infections, systemic infections (such as bacteraemia and sepsis), skin and soft tissue infections (including burn patients), surgical infections; intraabdominal infections and lung infections (including those in patients with cystic fibrosis).
  • a bacterial infection selected from urinary tract infections, systemic infections (such as bacteraemia and sepsis), skin and soft tissue infections (including burn patients), surgical infections; intraabdominal infections and lung infections (including those in patients with cystic fibrosis).
  • the compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof display intrinsic antibacterial properties and have the ability to improve permeability of the outer membrane of Gram- negative bacteria to other antibacterial agents.
  • Their use in combination with another antibacterial agent might offer some further advantages such as lowered side-effects of drugs due to lower doses used or shorter time of treatment, more rapid cure of infection shortening hospital stays, increasing spectrum of pathogens controlled, and decreasing incidence of development of resistance to antibiotics.
  • the antibacterial agent for use in combination with a compound of formula I according to this invention will be selected from the group consisting of a penicillin antibiotic (such as ampicillin, piperacillin, penicillin G, amoxicillin, or ticarcillin), a cephalosporin antibiotic (such as ceftriaxone, cefatazidime, cefepime, cefotaxime) a carbapenem antibiotic (such as imipenem, or meropenem), a monobactam antibiotic (such as aztreonam), a fluoroquinolone antibiotic (such as ciprofloxacin, moxifloxacin or levofloxacin), a macrolide antibiotic (such as erythromycin or azithromycin), an aminoglycoside antibiotic (such as amikacin, gentamycin or tobramycin), a glycopeptide antibiotic (such as vancomycin or teicoplanin), a tetracycline antibiotic (such as tetracycline, oxyte
  • the compounds of formula I according to this invention, or the pharmaceutically acceptable salt thereof, may moreover be used for the preparation of a medicament, and are suitable, for the prevention or treatment (and especially the treatment) of infections caused by biothreat Gram negative bacterial pathogens as listed by the US Center for Disease Control (the list of such biothreat bacterial pathogens can be found at the web page (https://www.selectagents.gov/ SelectAgentsandToxinsL.ist.html), and in particular by Gram negative pathogens selected from the group consisting of Yersinia pestis, Francisella tularensis (tularemia), Burkholderia pseudomallei and Burkholderia mallei.
  • One aspect of this invention therefore relates to the use of the compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof according to one of embodiments 1 ) to 24) for the manufacture of a medicament for the prevention or treatment of a bacterial infection (in particular one of the previously mentioned infections caused by Gram-negative bacteria, especially by multi-drug resistant Gram-negative bacteria).
  • Another aspect of this invention relates to The compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof according to one of embodiments 1 ) to 24) for the prevention or treatment of a bacterial infection (in particular for the prevention or treatment of one of the previously mentioned infections caused by Gram-negative bacteria, especially by multi-drug resistant Gram-negative bacteria).
  • bacterial infections can also be treated using compounds of formula I (or pharmaceutically acceptable salts thereof) in other species like pigs, ruminants, horses, dogs, cats and poultry.
  • a pharmaceutical composition according to the present invention contains at least one compound of formula I (or a pharmaceutically acceptable salt thereof) as the active ingredient and optionally carriers and/or diluents and/or adjuvants, and may also contain additional known antibiotics.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21 st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula I or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, nontoxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • Another aspect of the invention concerns a method for the prevention or the treatment of a Gram-negative bacterial infection in a patient, comprising the administration to said patient of a pharmaceutically active amount of a compound of formula I according to one of embodiments 1 ) to 24) or a pharmaceutically acceptable salt thereof.
  • the invention provides a method for the prevention or the treatment of a bacterial infection caused by Gram-negative bacteria (notably for the prevention or treatment of a bacterial infection caused by Acinetobacter baumannii bacteria, Escherichia coli bacteria, Klebsiella pneumoniae bacteria or Pseudomonas aeruginosa bacteria, and in particular for the prevention or treatment of a bacterial infection caused by quinolone-resistant Acinetobacter baumannii, quinolone-resistant Escherichia coli bacteria or quinolone-resistant Klebsiella pneumoniae bacteria) in a patient, comprising the administration to said patient of a pharmaceutically active amount of a compound of formula I according to one of embodiments 1 ) to 47) or a pharmaceutically acceptable salt thereof.
  • This invention thus, relates to the compounds of formula I as defined in embodiment 1 ), or further limited under consideration of their respective dependencies by the characteristics of any one of embodiments 2) to 24), and to pharmaceutically acceptable salts thereof. It relates furthermore to the use of such compounds as medicaments, especially for the prevention or treatment of a bacterial infection, in particular for the prevention or treatment of a bacterial infection caused by Gram-negative bacteria (notably for the prevention or treatment of a bacterial infection caused by Acinetobacter baumannii bacteria, Escherichia coli bacteria, Klebsiella pneumoniae bacteria or Pseudomonas aeruginosa bacteria, and in particular for the prevention or treatment of a bacterial infection caused by quinolone-resistant Acinetobacter baumannii : quinolone-resistant Escherichia coli bacteria or quinolone-resistant Klebsiella pneumoniae bacteria).
  • PG or PG' is TMSE: by using fluoride anion sources such as BF3.etherate complex in MeCN at 0°C, TBAF in THF between 0°C and +40°C or HF in MeCN or water between 0°C and +40°C, or using acidic conditions such as AcOH in THF/MeOH or HCI in MeOH;
  • fluoride anion sources such as BF3.etherate complex in MeCN at 0°C, TBAF in THF between 0°C and +40°C or HF in MeCN or water between 0°C and +40°C, or using acidic conditions such as AcOH in THF/MeOH or HCI in MeOH
  • PG or PC is allyl: by treatment with Pd(PPh3)4 in a solvent such as MeOH in presence of K2CO3 or a scavenger such as dimedone, morpholine or tributyltin hydride.
  • Generajjeacj n technic carboxylic acid is reacted with the hydroxylamine or amine derivative in the presence of an activating agent such as DCC, EDC, HOBT, n-propylphosphonic cyclic anhydride, HATU or DSC, in a dry aprotic solvent such as DCM, MeCN or DMF between -20°C and 60°C (see G. Benz in Comprehensive Organic Synthesis, B.M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991 ), vol. 6, p. 381 ).
  • an activating agent such as DCC, EDC, HOBT, n-propylphosphonic cyclic anhydride, HATU or DSC
  • the carboxylic acid can be activated by conversion into its corresponding acid chloride by reaction with oxalyl chloride or thionyl chloride neat or in a solvent like DCM between -20° and 60°C. Further activating agents can be found in R. C. Larock, Comprehensive Organic Transformations. A guide to Functional Group Preparations, 2 nd Edition (1999), section nitriles, carboxylic acids and derivatives, p. 1941-1949 (Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto).
  • GeneraJ.reactipn.techm aromatic halide (typically a bromide) is reacted with the required boronic acid derivative or its boronate ester equivalent (e.g. pinacol ester) in the presence of a palladium catalyst and a base such as K2CO3, CS2CO3, K3PO4, tBuONa or tBuOK between 20 and 120°C in a solvent such as toluene, THF, dioxane, DME or DMF, usually in the presence of water (20 to 50%).
  • a palladium catalysts are triarylphosphine palladium complexes such as Pd(PPh 3 )4.
  • These catalysts can also be prepared in situ from a common palladium source such as Pd(OAc)2 or Pd2(dba)3 and a ligand such as trialkylphosphines (e.g. PCy3 or P(tBu)3), dialkylphosphinobiphenyls (e.g. S-Phos) or ferrocenylphosphines (e.g. Q-phos).
  • a commercially available precatalyst based on palladacycle e.g. SK-CC01-A
  • W-heterocyclic carbene complexes e.g. PEPPSITM-IPr
  • the reaction can also be performed by using the corresponding aromatic triflate.
  • an iridium photosensitizer and an amine can be employed in combination with the nickel catalyst to perform the said cross-coupling reaction as described by Paul, A and al in J. Org. Chem. (2017) 82, 1996-2003.
  • Tris(trimethylsilyl)silane can also be used in such a reaction as described by Zhang, P and al in J. Am. Chem. Soc. (2016) 138, 8084-8087. GeneraJ. reason. technjg reaction between the amine and the aldehyde or ketone is performed in a solvent system allowing the removal of the formed water through physical or chemical means (e.g.
  • Such solvent is typically toluene, Hex, THF, DCM or DCE or a mixture of solvents such as DCE/MeOH.
  • the reaction can be catalyzed by traces of acid (usually AcOH).
  • the intermediate imine is reduced with a suitable reducing agent (e.g. NaBH4, NaBHCIS , or NaBH(OAc)3 or through hydrogenation over a noble metal catalyst such as Pd/C.
  • a suitable reducing agent e.g. NaBH4, NaBHCIS , or NaBH(OAc)3 or through hydrogenation over a noble metal catalyst such as Pd/C.
  • the reaction is carried out between -10°C and 1 10°C, preferably between 0°C and 60°C.
  • the reaction can also be carried out in one pot. It can also be performed in protic solvents such as MeOH or water in presence of a picoline-borane complex ⁇ Tetrahedron (2004), 60, 7899-7906).
  • the reaction is performed in the presence of tetrakis(triphenylphosphine)palladium(0) in the presence of an allyl cation scavenger such as morpholine, dimedone or tributyltin hydride between 0°C and 50°C in a solvent such as THF.
  • an allyl cation scavenger such as morpholine, dimedone or tributyltin hydride between 0°C and 50°C in a solvent such as THF.
  • the ester side chain is benzyl
  • the reaction is performed under hydrogen in the presence of a noble metal catalyst such as Pd/C in a solvent such as MeOH, THF or EA.
  • Pre aration of t e.compou ⁇ compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods.
  • Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures.
  • T and M have the same meaning as in formula I and PG 1 represents THP, TMSE, trityl, (2- methylpropoxy)ethyl, methoxymethyl, allyl, tBu, COOtBu or COtBu using general reaction technique 1.
  • the reaction can also be performed with racemic material and the (R) enantiomer can be obtained by chiral HPLC separation.
  • the enantiomers can be separated using methods known to one skilled in the art, e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-01 (R,R) (10 m) column, a Daicel ChiralCel OD-H (5-10 m) column, or a Daicel ChiralPak IA (10 m) or AD-H (5 m) column.
  • a chiral stationary phase such as a Regis Whelk-01 (R,R) (10 m) column, a Daicel ChiralCel OD-H (5-10 m) column, or a Daicel ChiralPak IA (10 m) or AD-H (5 m) column.
  • Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in the presence or absence of an amine such as TEA or diethylamine) and eluent B (Hex), at a flow rate of 0.8 to 150 mL/min.
  • EtOH eluent A
  • Hex eluent B
  • the compounds of formula II can be obtained by:
  • a CB has the same respective meanings as in formula I, with a compound of formula IX using general reaction technique 4 (this reaction can also be performed with racemic compound of formula IX and the trans (R)-enantiomer can then be obtained by chiral HPLC separation of the reaction product);
  • T is as defined in formula I.
  • the derivatives of formula I-3 can be obtained (Scheme 1 ) by reaction of the pyrrole aldehydes of formula 1-1 with the amine of formula I-2 using general reaction technique 5.
  • the derivatives of formula I-4 can be obtained from the derivatives of formula I-3 by treatment with CDI in a solvent such as THF in the presence of a base such as NaH; this reaction can be performed at a temperature ranging from 0 to 50°C, and ideally at rt.
  • the compounds of formula I-4 can be transformed into the compounds of formula VI using general reaction technique 6. These reactions can also be performed with racemic material and the (R) enantiomer can be obtained by chiral HPLC separation at any step when suitable.
  • the derivatives of formula 11-2 can be obtained (Scheme 2) by reaction of the thiophene carboxylic acids of formula 11-1 with the amine of formula I-2 using general reaction technique 2.
  • the derivatives of formula II-2 are treated with NBS in a solvent such as CCU in the presence of a radical initiator such as AIBN; this reaction, usually performed at reflux, affords the bromo-methyl derivatives of formula 11— 3 _
  • the latter are subsequently transformed to the compounds of formula 11-4 by treatment with a base such as LDA or LiHMDS in a solvent such as THF.
  • the reaction can be carried out at a temperature ranging between -20°C and rt and ideally at rt.
  • the derivatives of formula 11-4 can be transformed into the compounds of formula VI using general reaction technique 6.
  • T has the same meaning as in formula I.
  • the reactions can also be performed with racemic material and the (R)-enantiomer can be obtained by chiral HPLC separation at any step when suitable.
  • the derivatives of formula IV-3 wherein D 1 and D 2 represent each (Ci-C2)alkyl or when taken together represent CH2C(Me)2CH2, C(Me)2C(Me)2 or 1 ,2-phenyl can be obtained (Scheme 4) from the derivatives of formula IV-1 by addition of boranes of formula IV-2 wherein D 1 and D 2 have the same meaning.
  • the reaction can be catalysed by zirconium complexes such as the Schwartz's reagent (Cp2ZrHCI) in presence of a base such as TEA.
  • the derivatives of formula IV-3 wherein D 1 and D 2 represent each represent 1 ,2-phenyl can be obtained (Scheme 4) from the derivatives of formula IV-1 by addition of catecholborane.
  • the derivatives of formula Villa can then be obtained by zinc promoted cyclopropanation reaction using diiodoethane and TFA as reagents. The reaction can be performed in DCM at a temperature ranging from 0°C to reflux and ideally at rt.
  • the derivatives of formula IV-3 wherein D 1 and D 2 represent each H can be obtained (Scheme 4) from the derivatives of formula IV-3 wherein D 1 and D 2 do not represent each H by treatment with aqueous sodium periodate followed by an acidic treatment with diluted hydrochloric acid.
  • the potassium trifluoroborate salt of formula VII lb wherein A and R 2 have the same meanings as in formula I, can be prepared from the compounds of Villa wherein D 1 and D 2 represent each (Ci-C2)alkyl or when taken together represent CH2C(Me)2CH2, C(Me)2C(Me)2 or 1 ,2-phenyl by treatment with an aqueous solution of potassium fluoride.
  • M is as defined in formula I
  • Y represents a halogen (such as iodine or bromine)
  • R represents (Ci-C4)-alkyl
  • PG 1 has the same meaning as in formula II.
  • the reactions can also be performed with racemic material and the (R)-enantiomer can be obtained by chiral HPLC separation at any step when suitable.
  • the compounds of formula V-1 can be transformed to the compounds of formula V-2 using general reaction technique 5.
  • the compounds of formula V-2 can be further reacted with the compounds of formula VII using general reaction technique 2, thus affording the compounds of formula IX.
  • the compounds of formula II-5 and II-6 can be prepared by standard methods known to one skilled in the art.
  • the compound of formula 1-2 can be prepared as described in the section entitled "EXAMPLES” hereafter (see Preparation A), or by standard methods known to one skilled in the art.
  • Y b represents iodine or bromine and A cp and R 2 have the same respective meanings than in formula I.
  • the derivatives of formula 1-1 can be obtained (Scheme 7) by reaction of the pyrrole aldehydes of formula VII- 1 wherein Y represents bromine or iodine by reaction with compounds of formula Villa or VI lib using general reaction technique 3.
  • the compounds of formula 11-1 can be prepared as summarised in Scheme 8 hereafter.
  • Y represents iodine or bromine and A cp and R 2 have the same respective meanings than in formula I.
  • R represents (Ci-C4)alkyl.
  • the derivative of formula VIII-2 can be obtained (Scheme 8) by reaction of the compound of formula VI 11-1 wherein Yb represents bromine or iodine by reaction with compounds of formula Villa or VI I lb following general reaction technique 3.
  • the compound of formula 11-1 can then be obtained using general reaction technique 6.
  • Y represents bromine or iodine.
  • the derivative of formula IX-1 can be obtained (Scheme 9) by reaction of the pyrrole aldehyde of formula VI 1-1 with the amine of formula I-2 using general reaction technique 5.
  • the derivative of formula V-1 can then be obtained from the derivatives of formula IX-1 by treatment with CDI in the presence of a base such as NaH in a solvent such as THF; this reaction can be performed at a temperature ranging from 0°C to 50°C, and ideally at rt.
  • the reaction can also be performed with racemic material and the (R)-enantiomer can be obtained by chiral HPLC separation at any step when suitable.
  • the compounds of formula V-1 wherein Y represents bromine or iodine, R represents ethyl and M represents M1 can be prepared as summarised in Scheme 10 hereafter.
  • Y represents bromine or iodine.
  • the oxime of formula X-1 can be obtained (Scheme 10) by reaction of the pyrrole aldehydes of formula VI-1 with hydroxylamine in AcOH in the presence of NaOAc.
  • the oxime derivatives of formula X-1 can be reduced to the amine derivative of formula X-2 by treatment with Zn in a solvent such as AcOH.
  • the derivative of formula X-3 can be obtained from the derivative of formula X-2 by treatment with CDI in a solvent such as THF in the presence of a base such as NaH. This reaction can be performed at a temperature ranging from 0 to 50°C, and ideally at rt.
  • the compound of formula V-5 can then be transformed into the compounds of formula VI-1 by treatment with the bromide of formula X-4 in the presence of a base such as NaH and in a solvent such as THF or DMF.
  • a base such as NaH
  • a solvent such as THF or DMF.
  • the reaction can also be performed with racemic material and the (R)-enantiomer can be obtained by chiral HPLC separation at any step when suitable.
  • Y represents bromine or iodine.
  • the compounds of formula Xl-I can be transformed (Scheme 1 1 ) to the amide derivatives of formula XI-2 by reaction with the amine of formula I-2 using general reaction technique 2.
  • the resulting derivatives of formula XI-2 can be transformed to the derivatives of formula X-3 by treatment with NBS in a solvent such as CCU in the presence of a radical initiator such as AIBN; this reaction is usually performed at reflux.
  • the resulting bromo derivatives of formula XI-3 is subsequently transformed to the compounds of formula V-1 by treatment with a base such as LDA or LiHMDS in a solvent such as THF.
  • the reaction can also be performed with racemic material and the (R)-enantiomer can be obtained by chiral HPLC separation at any step when suitable.
  • Y represents bromine or iodine.
  • the compounds of formula V-1 can be obtained (Scheme 12) by reaction of the compounds of formula XI 1-1 with the amine of formula I-2 in DCM in presence of acetic acid at a temperature ranging between rt and 40°C, and ideally at rt.
  • the reaction can also be performed with racemic material and the (R)-enantiomer can be obtained by chiral HPLC separation at any step when suitable.
  • CCs were performed using Brunschwig 60A silica gel (0.032-0.63 mm) or using an ISCO CombiFlash system and prepacked S1O2 cartridges, elution being carried out with either Hept-EA or DCM-MeOH mixtures with an appropriate gradient.
  • the compounds contained an acid function, 1 % of AcOH was added to the eluent(s).
  • the compounds contained a basic function, 25% aq. NH4OH was added to the eluents.
  • MS 2 Column: Zorbax RRHD, 1.8 ⁇ , 3.0 x 50 mm; Injection volume: 0.15 ⁇ ; Column oven temperature: 40°C; Detection: UV 210 nm, ELSD and MS; MS ionization mode: ESI+; Eluents: A: H 2 0; and B: MeCN; Flow rate: 0.8 mL/min; Gradient: 5% B to 95% B (0.0 min - 1.2 min), 95% B (1.2 min - 1.9 min).
  • the number of decimals given for the corresponding [M+H + ] peak(s) of each tested compound depends upon the accuracy of the LC-MS device actually used.
  • the prep-HPLC purifications were performed on a Gilson HPLC system, equipped with a Gilson 215 autosampler, Gilson 333/334 pumps, Dionex MSQ Plus detector system, and a Dionex UVD340U (or Dionex DAD-3000) UV detector, using the following respective conditions:
  • Method 1 Column: Waters Atlantis T3 OBD, 10 ⁇ , 30 75 mm; Flow rate: 75 mL/min; Eluents: A: H 2 0 + 0.1 % HCOOH; B: MeCN + 0.1 % HCOOH; Gradient: 90% A to 5% A (0.0 min - 4.0 min), 5% A (4.0 min - 6.0 min).
  • Method 2 Column: Waters XBridge C18, 10 ⁇ , 30x75 mm; Flow rate: 75 mL/min; Eluents: A: H 2 0 + 0.5% NH 4 OH solution (25%); B: MeCN; Gradient: 90% A to 5% A (0.0 min - 4.0 min), 5% A (4.0 min - 6.0 min).
  • Method 3 Column: Agilent Zorbax SB-AQ, 5 ⁇ , 30 ⁇ 75 mm; Flow rate: 75 mL/min; Eluents: A: H 2 0 + 0.5% HCOOH; B: MeCN; Gradient: 90% A to 5% A (0.0 min - 4.0 min), 5% A (4.0 min - 6.0 min). Besides, semi-preparative and analytical chiral HPLCs were performed using the conditions herafter.
  • Semi-preparative chiral HPLC Method A The semi-preparative chiral HPLC is performed on a Daicel ChiralPak AS-H column (250 x 20 mm, 20 ⁇ ) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralPak AS-H column (250 x 4.6 mm, 5 ⁇ ) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.
  • Semi-preparative chiral HPLC Method B The semi-preparative chiral HPLC is performed on a Daicel ChiralPak IA column (30 x 250 mm, 5 ⁇ ) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralPak IA column (4.6 x 250 mm, 5 ⁇ ) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.
  • Semi-preparative chiral HPLC Method C The semi-preparative chiral HPLC is performed on a Daicel ChiralCel OJ-H column (20 x 250 mm; 5 ⁇ ) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralCel OJ-H column (4.6 x 250 mm; 5 ⁇ ) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.
  • Semi-preparative chiral HPLC Method D The semi-preparative chiral HPLC is performed on a Daicel ChiralCel IB column (30 x 250 mm; 5 ⁇ ) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralCel IB column (4.6 x 250 mm; 5 ⁇ ) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.
  • Semi-preparative chiral HPLC Method E The semi-preparative chiral HPLC is performed on a Daicel ChiralCel OZ-H column (30 x 250 mm; 5 ⁇ ) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralCel OZ-H column (4.6 x 250 mm; 5 ⁇ ) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.
  • PrQcedure.B To the THP-protected hydroxamic acid derivative (0.156 mmol) in EtOH (2.6 mL) is added PPTS (0.023 g; 0.09 mmol). The mixture is stirred at 80°C for 2 h, cooled to rt and directly purified by CC (DCM- MeOH gradient) or by prep-HPLC using a suitable method.
  • Pr.Qcedure.C The potassium trifluoroborate salt (0.53mmol), the halo-derivative (0.44mmol), PdCl2(dppf).DCM (0.02g; 0.02 mmol), Cs 2 C0 3 (0.49 g; 1.5 mmol) are dissolved in THF (4.31 mL) and water (0.89 mL). The reaction mixture is stirred overnight under reflux. The reaction mixture is partitioned between EA (15mL) and H 2 0 (10mL). The evaporation residue is purified by CC using an appropriate solvent.
  • Procedure.F Cul (0.036 g; 0.189 mmol), PdCI 2 (PPh 3 ) 2 (0.072 g; 0.102 mmol), (trimethylsilyl)ethynyl acetylene (12.1 mmol) and the halo derivative (0.581 mmol) are introduced in a two-necked round flask. The atmosphere is flushed with nitrogen during 30 min, then degassed THF (21 mL) and degassed TEA (2.5 mL; 18.1 mmol) are added. The suspension is stirred under nitrogen atmosphere at 50°C for 2 h. After concentration to dryness, the residue is then purified by CC using an appropriate solvent.
  • Vial B A separate 5 mL screw-cap vial is charged with NiCfe-glyme (0.0028 g, 0.012 mmol) and 4,4-di-tert-butyl-2,2-bipyridine (0.0034 g, 0.012 mmol). The vial is sealed, evacuated and backfilled with N2. Degassed DME (1 mL) is added and the mixture is stirred for exactly 5 min to obtain a stock solution of Ni- precatalyst. 0.36 mL of this solution is transferred via cannula into vial A. The suspension in vial A is again degassed by bubbling N2 through the mixture for 10 min.
  • A. v. (2R)-tert-Butyl 4-amino-2-methyl-2-(methylsulfonyl)butanoate A solution of intermediate A.iv (45 g; 162 mmol) in a mixture of iBuOH/EA (1/1 , 900 mL) was treated with 10% Pd/C (2.3 g). The suspension was stirred under hydrogen for 4 h. Then 10% Pd/C (0.5 g) was added to the suspension and the reaction was stirred under hydrogen for 2 days. The catalyst was filtered off and the filtrate concentrated to dryness to afford the crude material which crystallized on standing (grey solid; 40.6 g; 99% yield).
  • reaction mixture was quenched with NH4CI (30 mL) and extracted with DCM (2 x 20 mL). The combined org. layers were washed with NaHCC>3 (1 M, 20 mL) then brine (10mL). The evaporation residue afforded the title compound (2.2 g; >95% yield) as a yellow oil.
  • step C.iii (1.22 g) was prepared as a white solid.
  • 1 H NMR acetone-cie
  • Preparation I Potassium ((1 S,2S)-2-(4-((benzoyloxy)methyl)phenyl)cyclopropyl)trifluoroborateStarting from 2-(4-ethynylphenyl)metanol (commercial, 2.1 g; 15.9 mmol) and proceeding successively in analogy to Preparation D, step D.ii (>95% yield), Preparation, steps C.i (56% yield), C.ii (59% yield) and C.iii (65% yield), the title compound (0.207 g) was prepared, after final purification by CC (Hept-EA gradient) as a colorless oil.
  • CC Hept-EA gradient
  • PI (3-Bromocyclobutoxy)(tert-butyl)diphenylsilane To a solution of 3-bromocyclobutan-1 -ol (3.750 g, 24.8 mmol) in DCM (70 mL) was added imidazole (2.029 g, 29.8 mmol), TBDPS-CI (7.75 mL; 29.8 mmol) and DMAP (0.303 g, 2.48 mmol) The reaction proceeded at rt for 16h. Water ( 20 mL) was added and the two layers were separated . The evaporation residue was purified by CC ( EA-Hept gradient) to afford the title compound as a colorless oil.
  • P.v 4-(3-bromocyclobutyl)phenethyl benzoate A mixture of intermediate P.iv. (1.130 g; 3.02 mmol) and lithium bromide (0.39 g; 4.5 mmol) in DMF (20 mL) was stirred at 90°c for 16h. The reaction minxture was partitioned between water (1 mL)and diethyl ether (5 mL). The evaporation residue was purified by CC (EA-Hept gradient) to afford the title compound (0.614 g; 56% yield) as a white solid.
  • R.iii (1-(4-(3-Bromocyclobutyl)phenyl)cyclopropyl)methyl benzoate: Starting from intermediate R.ii (6.66 g, 11.9 mmol) and proceeding successively in analogy to Preparation P, steps P.iii (78% yield), P.iv (92% yield) and P.v (76% yield), the title compound (3.14 g, 69% yield) was obtained, after purification by CC using an EA-Hept gradient, as a yellowish oil.
  • T.ii Benzyl (1-(4-(3-bromocyclobutyl)phenyl)cyclopropyl)carbamate: Starting from intermediate T.i (6.94 g, 10.5 mmol) and proceeding successively in analogy to Preparation P, steps P.iii (92% yield), P.iv (93% yield) and P.v (65% yield), the title compound (2.95 g) was obtained, after purification by CC using an EA-Hept gradient, as a white solid.
  • Ethyl (E)-3-((1s : 3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)acrylate To an ice-chilled suspension of NaH (60% in mineral oil, 0.578 g; 14.4 mmol) in -DME (40 mL), was added triethylphosphonoacetate (2.92 mL; 14.4 mmol). The reaction mixture was stirred for 30 min at rt and (1 s*,3s*)-3-((iert- butyldiphenylsilyl)oxy)cyclobutane-1-carbaldehyde (prepared as described by Fu, J. and al.
  • V.iii. 3-((1s* : 3r*)-3-((tert-Butyldiphenylsilyl)oxy)cyclobutyl)propan-1-ol To an ice-chilled solution of intermediate V.ii (4.8 g, 9.74 mmol) in THF (50 mL) was slowly added a LiAIH 4 solution (2M in THF) (4.9 mL; 9.74 mmol). The reaction was allowed to warm to rt over 30 min. After cooling to 0°C, water (1 mL), EA (100 mL) and 1 M NaOH (2 mL) were carefully added and the reaction mixture was stirred for 5 min.
  • V.iv. 3-((1s*,3r*)-3-Bromocyclobutyl)propyl benzoate Starting from intermediate V.iii (4.61 g, 10.4 mmol) and proceeding successively in analogy to Preparation Q, step Q.i, (76% yield), Preparation P, steps P.iii (80% yield), P.iv (86% yield) and P.v (62% yield), the title compound (1.09 g) was obtained, after purification by CC using an EA-Hept gradient, as a white solid.
  • W.iii 4-((1s,3r)-3-Bromocyclobutyl)butyl benzoate: Starting from intermediate W.ii (1.55 g, 6.24 mmol) and proceeding successively in analogy to Preparation P, steps P.iv (93% yield) and P.v (44% yield), the title compound (0.8 g) was obtained, after purification by CC using an EA-Hept gradient, as a colorless oil.
  • Example 1 and Example 2 (2/?)-A/-Hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-oxo-2-((1 S,2S)-2- phenylcyclopropyl)-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)butanamide and (2/?)-A/-hydroxy-2-methyl- 2-(methylsulfonyl)-4-(6-oxo-2-((1 /?,2/?)-2-phenylcyclopropyl)-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5- yl)butanamide:
  • Example 1 and Example 2 refer to the first-eluting enantiomer and the second-eluting enantiomer respectively. Both isomers displayed identical NMR, MS and t R .
  • MS (ESI, m/z): 449.0 [M+H + ] for C 2 iH24N 2 O5S2; tR 0.75 min.
  • Example 3 and Example 4 (2 ?)-4-(2-((1 S,2S)-2-(2-Fluorophenyl)cyclopropyl)-6-oxo-4,6-dihydro-5H- thieno[2,3-c]pyrrol-5-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide and (2 ?)-4-(2-((1 ?,2 ?)-2-(2- fluorophenyl)cyclopropyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-A/-hydroxy-2-methyl-2- (methylsulfonyl)butanamide
  • Example 3 and Example 4 refer to the first-eluting enantiomer and the second-eluting enantiomer respectively. Both isomers displayed identical NMR, MS and t R .
  • 1 H NMR (DMSO-cie) ⁇ : 10.95 (s, 1 H); 9.20 (s, 1 H); 7.26 (m, 1 H); 7.16-7.20 (m, 3H); 7.08 (s, 1 H); 4.37-4.42 (m, 2H); 3.37-3.58 (overlapped m, 2H); 3.07 (s, 3H); 2.50-2.58 (overlapped m, 2H); 2.37-2.41 (m, 1 H); 1.95 (m, 1 H); 1.70 (m, 1 H); 1.53-1.58 (overlapped m, 1 H); 1.53 (s, 3H).
  • MS (ESI, m/z): 467.2 [M+H + ] for C21 H23N2O5FS2; t R 0.76 min.
  • Example 5 and Example 6 (2 ?)-4-(2-((1 S,2 ?)-2-((£)-2-Cyclopropylvinyl)cyclopropyl)-6-oxo-4,6- dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide and (2 ?)-4-(2-((1 S,2 ?)-2-((£)-2-Cyclopropylvinyl)cyclopropyl)-6-oxo-4,6- dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide and (2 ?)-4-(2-((1 S,2 ?)-2-((£)-2-Cyclopropylvinyl)cyclopropyl)-6-oxo-4,6- dihydro-5H-thieno[2,3-c]
  • Example 5 and Example 6 refer to the first-eluting enantiomer and the second- eluting enantiomer respectively. Both isomers displayed identical NMR, MS and tR. 1 H NMR (DMSO-cie) ⁇ : 10.92 (br.s, 1 H); 8.18 (br.s, 1 H); 6.92 (s, 1 H); 5.21 (m, 1 H); 5.13 (m, 1 H); 4.37-4.29 (m, 2H); 3.52 (m, 1 H); 3.36 (m, 1 H); 3.05 (s, 3H); 2.93 (m, 1 H); 2.21 (m, 1 H); 1.93 (m, 1 H); 1.70 (m, 1 H); 1.51 (s, 3H); 1.34 (m, 1 H); 1.20-1.17 (m, 2H); 0.66-0.62 (m, 2H); 0.33-0.29 (m, 2H). MS2 (ESI, m/z): 439.2 [M+H + ] for C20H26N2O
  • Example 7 (2 ?)-A/-Hydroxy-4-(6-((1S*,2S*)-2-(4-(2-hydroxyethyl)phenyl)cyclopropyl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide amide
  • Example 8 (2 ?)-4-(6-((1S*,2S*)-2-(2-Fluorophenyl)cyclopropyl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)- yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
  • Example 13 and Example 14 (2 ?)-A/-Hydroxy-4-(2-((1 S,2S)-2-(4-(hydroxymethyl)phenyl)cyclopropyl)-6- oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-2-methyl-2-(methylsulfonyl)butanamide and (2R)-N- hydroxy-4-(2-((1 ?,2 ?)-2-(4-(hydroxymethyl)phenyl)cyclopropyl)-6-oxo-4,6-dihydro-5H-thieno[2,3- c]pyrrol-5-yl)-2-methyl-2-(methylsulfonyl)butanamide
  • Example 13 and Example 14 refer to the first-eluting enantiomer and the second- eluting enantiomer respectively. Both isomers displayed identical NMR, MS and tR.
  • Example 15 (2 ?)-A/-Hydroxy-4-(6-((1 S*,2S*)-2-(4-(hydroxymethyl)phenyl)cyclopropyl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide
  • Example 16 (2 ?)-A/-Hydroxy-4-(6-((1 S*,2S*)-2-(4-(hydroxymethyl)phenyl)cyclopropyl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide
  • Example 18 (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-((1r,3 ?)-3-phenylcyclobutyl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide
  • Example 20 (2 ?)-A/-hydroxy-4-(6-((1r,3 ?)-3-(4-(2-hydroxyethyl)phenyl)cyclobutyl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide
  • pyrrolo[1,2-c]imidazol-6-yl)cyclobutyl)phenethyl benzoate Starting from methyl (2R)-4-(6-bromo-3-oxo-1 /-/- pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanoate (prepared as described by Blumstein, A.C.
  • Example 21 (2 ?)-4-(6-((1 S,3 ?)-3-(4-((1S)-1 ,2-dihydroxyethyl)phenyl)cyclobutyl)-3-oxo-1H-pyrrolo[1,2- c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
  • pyrrolo[1 : 2-c]imidazol-6-yl)cyclobutyl)phenyl)ethane-1 2-diyl dibenzoate: Starting from methyl (2R)-4-(6- bromo-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanoate (prepared as described by Blumstein, A.C.
  • Example 22 (2 ?)-N-Hydroxy-4-(6-((1r,3 ?)-3-(4-(1-(hydroxymethyl)cyclopropyl)phenyl)cyclobutyl)-3- oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide
  • Example 24 (2 ?)-N-Hydroxy-4-(6-((1r,3 ?)-3-(4-(1-(hydroxymethyl)cyclopropyl)phenyl)cyclobutyl)-3- oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide
  • Example 25 (2 ?)-4-(6-((1r,3 ?)-3-(4-((3-fluoroazetidin-1-yl)methyl)phenyl)cyclobutyl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
  • Example 27 (2 ?)-N-Hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-((1r,3 ?)-3-(4-(oxetan-3- yl)phenyl)cyclobutyl)-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide
  • Example 28 ((2 ?)-A/-Hydroxy-4-(6-((1s,3 ?)-3-(3-hydroxypropyl)cyclobutyl)-3-oxo-1H-pyrrolo[1,2- c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide
  • Example 30 (2 ?)-A/-Hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-((1r,3 ?)-3-(4- (morpholinomethyl)phenyl)cyclobutyl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide
  • E p nentaJ. methods Minimal Inhibitory Concentrations (MICs; mg/L) were determined in cation-adjusted Mueller-Hinton Broth by a microdilution method following the description given in "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that grow Aerobicallf, Approved standard, 7 th ed., Clinical and Laboratory Standards Institute (CLSI) Document M7-A7, Wayne, PA, USA (2006). Results:. All Example compounds were tested against several Gram-positive and Gram-negative bacteria. Typical antibacterial test results are given in Table 1 hereafter (MICs in mg/L).
  • K. pneumoniae A-651 is a multiply-resistant strain (in particular quinolone-resistant), while E. coli ATCC25922 and P. aeruginosa ATCC27853 are quinolone- sensitive strains.

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Abstract

L'invention concerne des composés de formule (I) dans laquelle M représente ou et T représente un radical cyclopropyle ou cyclobutyle tel que défini dans la description. L'invention concerne en outre l'utilisation desdits composés en tant qu'agents antibactériens, en particulier contre des micro-organismes à Gram-négatif, et des procédés de fabrication desdits composés.
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