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WO2019038362A1 - Pyrroloimidazolones antibactériennes - Google Patents

Pyrroloimidazolones antibactériennes Download PDF

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Publication number
WO2019038362A1
WO2019038362A1 PCT/EP2018/072737 EP2018072737W WO2019038362A1 WO 2019038362 A1 WO2019038362 A1 WO 2019038362A1 EP 2018072737 W EP2018072737 W EP 2018072737W WO 2019038362 A1 WO2019038362 A1 WO 2019038362A1
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Prior art keywords
methyl
methylsulfonyl
hydroxy
imidazol
pyrrolo
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PCT/EP2018/072737
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English (en)
Inventor
Stefan Diethelm
Gaëlle MATHIEU
Philippe Panchaud
Jean-Philippe Surivet
Naomi TIDTEN-LUKSCH
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Idorsia Pharmaceuticals Ltd
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Idorsia Pharmaceuticals Ltd
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Publication of WO2019038362A1 publication Critical patent/WO2019038362A1/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

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.
  • X represents sulfur or oxygen
  • R 3C represents hydrogen, halogen (especially fluorine) or (Ci-C3)alkyl (especially methyl);
  • A represents a group selected from a list consisting of A A , A B , A c , A D , A E , A F , A G and A H as defined below:
  • R 1A represents hydrogen, to-hydroxy-(Ci-C3)alkyl, 1 -ami nocycloprop- 1 -yl , 1-(3-fluoroazetidin-1- yl)methylcycloprop-1-yl, 1-(3-hydroxyazetidinecarbonyloxymethyl)cycloprop-1-yl, 1 -hydroxycycloprop-1 -yl, 1- hydroxymethylcycloprop-1-yl, 2-(1 ,2-dihydroxyethyl)cycloprop-1-yl, 3-hydroxy-oxetan-3-yl, 3- (hydroxymethyl)oxetan-3-yl, 1-methylazetidin-3-yl, 1-(morpholin-4-yl-methyl)cycloprop-1-yl, or 1- (tetrahydrofuran-3-yl)oxycarbonylazetidin-3-yl;
  • R 1B represents -hydroxy-(Ci-C3)alkyl , 1 -hydroxymethylcycloprop-1 -yl or 2-(1 ,2-dihydroxyethyl) cycloprop-1- yi;
  • R 1C represents hydroxy, ⁇ -hydroxy-(C1-C3)alkyl, 3-hydroxy-oxetan-3-yl, 3-(hydroxymethyl)oxetan-3-yl, 1- hydroxycycloprop-1-yl, 1-hydroxymethylcycloprop-1-yl, 2-(1 ,2-dihydroxyethyl)cycloprop-1-yl, 1-oxoprop-1-yl, 1 -(3-fluoroazetidin-1 -yl)prop-1 -yl, 1 -(3-fluoroazetidin-1 -yl)methylcycloprop-1 -yl, 1 -(3-hydroxyazetidine carbonyloxymethyl)cycloprop-1 -yl or 1 -(morpholin-4-yl-methyl)cycloprop-1 -yl;
  • R 1D represents methyl or 2-hydroxyethyl
  • R 3E represents hydrogen, to-hydroxy-(Ci-C3)alkyl, oxetan-3-yl, 1 ,2-dihydroxyethyl, 1-(oxetan-3- yl methyl )azetid in-3-y I , (1-methyl)azetidin-3-yl or (3-fluoroazetidin-1-yl)methyl-;
  • R 2F represents hydrogen or ⁇ -hydroxy-(C1-C3)alkyl
  • R 5H represents hydrogen
  • R 1 represents hydrogen, -P(0)(OH) 2 , -S(0)2(OH), phosphonooxymethyl or L represented below:
  • R 2 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)-(Ci-C4)alkyl (especially 2-(2-(phosphonooxy)-phenyl)-ethyl) or [2-(phosphonooxy-(Ci-C4)alkyl)-phenyl]-(Ci-C4)alkyl;
  • the prodrug comprising the group (di(Ci-C4)alkylamino)-(Ci-C4)alkyl-carbonyloxy (occurring when R 2 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 2 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 2 represents (2-(phosphonooxy)-phenyl)-(Ci-C4)alkyl) notably refers to one of the groups represented below
  • prodrugs may be formed by substituting a hydrogen of a hydroxy group, wherein said hydroxy group is present in R A , R B , R C , R D , R 3E or R 2F ; by any one of -P(0)(OH) 2 , -S(0) 2 (OH), phosphonooxymethyl or L.
  • Another embodiment of the invention relates to compounds according to embodiment 1 ) wherein R 1 represents -P(0)(OH) 2 .
  • Another embodiment of the invention relates to compounds according to embodiment 1 ) wherein R 1 represents -S(0) 2 (OH).
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M A .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M B .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M c .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M D .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M E .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M F .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M G .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M H .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M'.
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M J .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M A , M B or M c .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M D , M E , M F M G , M H or M'.
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M A , M B , M c M D , M F or M'.
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 15) or 17) to 19), wherein X represents sulfur.
  • FIG. 21 Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 15) or 17) to 19), wherein X represents oxygen.
  • R 1A represents hydrogen, 1 -hydroxycycloprop-1 -yl, 1 -a m i n ocy cl o pro p- 1 -yl , 3-hydroxy-oxetan-3-yl, 1- hydroxymethylcycloprop-1 -yl, 3-(hydroxymethyl)oxetan-3-yl or 2-(1 ,2-dihydroxyethyl)cycloprop-1 -yl;
  • R 1B represents 2-(1 ,2-dihydroxyethyl)cycloprop-1 -yl
  • R 1C represnts -hydroxy-(Ci-C3)alkyl, 2-(1 ,2-dihydroxyethyl)cycloprop-1 -yl, 3-hydroxy-oxetan-3-yl, 1- hydroxymethylcycloprop-1-yl, 1 -hydroxycycloprop-1 -yl or 1-oxoprop-1-yl;
  • R 3E represents -hydroxy-(Ci-C3)alkyl, 1 ,2-dihydroxyeth-2-yl or (3-fluoroazetidin-1 -yl)methyl;
  • R 2F represents hydrogen
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 22), wherein A represents A A .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 22), wherein A represents A B .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 22), wherein A represents A c .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A D .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 22), wherein A represents A E .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 22), wherein A represents A F .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A G .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 22), wherein A represents A A , A B , A c , A E , A F or A G .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to
  • A represents A A , A c or A D .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A A , A B , A c , A E or A F .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A A , A B , A c , A E or A F ; and R 1A , R 1B R 1C , R 3E and R 2F are as defined in embodiment 22).
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 22), wherein A represents A A , A B , A c , A E or A G .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A E ; and R 3E is as defined in embodiment 22).
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A or A E .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A A or A E ; and R 1A and R 3E are as defined in embodiment 22).
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 22), wherein A represents A E , A F or A H .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A E or A F .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A E or A F ; and R 3E and R 2F are as defined in embodiment 22).
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), 20) or 22); wherein M represents M A , M B , M E , M F or M'; and A represents A A , A B , A E , A F or A c .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), 20) or 22); wherein M represents M D , M E , M F , M G , M H or M'; and A represents A A , A B , A F , A E or A c .
  • Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), 20) or 22); wherein M represents M A , M B or M c ; and A represents A A , A B , A F , A E or A c .
  • Another embodiment of the invention relates to a compound according to embodiment 1), which is (2R)- 2-(3-((4-(6-(2-cyclopropylthiazol-5-yl)-3-oxo-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-2- (methylsulfonyl)butanamido)oxy)-3-oxopropyl)phenyl dihydrogen phosphate; or a salt (in particular pharmaceutically acceptable salts) thereof.
  • halogen refers to fluorine, chlorine, bromine or iodine. It refers preferably to fluorine or chlorine and more preferably to fluorine.
  • alkyl refers to a straight or branched chain alkyl group containing from one to four carbon atoms.
  • (C x -C y )alkyl refers to a straight or branched chain alkyl group containing x to y carbon atoms.
  • a (Ci-C3)alkyl group contains from one to three carbon atoms.
  • Representative examples of alkyl groups include methyl, ethyl, propyl, /so-propyl, n-butyl, /so-butyl, sec-butyl and iert-butyl. Preferred are methyl and ethyl. Most preferred is methyl.
  • oo-hydroxy(Ci-C3)alkyl means a linear alkyl group which contains from one to three carbon atoms in which one terminal hydrogen atom is replaced with hydroxy.
  • examples of oo-hydroxy(Ci-C3)alkyl groups are hydroxy methyl, 2-hydroxyethyl and 3-hydroxypropyl; notably hydroxymethyl.
  • 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 alkyl group contains x to y carbon atoms.
  • a (Ci-C4)alkylamino group is an alkylamino group as defined before wherein the alkyl group contains from one to four carbon atoms.
  • alkylamino groups include methylamino, ethylamino and /so-propyl-amino; notably methylamino and ethylamino; and especially methylamino.
  • dialkylamino used alone or in combination, refers to an amino group wherein each hydrogen atom has been replaced by an alkyl group as defined before, whereby the alkyl 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 alkyl group independently contains x to y carbon atoms.
  • a di(Ci- C4)alkylamino group is a dialkylamino group as defined before wherein each alkyl group independently contains from one to four carbon atoms.
  • Representative examples of 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 alkyl 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 alkyl 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.
  • R 3C to M c can be either adjacent to the pyrroloimidazolone bicyclic ring system or to A; especially to A.
  • 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 Aerobically", 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 2H (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 2H (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.
  • a temperature range is described to be between 40 °C and 80 °C, this means that the end points 40 °C and 80 °C are included in the range; or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1 , 2, 3, or
  • the term "about” placed before a numerical value "X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
  • the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10°C to Y plus 10°C, and preferably to an interval extending from Y minus 5°C to Y plus 5°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.
  • the compounds of formula I or salts thereof may be used for disinfecting any hard surface, liquid, or semi-liquid.
  • 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.
  • Neisseria gonorrhoeae or Neisseria meningitidis such as Neisseria gonorrhoeae or Neisseria meningitidis
  • Pasteurella spp. such as Pasteurella multocida, Plesiomonas shigelloides
  • Porphyromonas spp. such as Porphyromonas asaccharolytica
  • Prevotella spp. such as Prevotella corporis, Prevotella intermedia or Prevotella endodontalis, Proteus 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 preceding lists of infections and pathogens are to be interpreted merely as examples and in no way as limiting.
  • the compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof may therefore be used for the preparation of a medicament, and are suitable, 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, especially by multi-drug resistant Gram-negative bacteria.
  • the compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof may more especially be used for the preparation of a medicament, and are suitable, for the prevention or treatment of a bacterial infection caused by Gram-negative bacteria selected from the group consisting of Citrobacter spp., Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Serratia marcescens, Stenotrophomonas maltophilia and Pseudomonas aeruginosa bacteria (notably of a bacterial infection caused by Gram-negative bacteria selected from the group consisting of Klebsiella pneumoniae and Pseudomonas aeruginosa bacteria, and in particular of a bacterial infection caused by Pseudomonas aeruginosa bacteria).
  • Gram-negative bacteria selected from the group consisting of Citrobacter spp., Enterobacter aerogenes, Enterobacter
  • 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 may more 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, intraabdominal infections and lung infections (including those in patients with cystic fibrosis), and in particular for the prevention or treatment of a bacterial infection selected from urinary tract infections and intraabdominal infections.
  • 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/SelectAgentsandToxinsList.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 any one of embodiments 1 ) to 47) 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 any one of embodiments 1 ) to 47) 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).
  • Yet another aspect of this invention relates to the compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof according to any one of embodiments 1 ) to 47) for use as a medicament.
  • a pharmaceutical composition containing, as active ingredient, a compound of formula I according to any one of embodiments 1 ) to 47), or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.
  • 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.
  • the present invention also relates to pharmacologically acceptable salts and to compositions and formulations of compounds of formula I.
  • 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.
  • the compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such as especially oral) or parenteral (including topical application or inhalation) administration.
  • the compounds of formula I are suitable for inhibiting the LpxC enzyme of bacteria and thus for the prevention and/or treatment of bacterial infections in mammals, such as especially humans.
  • 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 any one of embodiments 1 ) to 47) 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.
  • the compounds of formula I according to this invention may also be used for cleaning purposes, e.g. to remove pathogenic microbes and bacteria from surgical instruments, catheters and artificial implants or to make a room or an area aseptic.
  • the compounds of formula I could be contained in a solution or in a spray formulation.
  • 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 47), 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 , quinolone-resistant Klebsiella pneumoniae bacteria or quinolone-resistant Pseudomonas aeruginosa).
  • 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;
  • the 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 (T3P), 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 (T3P), 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).
  • the 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, i-BuONa or i-BuOK between 20°C 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(PP i3)4.
  • 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(i-Bu)3), dialkylphosphinobiphenyls (e.g. S-Phos) or ferrocenylphosphines (e.g. Q-phos).
  • a commercially available precatalyst based on palladacycle e.g. SK-CC01 -A
  • /V-heterocyclic carbene complexes e.g. PEPPSITM-IPr
  • the reaction can also be performed by using the corresponding aromatic triflate. Further variations of the reaction are described in Miyaura and Suzuki, Chem. Rev. (1995), 95, 2457-2483, Bellina et al., Synthesis (2004), 2419-2440, Mauger and Mignani, Aldrichimica Acta (2006), 39, 17-24, Kantchev et al., Aldrichimica Acta (2006), 39, 97-1 1 1 , Fu, Acc. Chem. Res. (2008), 41 , 1555-1564, and references cited therein.
  • the 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. distillation of the solvent-water azeotrope or presence of drying agents such as molecular sieves, MgSC>4 or Na2SC>4).
  • 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, NaBHsCN, or NaBH(OAc)3 or through hydrogenation over a noble metal catalyst such as Pd/C.
  • a suitable reducing agent e.g. NaBH4, NaBHsCN, 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 hydrolysis is usually performed by treatment with an alkali hydroxide such as LiOH, KOH or NaOH in a water-dioxane or water-THF mixture between 0°C and 80°C.
  • an alkali hydroxide such as LiOH, KOH or NaOH
  • the release of the corresponding acid can also be performed in neat TFA or diluted TFA or HCI in an org. solvent such as ether or THF.
  • 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.
  • the 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.
  • a and M have the same meaning as in formula I and PG 1 represents THP, TMSE, trityl, (2- methylpropoxy)ethyl, methoxymethyl, allyl, f-Bu, COOi-Bu or COi-Bu 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 compounds of formula I thus obtained may be converted into their salts, and notably into their pharmaceutically acceptable salts using standard methods.
  • 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 ⁇ ) 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 ⁇ ) 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 DEA or TEA) and eluent B (Hex), at a flow rate of 0.8 to 150 mL/min.
  • PG A represents iert-butyl.
  • the reaction is performed in presence of a base such as tetrazole in a solvent such as acetonitrile at a temperature of about 0°C.
  • an oxidizing agent such as hydrogen peroxide in water or MCPBA
  • R 2 has the same meaning as in formula I.
  • Functional groups present on R 2 and A that would be incompatible with the reaction conditions abovementioned can be protected before performing said reaction and deprotected after performing said reaction.
  • c) reacting a compound of formula I wherein R 1 H, and A and M are as defined in formula I with a compound of formula V
  • Y a represents iodine, bromine or chlorine and PG A has the same meaning as in formula III.
  • the reaction can be performed in presence of a mineral base such as NaH or K2CO3 or in presence of an organic base such as TEA or DIPEA in a solvent such as THF at a temperature ranging between about -50°C and rt.
  • a mineral base such as NaH or K2CO3
  • an organic base such as TEA or DIPEA
  • THF a solvent
  • Functional groups present on A that would be incompatible with the reaction conditions abovementioned can be protected before performing said reaction and deprotected after performing said reaction.
  • Functional groups present on A that would be incompatible with the reaction conditions abovementioned can be protected before performing said reaction and deprotected after performing said reaction.
  • the compounds of formula I thus obtained may be converted into their salts, and notably into their pharmaceutically acceptable salts using standard methods.
  • 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 DEA or TEA) and eluent B (Hex), at a flow rate of 0.8 to 150 mL/min.
  • the compounds of formula II can be obtained by: i) reacting a compound of formula VI
  • D 1 and D 2 represent H, methyl or ethyl or D 1 and D 2 together represent CH 2 C(Me)2CH2 or C(Me)2C(Me)2 with a compound of formula IX
  • M represents M F , M H or M J , with a compound of formula IX wherein Y represents a halogen such as bromine or iodine.
  • the compound of formula X is first treated with a strong base such as TMPMgCI.LiCI, n-BuLi or NaOi-Bu at a temperature ranging between -78°C and rt.
  • the resulting magnesio, lithio or sodio species can be further reacted with ZnC before it is reacted with a compound of formula IX in presence of Pd(PP i3)4 or a palladium salt and an appropriate ligand.
  • 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 4.
  • 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°C to 50°C, and ideally at rt.
  • the compounds of formula 1-4 can be transformed into the compounds of formula VI using general reaction technique 5. 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.
  • a and M are as defined in formula I, Y c represents bromine or iodine, D 1 and D 2 represent H, methyl or ethyl or D 1 and D 2 together represent CH 2 C(Me)2CH 2 or C(Me) 2 C(Me) 2 , R 3 represents a (Ci-C 4 )alkyl group such as isopropyl.
  • the compounds of formula Villa can be obtained from the compounds of formula 11-1 by treatment with a strong base such as n-BuLi in an aprotic solvent such as THF at a temperature ranging from -78°C to 0°C, the resulting lithio species is subsequently reacted with a compound of formula 11-3.
  • the compounds of formula Villa can be obtained reacting a compound of formula 11-2 with a reagent of formula 11-4 according to general reaction technique 3.
  • the potassium trifluoroborate salts of formula Vlllb wherein A and M 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-C 2 )alkyl or when taken together represent CH2C(Me)2CH2, C(Me)2C(Me)2 by treatment with an aqueous solution of potassium hydrogen difluoride.
  • 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 111-1 can be transformed to the compounds of formula III-2 using general reaction technique 5.
  • the compounds of formula III-2 can be further reacted with the compounds of formula VII using general reaction technique 2, thus affording the compounds of formula IX.
  • the derivatives of formula 1-1 can be obtained (Scheme 4) by reaction of the pyrrole aldehydes of formula IV- 1 wherein Y represents bromine or iodine by reaction with compounds of formula Villa or VI lib using general reaction technique 3.
  • Y represents bromine or iodine.
  • the derivatives of formula V-1 can be obtained (Scheme 5) by reaction of the pyrrole aldehydes of formula IV- 1 with the amine of formula I-2 using general reaction technique 4.
  • the derivatives of formula 111-1 can then be obtained from the derivatives of formula V-1 by treatment with CD I 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.
  • Y represents bromine or iodine and R represents (Ci-C4)alkyl.
  • the oxime of formula VI-1 can be obtained (Scheme 6) by reaction of the pyrrole aldehydes of formula IV-1 with hydroxylamine in AcOH in the presence of NaOAc.
  • the oxime derivatives of formula VI-1 can be reduced to the amine derivatives of formula VI-2 by treatment with Zn in a solvent such as AcOH.
  • the derivatives of formula VI-3 can be obtained from the derivative of formula VI-2 by treatment with CD I 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°C to 50°C, and ideally at rt.
  • the compound of formula VI-3 can then be transformed into the compounds of formula 111-1 by treatment with the bromide of formula VI-4 in the presence of a base such as NaH and in a solvent such as THF or DMF.
  • the compounds of formula III, IV and V are commercially available or can be prepared by standard methods known to one skilled in the art.
  • the compounds of formula IV-1 wherein Y b is bromine or iodine are commercially available or can be prepared by standard methods known to one skilled in the art.
  • the compounds of formula 1-2, 11-3, 11-4 and VI-4 are commercially available or can be prepared by standard methods known to one skilled in the art.
  • 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.
  • 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:
  • 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.
  • 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.
  • the boronic acid (0.86 mmol), the halo-derivative (0.57 mmol), PdCI 2 (dppf).DCM (0.06 g; 0.075 mmol), K 3 P0 4 (0.367 g; 1.73 mmol) are dissolved in THF (5 mL).
  • the reaction mixture is stirred 2h under reflux.
  • the reaction mixture is partitioned between EA-MeOH (9-1 , 30 mL) and H2O (15 mL).
  • the evaporation residue is purified by CC using an appropriate solvent.
  • the boronic acid or boronate ester (0.21 mmol), the halo-derivative (0.17 mmol), PdCl2(dppf).DCM (0.015 g; 0.018 mmol), CS2CO3 (0.1 16 g; 0.357 mmol) and silver oxide (0.04 g; 0.27 mmol) are dissolved in dioxane (0.53 mL) and water (0.02 mL).
  • the reaction mixture is stirred under reflux until completion.
  • the reaction mixture is partitioned between EA (15 mL) and H2O (10 mL).
  • the evaporation residue is purified by CC using an appropriate solvent.
  • step A.iv the title compound (40.6 g; 99% yield) was obtained as a grey solid.
  • Preparation R 4,4,5,5-tetramethyl-2-(3-methyl-5-phenylthiophen-2-yl)-1,3,2-dioxaborolane Starting from 2-bromo-3-methyl-5-phenylthiophene (prepared as described by Join, B. and a/ in Angewandte Chemie, Int. Ed. 2009, 48, 3644-3647, 1.1 g; 4.35 mmol) and proceeding in analogy to Preparation H, step H.iii (41 % yield), the title compound (0.53 g) was obtained after purification by CC (Hept gradient) as a off- white solid.
  • Example 1 (2 ?)-4-(6-(5-ethynylthiophen-3-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2- methyl-2-(methylsulfonyl)butanamide:
  • Example 8 (2 ?)-4-(6-(4-((1-aminocyclopropyl)ethynyl)thiophen-2-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol- 2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
  • Example 13 (2 ?)-A/-hydroxy-4-(6-(4-((1 S*,2S*)-2-(hydroxymethyl)cyclopropyl)thiophen-2-yl)-3-oxo-1 H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide 131 ((1S ⁇ 2S 2-(5-(2-((2R)-3-Methyl-3-( ethylsulfonyl) -oxo ⁇
  • Example 17 (2 ?H-(6-(4-((£)-2-((1S ! 2S)-2-((2 ?)-1 ,2-dihydroxyethyl)cyclopropyl)vinyl)thiophen-2-yl) oxo-1H ⁇ yrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
  • Example 19 (2 ?)-4-(6-(4-(((1 S,2S)-2-(1 ,2-dihydroxyethyl)cyclopropyl)ethynyl)thiophen-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
  • Example 20 (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(4-phenylthiazol-2-yl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide
  • Example 24 (2 ?)-A/-hydroxy-4-(6-(4-((3-hydroxyoxetan-3-yl)ethynyl)furan-2-yl)-3-oxo-1H-pyrrolo[1 ,2- c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide
  • Example 25 (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(5-(thiophen-2-yl)isoxazol-3-yl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide
  • Example 28 (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(5-phenylisoxazol-3-yl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide: Starting from intermediate 25.
  • Example 29 (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(4-phenyloxazol-2-yl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide 291 (2R)-2-Methyl-2-(methylsulfonyl)-4-(3-oxo-6-(4 he
  • Example 35 (2 ?)-4-(6-(5-cyclopropylisoxazol-3-yl)-3-oxo-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)-A/- hydroxy-2-methyl-2-(methylsulfonyl)butanamide: Starting from intermediate 25.
  • Example 36 (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(3-phenyl-1 ,2,4-oxadiazol-5-yl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide
  • Example 37 (2 ?)-4-(6-(4-(2-((1 ?,2S)-2-((2 ?)-1,2-dihydroxyethyl)cyclopropyl)ethyl)thiophen-2-yl)-3-oxo- 1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide 371 (2R)-4-(6-(4-(2-((1R,2S)-2-((2R)-2,2-Dimethyl-1,3-d ⁇
  • Example 40 (2?)-N-hydroxy-4-(6-(5-((1-(hydroxymethyl)cyclopropyl)ethynyl)thiophen-2-yl)-3-oxo-1H- pyrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide 401.
  • step 2.ii the title compound (0.098 g) was obtained after purification by CC (Hept-EA-MeOH gradient) as an orange solid.
  • Example 42 (2 ?)-A/-hydroxy-4-(6-(4-((1-(hydroxymethyl)cyclopropyl)ethynyl)thiophen-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide Starting from intermediate 12. i (0.27 g; 0.48 mmol) and iert-butyl((1- ethynylcyclopropyl)methoxy)diphenylsilane (prepared as described in Chapoux, G. and al.
  • Example 45 (2 ?)-A/-hydroxy-4-(6-(5-((3-hydroxyoxetan-3-yl)ethynyl)thiophen-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide
  • Example 46 (2 ?)-A/-hydroxy-4-(6-(5-(2-(3-hydroxyoxetan-3-yl)ethyl)thiophen-2-yl)-3-oxo-1H-pyrrolo[1 ,2- c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide

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Abstract

L'invention concerne des composés de formule (I) dans laquelle M représente un cycle aromatique hétérocyclique à 5 chaînons et A est 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, ainsi que des procédés de fabrication desdits composés.
PCT/EP2018/072737 2017-08-24 2018-08-23 Pyrroloimidazolones antibactériennes Ceased WO2019038362A1 (fr)

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