WO2017093157A1 - Dérivés de pipéridine, de pyrrolidine et de 2-oxo-1,3-oxazinane en tant qu'inhibiteurs de pompes à efflux bactériennes pour le traitement d'infections microbiennes - Google Patents

Dérivés de pipéridine, de pyrrolidine et de 2-oxo-1,3-oxazinane en tant qu'inhibiteurs de pompes à efflux bactériennes pour le traitement d'infections microbiennes Download PDF

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WO2017093157A1
WO2017093157A1 PCT/EP2016/078938 EP2016078938W WO2017093157A1 WO 2017093157 A1 WO2017093157 A1 WO 2017093157A1 EP 2016078938 W EP2016078938 W EP 2016078938W WO 2017093157 A1 WO2017093157 A1 WO 2017093157A1
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methyl
phenyl
formula
compound
ring
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Bérangère GAUCHER
Jürg DREIER
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Basilea Pharmaceutica Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • 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
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
    • C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D265/10—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to compounds that act in combination with antimicrobial agents to enhance their potency, in particular inhibitors of microbial efflux pumps and use of these compounds in combination with antimicrobial compounds, in particular antibiotics, for treatment of bacterial and other microbial diseases.
  • Antibiotics are important and effective drugs to treat bacterial infections in many clinical settings.
  • the introduction of antibiotics to treat infectious diseases greatly improved public health in the twentieth century.
  • bacteria started to develop resistance mechanisms to evade the action of antibacterial agents.
  • the widespread use of various antibacterial agents promoted the evolution of multi-drug resistant pathogens and their global spread.
  • increased occurrence of resistant pathogens especially in hospitals and care centers, causes problems for the treatment of infections and leads to higher morbidity and mortality, longer treatment durations and increased costs (e.g.
  • Multidrug efflux pumps can expel a large variety of chemically different substances including medically important antibiotics and disinfectants. Such systems are perceived as the predominant underlying mechanism of multi-drug resistance in bacteria (e.g. Li et al. 2015. Clin. Microbiol. Rev. 28(2): 337-418; Nikaido 2011. Adv. Enzymol. Relat. Areas Mol. Biol. 77: 1-60; Poole 2005. J. Antimicrob.
  • Active drug transporters are divided into two major classes according to their mechanism of energization.
  • Primary transporters like the ABC-type transporters hydrolyze ATP (a primary cellular energy source) to power drug efflux.
  • ATP a primary cellular energy source
  • Most bacterial drug-efflux systems known today belong to the class of secondary transporters using energy stored in the transmembrane electrochemical potential of protons or sodium.
  • Transporters driven by this proton motive force can be further divided into four groups based on size as well as structural features. These groups are the major facilitator superfamily (MFS), the small multidrug resistance family (SMR), the resistance-nodulation-cell division family (RND), and the multidrug and toxic compound extrusion family (MATE) (for reviews see: Microbial Efflux Pumps Wu, Zhang, Brown Eds. Caister Academic Press 2013; Sun et al. 2014 Biochem. Biophys. Res. Commun. 453(2):254-267). Members of the RND family are highly relevant in terms of multidrug efflux and resistance since they accept a wide variety of substrates.
  • MFS major facilitator superfamily
  • SMR small multidrug resistance family
  • RTD resistance-nodulation-cell division family
  • MATE multidrug and toxic compound extrusion family
  • RND pumps are found in Gram-negative bacteria including the clinically relevant Enterobacteriaceae and glucose non-fermenters.
  • Well described members are AcrAB-TolC in Escherichia coli and MexAB-OprM in Pseudomonas aeruginosa.
  • X-ray structures of AcrAB-TolC and MexAB-OprM subunits were the first to be solved and boosted the understanding of the function of tripartite RND pumps (Nikaido H. 2011 Adv. Enzymol. Relat Areas Mol. Biol. 77: 1-60; Murakami S. 2008. Curr. Opin. Struct. Biol. 18:459-465; Ruggerone et al. 2013. Curr.
  • Binding sites for a few substrates and inhibitors could be determined and computational simulation were used to describe dynamic interactions of substrates and inhibitors with efflux pumps (reviewed in Yamaguchi et al. 2015. Front Microbiol. 6:327; Ruggerone et al. 2013 Curr. Topics Med. Chem. 13(24):3079-3100).
  • RND pumps The expression of RND pumps is regulated in response to environmental stress such as the presence of antibiotics (Morita et al. 2014. Front. Microbiol. 4, 422: doi: 10.3389/fmicb.2013.00422; Poole 2014. Can. J. Microbiol. 60:783-791). Enhanced efflux gene expression was found to cause antibiotic resistance. Many antibiotics lack activity against Gram-negative bacteria because of active drug efflux. Overexpression of MexAB-OprM for example, contributes substantially to fluoroquinolone- and ⁇ -lactam-resistance. MexXY, another RND pump from P.
  • aeruginosa contributes to decreased amikacin susceptibility and co-resistance to fluoroquinolones, carbapenems, and the cephalosporin antibiotic ceftazidime. Reduced or even lost activity due to efflux can be restored by efflux-pump inhibitors.
  • Efflux pumps also play a role in biofilm formation, quorum sensing, virulence and invasiveness. Hence, efflux pump inhibitors may be useful to combat several aspects of infections (e.g. Soto S. M. 2013. Virulence 4(3): 223-229; Hirakata et al. 2009. Int. J. Antimicrob. Agents. 34: 343-346).
  • Phenylalanine-arginine beta-naphthylamide (MC-207,110 or PABN) from a series of peptidomimetic compounds and the pyridopyrimidine derivative D 13-9001 are well studied examples of efflux-pump inhibitors.
  • EP1652839 and WO 00/01714 describe drug efflux pump inhibitors.
  • the present invention provides new compounds and methods for treating bacterial infections.
  • the invention provides a compound of formula I for use in a method of treating a subject with a microbial infection or susceptible to a microbial infection, said method comprising administering the compound of formula I to said subject, wherein said subject is receiving the compound of formula I in combination with an antimicrobial agent and wherein the compound of formula I is
  • X represents a bond or -CH 2 -
  • AR1 and AR2 represent phenyl
  • Rl, R2 and R3 represent independently hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, CpCealkoxy or Cp Cehaloalkoxy;
  • R4 represents hydrogen, halogen, CpCealkyl optionally substituted by 1 to 5 RlOa, C2-Cealkenyl optionally substituted by 1 to 5 RlOa, C r C 6 alkylene-R10b, C 2 -C 6 alkenylene-R10b, C(0)ORl la, CHO,
  • R5, R6 and R7 represent independently hydrogen, halogen, CpCealkyl, CpCehaloalkyl, CpCealkoxy or Cp Cehaloalkoxy;
  • R8 represents methyl or is absent, and when R8 is present the respective nitrogen atom carries a positive charge;
  • R9a and R9b represent independently hydrogen or methyl;
  • RlOa represents independently at each occurrence halogen, hydroxyl, CpCealkoxy or CpCehaloalkoxy
  • RlOb represents C 3 -C 8 cycloalkyl, C(0)ORl la, CHO, C(0)N(R12)R13, N(R12)R13, Cycle-P or Cycle-Q
  • Rl la and Rl lb represent independently at each occurrence hydrogen or CpCealkyl
  • R12 and R13 represent independently at each occurrence hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl or Cp C 4 alkoxy-C i -C 4 alkyl;
  • R14 represents CpCealkyl, CpCehaloalkyl, C 2 -C 6 alkenyl, C2-C 6 haloalkenyl, CpCealkylene-Cycle-P or Cp C 6 alkylene-Cycle-Q;
  • Cycle-P represents independently at each occurrence a saturated or partially unsaturated C 5 -C6 carbocyclic ring optionally substituted by 1 to 3 R15, or a saturated or partially unsaturated 5- or 6-membered heterocyclic ring optionally substituted by 1 to 3 Rl 5 containing carbon atoms as ring members and one or two ring members independently selected from N(R1 lb) and O;
  • Cycle-Q represents independently at each occurrence phenyl optionally substituted by 1 to 3 Rl 6 or a 5- to 6-membered heteroaryl ring containing one to four heteroatoms independently selected from O, S and N, optionally substituted by 1 to 3 R16;
  • R15 and R16 represent independently at each occurrence halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy or Ci-C 4 haloalkoxy;
  • the compound of formula I is administered to the subject as a component of a combined therapy with an antimicrobial agent.
  • the subject may have been treated with the antimicrobial agent prior to administration with the compound of formula I, or the treatment with the antimicrobial agent may be simultaneous with, or after administration of the compound of formula I.
  • the invention provides a compound of formula I for use in a method for preventing or treating a microbial infection in a subject in combination with an antimicrobial agent.
  • the invention provides a compound of formula I for use in a method of treating a subject with a microbial infection or susceptible to a microbial infection, said method comprising administering the compound of formula I in combination with an antimicrobial agent to said subject.
  • the invention provides a compound of formula I in the manufacture of a medicament for preventing or treating a microbial infection in a subject in combination with an antimicrobial agent.
  • the invention provides use of a compound of formula I in the manufacture of a medicament for treating a subject with a microbial infection or susceptible to a microbial infection, said method comprising administering the compound of formula I to said subject, and wherein said subject is receiving the compound of formula I in combination with an antimicrobial agent.
  • the invention provides use of a compound of formula I in the manufacture of a medicament for treating a subject with a microbial infection or susceptible to a microbial infection, said method comprising administering the compound of formula I in combination with an antimicrobial agent.
  • the invention provides a pharmaceutical product comprising a compound of formula I and an antimicrobial agent.
  • the invention provides a method of treating a subject with a microbial infection or susceptible to a microbial infection, said method comprising administering the compound of formula I to said subject, and wherein said subject is receiving the compound of formula I in combination with an antimicrobial agent.
  • the invention provides a method of preventing or treating a subject with a microbial infection or susceptible to a microbial infection, said method comprising administering the compound of formula I to said subject, and wherein said subject is receiving the compound of formula I in combination with an antimicrobial agent.
  • the invention provides a method of treating a subject with a microbial infection or susceptible to a microbial infection, said method comprising administering the compound of formula I in combination with an antimicrobial agent to said subject.
  • Reference to microbial infections preferably refers to bacterial infections, and reference to antimicrobial agents preferably refers to antibiotics.
  • Rl, R2 and R3 is independently Br, C 2 -Cealkyl, Ci-Cehaloalkyl, C 2 -Cealkoxy or Ci-Cehaloalkoxy; or
  • R4 represents CI, F, CpCealkyl optionally substituted by 1 to 5 RlOa, C 2 -Cealkenyl optionally substituted by 1 to 5 RlOa, CpCealkylene-RlOb, C 2 -C 6 alkenylene-R10b,
  • C(0)ORl la CHO, C(0)N(R12)R13 or 0-R14 and R14 represents R14 C 2 -C 6 alkyl, C r Cehaloalkyl, C2-C 6 alkenyl, C2-C 6 haloalkenyl, Ci-Cealkylene-Cycle-P or CpCealkylene- Cycle-Q;
  • Rl , R2 and R3 is Br or C2-Cealkyl
  • R4 is 0-C 2 -C 4 alkenyl
  • R4 and L2 are at the meta positions on AR2 with respect to the position of LI ;
  • 3-Pyrrolidinemethanamine l-[2-[4-(phenylmethoxy)phenyl]ethyl]- e.g. (CAS 1872172-00-3); 3-Pyrrolidinemethanamine, l-[[4-(phenylmethoxy)phenyl]methyl]- e.g. (CAS 1871764-73-6); 25 3-Pyrrolidinamine, N-methyl-l-[[2-(phenylmethoxy)phenyl]methyl]- e.g. (CAS 1871593-19-9);
  • 3-Pyrrolidinamine N-methyl-l-[2-[3-(phenylmethoxy)phenyl]ethyl]- e.g. (CAS 1854313-33-9); 3-Pyrrolidinemethanamine, l-[[2-(phenylmethoxy)phenyl]methyl]- e.g. (CAS 1852302-19-2).
  • At least one of Rl, R2, R3 and R4 is not hydrogen.
  • Each alkyl moiety either alone or as part of a larger group such as alkoxy or alkylene is a straight or branched chain and is preferably Ci-Cealkyl, more preferably Ci-C 4 alkyl. Examples include methyl, ethyl, n- propyl, prop-2-yl, « -butyl, but-2-yl, 2-methyl-prop-l -yl or 2-methyl-prop-2-yl.
  • alkoxy examples include methoxy, ethoxy, n-propoxy, z ' o-propoxy, n-butoxy, eobutoxy, teri-butoxy, n-pentoxy, neo- pentoxy, n-hexoxy.
  • alkoxy may include further substitutents such as halogen atoms leading to haloalkoxy moieties.
  • alkoxyalkyl refers to an R-O-R' moiety in which the R and R' groups are alkyl groups.
  • Examples include methoxymethyl, methoxyethyl, methoxypropyl and methoxybuyl.
  • Each alkylene moiety is a straight or branched chain and is, for example, -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, - CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 - or -CH(CH 2 CH 3 )-.
  • Each alkenyl moiety either alone or as part of a larger group such as alkenyloxy or alkenylene is a straight or branched chain and is preferably C 2 -Cealkenyl, more preferably C 2 -C 4 alkenyl.
  • Each moiety can be of either the (E)- or ( ⁇ -configuration. Examples include vinyl and allyl.
  • a compound of the present invention comprising an alkenyl moiety thus may include either said compound with said alkenyl moiety in its (E)- configuration, said compound with said alkenyl moiety in its ( ⁇ -configuration and mixtures thereof in any ratio.
  • Each haloalkyl moiety either alone or as part of a larger group such as haloalkoxy is an alkyl group substituted by one or more of the same or different halogen atoms. Examples include difluoromethyl, trifluoromethyl, chlorodifluoromethyl and 2,2,2-trifluoro-ethyl.
  • Haloalkyl moieties include for example 1 to 5 halo substituents, or 1 to 3 halo substituents.
  • Each haloalkenyl moiety either alone or as part of a larger group such as haloalkenyloxy is an alkenyl group substituted by one or more of the same or different halogen atoms. Examples include,2-difluoro-vinyl and 1 ,2-dichloro-2-fluoro-vinyl.
  • Haloalkenyl moieties include for example 1 to 5 halo substituents, or 1 to 3 halo substituents.
  • Each cycloalkyl moiety can be in mono- or bi-cyclic form, typically and preferably in mono-cyclic form, and preferably contains 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms.
  • monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • heteroaryl refers to an aromatic ring system containing at least one heteroatom, and preferably up to three heteroatoms selected from nitrogen, oxygen and sulfur as ring members. Heteroaryl rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring. Examples include pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, tetrazolyl, furanyl, and thiophenyl.
  • heterocyclic ring refers to a saturated or partially unsaturated carbocyclic ring containing one to four heteroatoms selected from nitrogen, oxygen and sulfur as ring members. Such rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring.
  • Examples include tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl and morpholinyl.
  • Certain compounds of formula I may contain one or two or more centers of chirality and such compounds may be provided as pure enantiomers or pure diastereoisomers as well as mixtures thereof in any ratio.
  • the compounds of the invention also include all tautomeric forms of the compounds of formula I.
  • the compounds of formula I may also be solvated, especially hydrated, which are also included in the compounds of formula I. Solvation and hydration may take place during the preparation process.
  • Reference to compounds of the invention includes pharmaceutically acceptable salts of said compounds.
  • pharmaceutically acceptable salts of the compounds of formula (I) are salts of physiologically acceptable mineral acids, such as hydrochloric acid, sulfuric acid and phosphoric acid, or salts of organic acids, such as methanesulfonic acid, / toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid.
  • pharmacologically acceptable salts of the compounds of formula (I) are alkali metal and alkaline earth metal salts such as, for example, sodium, potassium, lithium, calcium or magnesium salts, ammonium salts or salts of organic bases such as, for example, methylamine, dimethylamine, triethylamine, piperidine, ethylenediamine, lysine, choline hydroxide, meglumine, morpholine or arginine salts.
  • alkali metal and alkaline earth metal salts such as, for example, sodium, potassium, lithium, calcium or magnesium salts
  • ammonium salts or salts of organic bases such as, for example, methylamine, dimethylamine, triethylamine, piperidine, ethylenediamine, lysine, choline hydroxide, meglumine, morpholine or arginine salts.
  • Ring A represents a ring selected from azetidine, pyrrolidine, piperidine, l,3-oxazolidin-2-one and l,3-oxazinan-2-one; more preferably, Ring A represents a ring selected from azetidine, pyrrolidine, piperidine and l,3-oxazinan-2-one; even more preferably Ring A represents a ring selected from pyrrolidine and piperidine.
  • X represents a bond or -CH 2 -.
  • X represents a bond when Ring A is a 6-membered ring, and - CH 2 -when Ring A is a 4- or 5-membered ring.
  • X is at the 3-position on the pyrrolidine ring.
  • X is at the 4-position on the piperidine ring.
  • X is at the 5-position on the 1 ,3-oxazinan- 2-one ring.
  • R9a and R9b represent independently hydrogen or methyl.
  • R9a and R9b represent hydrogen.
  • Ring A represents a ring selected from azetidine, pyrrolidine, piperidine, l ,3-oxazolidin-2-one and l ,3-oxazinan-2-one, wherein X is at the 3-position of the azetidine ring, at the 3-position on the pyrrolidine ring, at the 4-position on the piperidine ring, at the 4-position on the 1 ,3- oxazolidin-2-one ring, and at the 5-position on the 3-oxazinan-2-one ring.
  • Ring A represents a ring selected from pyrrolidine, piperidine, and l ,3-oxazinan-2-one, wherein X is at the 3- position on the pyrrolidine ring, at the 4-position on the piperidine ring, at the 4-position of the 1 ,3- oxazolidin-2-one ring, and wherein X is -CH 2 - when Ring A is pyrrolidine or l ,3-oxazinan-2-one and a bond when the Ring A is piperidine.
  • ASC is ASC-a, ASC-b, ASC-c or ASC-d
  • ASC is ASC-a, ASC-b or ASC-c, even more preferably ASC-a or ASC-b.
  • Rl represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy or CpCehaloalkoxy.
  • Rl include hydrogen, F, CI, Br, I, CF 3 , -O-methyl, -O-ethyl, -O-propyl, O-butyl, methyl, ethyl, propyl, and butyl (e.g. i-butyl).
  • Rl represents hydrogen, halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Cp C 4 alkoxy or Ci-C 4 haloalkoxy.
  • Rl represents hydrogen, halogen, Ci-C 4 alkyl, Cihaloalkyl or Ci-C 2 alkoxy. Again more preferably, Rl represents hydrogen, halogen, Ci-C 4 alkyl or CF 3 . Still more preferably, Rl represents hydrogen, F, CI, Br, i-butyl or CF 3 .
  • R2 represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy or CpCehaloalkoxy.
  • R2 include hydrogen, F, CI, Br, I, CF 3 , -O-methyl, -O-ethyl, -O-propyl, O-butyl, methyl, ethyl, propyl, and butyl (e.g. i-butyl).
  • R2 represents hydrogen, halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Cp C 4 alkoxy or Ci-C 4 haloalkoxy.
  • R2 represents hydrogen, halogen, Ci-C 4 alkyl, Cihaloalkyl or Ci-C 2 alkoxy. Again more preferably, R2 represents hydrogen, halogen, Ci-C 4 alkyl or CF 3 . Still more preferably, R2 represents hydrogen, F, CI, Br, i-butyl or CF 3 .
  • R3 represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy or CpCehaloalkoxy.
  • R3 include hydrogen, F, CI, Br, I, CF 3 , -O-methyl, -O-ethyl, -O-propyl, -O-butyl, methyl, ethyl, propyl, and butyl (e.g. i-butyl).
  • R3 represents hydrogen, halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Cp C 4 alkoxy or Ci-C 4 haloalkoxy.
  • R3 represents hydrogen, halogen, Ci-C 4 alkyl, Cihaloalkyl or Ci-C 2 alkoxy. Again more preferably, R3 represents hydrogen, halogen, Ci-C 4 alkyl or CF 3 . Still more preferably, R3 represents hydrogen, F, CI, Br, i-butyl or CF 3 . Most preferably, R3 represents hydrogen.
  • R4 represents hydrogen, halogen, CpCealkyl optionally substituted by 1 to 5 RlOa, C 2 -C 6 alkenyl optionally substituted by 1 to 5 RlOa, C r C 6 alkylene-R10b, C 2 -C 6 alkenylene-R10b, C(0)0R1 la, CHO,
  • R4 represents hydrogen, halogen, Ci-C 4 alkyl, C 2 -C 4 alkenyl, C r C 4 alkylene-R10b, C 2 -C 6 alkenylene-R10b, C(0)ORl la, CHO, C(0)N(R12)R13 or 0-R14. More preferably, R4 represents hydrogen, halogen, Ci-C 4 alkyl, C 2 -C 4 alkenylene-R10b,
  • R4 represents hydrogen, halogen, C r C 4 alkyl, C 2 -C 4 alkenylene-R10b, CHO, C(0)N(R12)R13 or 0-R14. Still more preferably, R4 represents hydrogen, halogen, C r C 4 alkyl, C 2 -C 4 alkenylene-R10b, C(0)N(R12)R13 or 0-R14.
  • RlOa represents independently at each occurrence halogen, hydroxyl, CpCealkoxy or d-Cehaloalkoxy.
  • RlOa represents independently at each occurrence halogen, hydroxyl or Ci-C 4 alkoxy.
  • RlOb represents C 3 -C 8 cycloalkyl, C(0)ORl la, CHO, C(0)N(R12)R13, N(R12)R13, Cycle-P or Cycle-Q.
  • RlOb represents C(0)0R1 la, CHO or C(0)N(R12)R13, more preferably RlOb represents C(0)ORl la.
  • Rl la represents hydrogen or CpCealkyl, preferably Rl la represents hydrogen or Ci-C 4 alkyl, even more preferably Rl 1 a represents Ci-C 4 alkyl.
  • Rl lb represents hydrogen or CpCealkyl, preferably Rl lb represents hydrogen or Ci-C 4 alkyl.
  • R12 represents hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl or Ci-C 4 alkoxy-Ci-C 4 alkyl.
  • R12 represents
  • R13 represents hydrogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl or Ci-C 4 alkoxy-Ci-C 4 alkyl.
  • R13 represents hydrogen, Ci-C 4 alkyl or Ci-C 4 alkoxy-Ci-C 4 alkyl. More preferably, R13 represents hydrogen or Ci-C 2 alkyl.
  • Rl 3 represents hydrogen or methyl.
  • R14 represents CpCealkyl, CpCehaloalkyl, C 2 -Cealkenyl, C 2 -C 6 haloalkenyl, CpCealkylene-Cycle-P or Cp C 6 alkylene-Cycle-Q.
  • R14 represents CpCealkyl, C 2 -Cealkenyl or CpCealkylene-Cycle-Q. More preferably, R14 represents C 3 -C 6 alkyl, C 2 -Cealkenyl or C 2 -C 4 alkylene-Cycle-Q.
  • Cycle-P represents independently at each occurrence a saturated or partially unsaturated C 5 -C6 carbocyclic ring optionally substituted by 1 to 3 R15, or a saturated or partially unsaturated 5- or 6-membered heterocyclic ring optionally substituted by 1 to 3 Rl 5 containing carbon atoms as ring members and one or two ring members independently selected from N(R1 lb) and O.
  • Cycle-P represents
  • R15 represents independently at each occurrence halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy or Cp C ihaloalkoxy; and wherein more preferably Rl 5 represents independently at each occurrence halogen, methyl, halomethyl, methoxy or halomethoxy.
  • Cycle-Q represents independently at each occurrence phenyl optionally substituted by 1 to 3 Rl 6 or a 5- to 6-membered heteroaryl ring containing one to four heteroatoms independently selected from O, S and N, optionally substituted by 1 to 3 R16.
  • Cycle-Q represents independently at each occurrence phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, tetrazolyl, furanyl or thiophenyl, each optionally substituted by 1 to 3 R16.
  • Cycle-Q represents independently at each occurrence furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl. Still more preferably Cycle-Q represents
  • R15 represents halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy or Ci-C 4 haloalkoxy.
  • R15 represents halogen, methyl, halomethyl, methoxy or halomethoxy.
  • R16 represents halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy or Ci-C 4 haloalkoxy.
  • R16 represents halogen, methyl, halomethyl, methoxy or halomethoxy.
  • R4 preferably represents hydrogen, halogen, Ci-C 4 alkyl, C 2 -
  • Rl Ob represents C(0)ORl l a, CHO or C(0)N(R12)R13;
  • Rl 1 a represents hydrogen or C r C 4 alkyl;
  • R12 represents hydrogen, Ci-C 2 alkyl or Ci-C 4 alkoxy-Ci-C 4 alkyl;
  • R13 represents hydrogen or methyl;
  • R14 represents CpCealkyl, C 2 -Cealkenyl or CpCealkylene-Cycle-Q, wherein Cycle-Q represents a 5- to 6- membered heteroaryl ring containing one to four heteroatoms independently selected from O, S and N, optionally substituted by 1 to 3 R16.
  • R4 represents hydrogen, halogen, Ci-C 4 alkyl, C 2 -C 4 alkenyl, Ci-C 4 alkylene-R10b, C 2 - C 6 alkenylene-R10b, C(0)ORl l a, CHO, C(0)N(R12)R13 or 0-R14;
  • Rl Ob represents C(0)ORl l a, CHO or C(0)N(R12)R13;
  • Rl l a represents hydrogen or Ci-C 4 alkyl;
  • R12 represents hydrogen, Ci-C 2 alkyl or Cp C 4 alkoxy-Ci-C 4 alkyl;
  • R13 represents hydrogen or methyl;
  • R14 represents CpCealkyl, C 2 -Cealkenyl or Cp C 6 alkylene-Cycle-Q, wherein Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridin
  • R4 represents hydrogen, halogen, Ci-C 4 alkyl, C 2 -C 4 alkenylene-R10b,
  • Rl Ob represents C(0)ORl la
  • Rl l a represents hydrogen or C r C 4 alkyl
  • R12 represents hydrogen, Ci-C 2 alkyl or Ci-C 4 alkoxy
  • R13 represents hydrogen or methyl
  • R14 represents Cp Cealkyl, C 2 -Cealkenyl or CpCealkylene-Cycle-Q, wherein Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl.
  • R4 represents hydrogen, halogen, C 2 -C 4 alkenylene-R10b, C(0)N(R12)R13 or O- R14;
  • R12 represents hydrogen, Ci-C 2 alkyl or Ci-C 4 alkoxy-Ci-C 4 alkyl;
  • R13 represents hydrogen or methyl;
  • R14 represents CpCealkyl, C 2 -Cealkenyl or CpCealkylene-Cycle-Q, wherein Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl.
  • R4 represents hydrogen, CI, F, C 2 -C 4 alkenylene-R10b, C(0)N(R12)R13 or 0-R14;
  • Rl Ob represents C(0)0R1 l a;
  • Rl l a represents Ci-C 4 alkyl;
  • R12 represents hydrogen, Ci-C 2 alkyl or Cp C 4 alkoxy-Ci-C 4 alkyl;
  • R13 represents hydrogen or methyl;
  • R14 represents Ci-Cealkyl, C 2 -C 6 alkenyl or Cp C 6 alkylene-Cycle-Q, wherein Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl.
  • R4 represents hydrogen, CI, F, C 2 -C 4 alkenylene-R10b, C(0)N(R12)R13 or 0-R14;
  • Rl Ob represents C(0)ORl l a;
  • Rl l a represents Ci-C 4 alkyl;
  • R12 represents hydrogen, Ci-C 2 alkyl or Cp C 4 alkoxy-Ci-C 4 alkyl;
  • R13 represents hydrogen or methyl;
  • R14 represents CpCealkyl, C 2 -C 6 alkenyl or Cp C 6 alkylene-Cycle-Q, wherein Cycle-Q represents imidazolyl or pyridinyl.
  • the (E) configuration is preferred.
  • L2 represents -CH 2 -, -CH 2 -CH 2 - or -C(0)-CH 2 -.
  • L2 represents -CH 2 - or -CH 2 -CH 2 -.
  • Ring A represents pyrrolidine.
  • Ring A represents piperidine.
  • Ring A represents l ,3-oxazinan-2-one.
  • R8 represents methyl and the respective nitrogen atom carries a positive charge.
  • R8 is absent.
  • X represents a bond. In one embodiment, X represents -CH 2 -.
  • R9a represents hydrogen
  • R9a represents methyl
  • R9b represents hydrogen
  • R9b represents methyl
  • R9a and R9b represent hydrogen.
  • R9a and R9b represent methyl
  • R9a represents methyl and R9b represents hydrogen.
  • ASC represents ASC-a.
  • ASC represents ASC-b.
  • ASC represents ASC-c.
  • ASC represents ASC-d.
  • Rl represents CI
  • Rl represents Br
  • Rl represents CF 3 .
  • Rl represents C 2 -C 6 alkyl.
  • Rl represents C palkyl
  • Rl represents teri-butyl
  • R2 represents hydrogen
  • R2 represents CI
  • R2 represents Br.
  • R3 represents hydrogen
  • R2 and R3 represent hydrogen.
  • Rl and R2 are both not hydrogen.
  • Rl represents CI and R2 represents Br.
  • Rl represents ⁇ -Bu and R2 represents hydrogen.
  • R4 is not hydrogen
  • R4 represents H.
  • R4 represents CI
  • R4 represents CF 3 .
  • R4 represents C 2 -C 6 alkyl.
  • R4 represents C palkyl
  • R4 represents teri-butyl
  • R4 represents 0-R14, wherein R14 represents C 2 -C 6 alkenyl. In one embodiment R4 represents 0-R14, wherein R14 is C 2 -C 4 alkenyl.
  • R4 represents 0-R14, wherein R14 represents allyl. In one embodiment R4 represents 0-R14, wherein R14 represents C 2 -C 6 alkyl, wherein R14 preferably represents C 4 alkyl.
  • R4 represents 0-R14, wherein R14 represents iso-butyl.
  • R4 represents 0-R14, wherein R14 represents (CH 2 ) 2 -imidazole.
  • R4 represents C 2 -C 4 alkenylene-R10b, wherein RlOb represents C(0)0R1 la, and wherein Rl 1 a represents C 1 -C 4 alkyl.
  • R4 represents C(0)0R11 a, wherein Rl 1 a represents ethyl.
  • R4 represents CHO
  • R4 represents C(0)N(R12)R13, wherein R12 represents Ci-C 2 alkyl or Ci-C 4 alkoxy-Cr C 4 alkyl and wherein R13 represents hydrogen, Ci-C 4 alkyl or Ci-C 4 alkoxy-Ci-C 4 alkyl.
  • R4 is C(0)N(R12)R13, wherein R12 represents Ci-C 2 alkyl or Ci-C 4 alkoxy-Ci-C 4 alkyl and wherein R13 represents hydrogen or Ci-C 2 alkyl.
  • R4 represents C(0)N(R12)R13, wherein R12 represents Ci-C 2 alkyl or methoxy-Cr C 4 alkyl and wherein Rl 3 represents hydrogen or methyl.
  • R4 represents C(0)N(R12)R13, wherein R12 represents methoxy-Ci-C 4 alkyl and wherein Rl 3 represents hydrogen or methyl.
  • R4 represents C(0)NH(CH 2 ) 3 OCH 3 .
  • R4 represents C(0)NH 2 .
  • At least one of Rl, R2 and R4 is not hydrogen.
  • R5 represents hydrogen
  • R6 represents hydrogen
  • R7 represents hydrogen
  • R5, R6 and R7 represent hydrogen.
  • R4 is not hydrogen and R5, R6 and R7 represent hydrogen.
  • Rl is not hydrogen
  • R2 and R3 represent hydrogen
  • R4 is not hydrogen
  • R5, R6 and R7 represent hydrogen
  • Rl and R2 are not hydrogen
  • R3 represents hydrogen
  • R4 is not hydrogen
  • R5, R6 and R7 represent hydrogen
  • Rl and R2 are not hydrogen, and R3, R4, R5, R6 and R7 represent hydrogen.
  • Rl, R2 and R3 represent hydrogen
  • R4 is not hydrogen
  • R5, R6 and R7 represent hydrogen
  • LI represents -CH 2 -0-.
  • LI represents -0-CH 2 -.
  • LI represents -CH 2 -S-.
  • LI represents -S-CH 2 -.
  • LI represents -C(CH 3 ) 2 -.
  • L2 represents -CH 2 - In one embodiment L2 represents -(CH 2 ) 2 -.
  • L2 represents -C(0)-(CH 2 )-.
  • L2 is at the meta position on AR2 with respect to the position of LI .
  • L2 is at the meta position on AR2 with respect to the position of LI and L2 is at the meta position on AR2 with respect to R4.
  • L2 is at the meta position on AR2 with respect to the position of LI
  • L2 is at the ortho position on AR2 with respect to the position of LI .
  • L2 is at the para position on AR2 with respect to the position of LI .
  • L2 and R4 are at the meta positions on AR2 with respect to the position of LI and R4 is not hydrogen.
  • R5, R6 and R7 represent hydrogen
  • L2 and R4 are at the meta positions on AR2 with respect to the position of LI
  • R4 is not hydrogen
  • R3, R5, R6 and R7 represent hydrogen.
  • R3, R5, R6 and R7 are hydrogen, L2 and R4 are at the meta positions on AR2 with respect to the position of LI, and R4 is not hydrogen.
  • Rl and R2 are not hydrogen and Rl is at the para position and R2 is at the ortho position on AR1 with respect to LI, and R3, R5, R6 and R7 are hydrogen, R4 is not hydrogen, and L2 and R4 are at the meta positions on AR2 with respect to the position of LI .
  • Rl is not hydrogen and is at the para position on AR1 with respect to LI
  • R2, R3, R5, R6 and R7 are hydrogen
  • R4 is not hydrogen
  • L2 and R4 are at the meta positions on AR2 with respect to the position of LI .
  • Rl is not hydrogen and is at the para position on AR1 with respect to LI
  • R2, R3, R4, R5, R6 and R7 are hydrogen and L2 is at the meta position on AR2 with respect to the position of LI
  • Rl is not hydrogen and is at the meta position on AR1 with respect to LI
  • R2, R3, R4, R5, R6 and R7 represent hydrogen and L2 is at the para position on AR2 with respect to the position of LI .
  • Rl is not hydrogen and is at the meta position on AR1 with respect to LI
  • R2, R3, R4, R5, R6 and R7 represent hydrogen and L2 is at the meta position on AR2 with respect to the position of LI .
  • Rl, R2 and R3 represent hydrogen and L2 is at the meta position on AR2 with respect to the position of LI .
  • R4 represents hydrogen, halogen, Ci-C 4 alkyl, C 2 -C 6 alkenylene-R10b,
  • C(0)ORl l a CHO, C(0)N(R12)R13 or 0-R14; R5, R6 and R7 represent hydrogen;
  • Rl Ob represents C(0)ORl l a, CHO or C(0)N(R12)R13;
  • Rl l a represents hydrogen or C r C 4 alkyl;
  • R12 represents hydrogen, Ci-C 2 alkyl or Ci-C 4 alkoxy-Ci-C 4 alkyl;
  • R13 represents hydrogen or methyl;
  • R14 represents Ci-Cealkyl, C 2 - Cealkenyl or CpCealkylene-Cycle-Q;
  • Cycle-Q represents a 5- to 6-membered heteroaryl ring containing one to four heteroatoms independently selected from O, S and N, optionally substituted by 1 to 3 R16.
  • Ring A represents a ring selected from azetidine, pyrrolidine, piperidine or l ,3-oxazinan-2-one;
  • Rl and R2 represent independently hydrogen, halogen or Ci-C 4 alkyl;
  • R3 represents hydrogen;
  • R4 represents hydrogen, halogen, Ci-C 4 alkyl, C 2 -C 4 alkenyl, Ci-C 4 alkylene-R10b, C 2 - C 4 alkenylene-R10b, C(0)ORl l a, CHO, C(0)N(R12)R13 or 0-R14;
  • R5, R6 and R7 represent hydrogen;
  • R9a and R9b represent hydrogen;
  • RlOb represents C(0)ORl l a;
  • Rl l a represents hydrogen or Ci-C 4 alkyl;
  • R12 represents Ci-C 4 alkyl or Ci-C 4 alkoxy-Ci-C 4 alkyl;
  • R13 represents hydrogen;
  • R14 represents
  • Ring A represents a ring selected from pyrrolidine, piperidine;
  • Rl and R2 represent independently hydrogen, halogen or Ci-C 4 alkyl;
  • R3 represents hydrogen;
  • R4 represents 0-R14;
  • R5, R6 and R7 represent hydrogen;
  • R9a and R9b represent hydrogen;
  • R12 represents Ci-C 4 alkyl or Cp C 4 alkoxy-Ci-C 4 alkyl;
  • R13 represents hydrogen;
  • R14 represents Ci-Cealkyl, C 2 -Cealkenyl or CpCealkylene- Cycle-Q;
  • Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl;
  • L2 represents
  • Ring A represents a ring selected from pyrrolidine, piperidine;
  • Rl and R2 represent independently hydrogen, halogen or Ci-C 4 alkyl;
  • R3 represents hydrogen;
  • R4 represents 0-R14;
  • R5, R6 and R7 represent hydrogen;
  • R9a and R9b represent hydrogen;
  • R12 represents Ci-C 4 alkyl or Cp C 4 alkoxy-Ci-C 4 alkyl;
  • R13 represents hydrogen;
  • R14 represents CpCealkyl, C 2 -Cealkenyl or CpCealkylene- Cycle-Q;
  • Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl;
  • L2 represents
  • Ring A represents a ring selected from azetidine, pyrrolidine, piperidine and l,3-oxazinan-2-one and R8 represents methyl.
  • Ring A represents a ring selected from pyrrolidine, piperidine and 1,3- oxazinan-2-one and R8 represents methyl.
  • Ring A represents a ring selected from pyrrolidine and piperidine and R8 represents methyl.
  • Ring A represents a ring selected from azetidine, pyrrolidine, piperidine or l,3-oxazinan-2-one
  • L2 represents -CH 2 -, -CH 2 -CH 2 - or -C(0)-CH 2 -
  • L2 represents - CH 2 - or -CH 2 -CH 2 - and R9a and R9b represent independently hydrogen or methyl, and preferably R9a and R9b represent hydrogen.
  • Ring A represents a ring selected from azetidine, pyrrolidine, piperidine or l,3-oxazinan-2-one
  • L2 represents -CH 2 -, -CH 2 -CH 2 - or -C(0)-CH 2 -, preferably-CH 2 - or -CH 2 -CH 2 -
  • R9a and R9b represent independently hydrogen or methyl
  • R9a and R9b represent hydrogenJn
  • Ring A represents a ring selected from azetidine, pyrrolidine, piperidine or l,3-oxazinan-2-one
  • L2 represents - CH 2 -, -CH 2 -CH 2 - or -C(0)-CH 2 -, preferably-CH 2 - or -CH 2 -CH 2 -
  • LI
  • Ring A represents a ring selected from pyrrolidine, piperidine or 1,3- oxazinan-2-one, wherein X is at the 2- or 3-position on the pyrrolidine ring, at the 4-position on the piperidine ring and at the 5-position on the l,3-oxazinan-2-one ring and R9a and R9b represent
  • R9a and R9b represent hydrogen.
  • Ring A represents a ring selected from pyrrolidine, piperidine or 1,3- oxazinan-2-one, wherein X is at the 2- or 3-position on the pyrrolidine ring, at the 4-position on the piperidine ring and at the 5-position on the l,3-oxazinan-2-one ring, L2 represents -CH 2 -, -CH 2 -CH 2 - or - C(0)-CH 2 -, preferably-CH 2 - or -CH 2 -CH 2 - and R9a and R9b represent independently hydrogen or methyl, and preferably R9a and R9b represent hydrogen.
  • Ring A represents a ring selected from pyrrolidine, piperidine or 1,3- oxazinan-2-one, wherein X is at the 2- or 3-position on the pyrrolidine ring, at the 4-position on the piperidine ring and at the 5-position on the l,3-oxazinan-2-one ring,
  • L2 represents -CH 2 -, -CH 2 -CH 2 - or - C(0)-CH 2 -, preferably-CH 2 - or -CH 2 -CH 2 -
  • R9a and R9b represent independently hydrogen or methyl, and preferably R9a and R9b represent hydrogen.
  • Ring A represents a ring selected from pyrrolidine, piperidine or 1,3- oxazinan-2-one, wherein X is at the 2- or 3-position on the pyrrolidine ring, at the 4-position on the piperidine ring and at the 5-position on the l,3-oxazinan-2-one ring,
  • L2 represents -CH 2 -, -CH 2 -CH 2 - or - C(0)-CH 2 -, preferably-CH 2 - or -CH 2 -CH 2 -
  • X is -CH 2 - and R9a and R9b represent independently hydrogen or methyl, and preferably R9a and R9b represent hydrogen.
  • Ring A represents a ring selected from pyrrolidine, piperidine or 1,3- oxazinan-2-one, wherein X is at the 2- or 3-position on the pyrrolidine ring, at the 4-position on the piperidine ring and at the 5-position on the l,3-oxazinan-2-one ring and R8 represents methyl.
  • Ring A represents a ring selected from pyrrolidine or piperidine, wherein X is at the 3-position on the pyrrolidine ring and at the 4-position on the piperidine ring and R8 represents methyl.
  • Rl and R2 represent independently hydrogen, halogen, Ci-C 4 alkyl, Cp C ihaloalkyl, Ci-C 4 alkoxy or Ci-C 4 haloalkoxy and R3 represents hydrogen.
  • Rl and R2 represent independently hydrogen, halogen, Ci-C 4 alkyl, Cihaloalkyl or Ci-C 2 alkoxy and R3 represents hydrogen.
  • Rl and R2 represent independently hydrogen, halogen, Ci-C 4 alkyl or CF 3 and R3 represents hydrogen.
  • Rl and R2 represent independently hydrogen, F, CI, Br, i-butyl or CF 3 and R3 represents hydrogen.
  • Rl and R2 represent independently hydrogen, F, CI, Br, i-butyl or CF 3 and R3 represents hydrogen, wherein at least one of Rl and R2 is not hydrogen and at least one or Rl and R2 is at the para position with respect to LI .
  • Rl and R2 represent independently F, CI, Br or CF 3 and R3 represents hydrogen, wherein Rl and R2 are at the ortho and para position with respect to LI .
  • Rl and R2 represent independently CI, Br or i-butyl and R3 represents hydrogen.
  • Rl and R2 represent independently CI or Br and R3 represents hydrogen.
  • the compound of formula I is a compound of formula 1-20
  • the compound of formula I is a compound of formula 1-22
  • the compound of formula I is a compound of formula 1-24
  • the compound of formula I is a compound of formula 1-20, 1-21 , 1-22, 1-23 or 1-24 wherein
  • Ring A represents a ring selected from azetidine, pyrrolidine, piperidine, l ,3-oxazolidin-2-one or 1 ,3- oxazinan-2-one;
  • Rl , R2 represent independently hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy or Cp Cehaloalkoxy;
  • R4 represents hydrogen, halogen, Ci-C 4 alkyl, C2-C 4 alkenyl, Ci-C 4 alkylene-R10b, C2-C 6 alkenylene-R10b, C(0)ORl l a, CHO, C(0)N(R12)R13 or 0-R14;
  • R8 represents methyl or is absent, and when R8 is present the respective nitrogen atom carries a positive charge
  • R9a and R9b represent independently hydrogen or methyl
  • Rl Ob represents C 3 -C 8 cycloalkyl, C(0)ORl l a, CHO, C(0)N(R12)R13, N(R12)R13, Cycle-P or Cycle-Q;
  • R14 represents Ci-Cealkyl, Ci-Cehaloalkyl, C2-Cealkenyl, C2-C 6 haloalkenyl, CpCealkylene-Cycle-P or Cp C 6 alkylene-Cycle-Q;
  • Cycle-P represents independently at each occurrence cyclopentyl or cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl or morpholinyl, each optionally substituted by 1 to 3 R15;
  • Cycle-Q represents independently at each occurrence phenyl or a 5- to 6-membered heteroaryl ring containing one to four heteroatoms independently selected from O, S and N, optionally substituted by 1 to 3 R16;
  • the compound of the invention is a compound of formula 1-20, 1-21 , 122, 123 or 1-24, as defined in embodiment A2, wherein R14 represents CpCealkyl, C2-Cealkenyl or CpCealkylene-Cycle-Q.
  • the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24, as defined in embodiment A3, wherein L2 represents -CH 2 -, -CH 2 -CH 2 - or -C(0)-CH 2 -.
  • the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24, as defined in embodiment A4, wherein Ring A represents a ring selected from azetidine, pyrrolidine, piperidine or l,3-oxazinan-2-one.
  • the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24, as defined in embodiment A5, wherein Rl 0b represents C(0)0R11 a, CHO or C(0)N(R12)R13.
  • the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24 as defined in embodiment A6, wherein R12 represents Ci-C 4 alkyl or Ci-C 4 alkoxy-Ci-C 4 alkyl; and
  • R13 represents hydrogen or methyl.
  • the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24 as defined in embodiment A7, wherein Rl and R2 represent independently hydrogen, halogen or Ci-C 4 alkyl.
  • the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24 as defined in embodiment A8, wherein R4 represents hydrogen, halogen, Ci-C 4 alkyl, C 2 -C 6 alkenylene-R10b, C(0)ORl la, CHO, C(0)N(R12)R13 or 0-R14; and RlOb represents C(0)ORl la.
  • the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24 as defined in embodiment A9, wherein Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl.
  • the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24 as defined in embodiment A10, wherein R13 represents hydrogen.
  • the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24 as defined in embodiment Al 1, wherein X is at the 2- or 3-position on the pyrrolidine ring, at the 4-position on the piperidine ring or at the 5-position on the l,3-oxazinan-2-one ring.
  • the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24, wherein
  • ASC is ASC-a, ASC-b or ASC-c
  • Rl and R2 represent independently hydrogen, halogen or Ci-C 4 alkyl
  • R4 represents hydrogen, halogen, C r C 4 alkyl, C 2 -C 6 alkenylene-R10b, C(0)ORl l a, CHO, C(0)N(R12)R13 or 0-R14;
  • R9a and R9b represent independently hydrogen or methyl
  • Rl Ob represents C(0)ORl l a
  • Rl l a represents hydrogen or Ci-C 4 alkyl
  • R12 represents Ci-C 4 alkyl or Ci-C 4 alkoxy-Ci-C 4 alkyl
  • R13 represents hydrogen
  • R14 represents Ci-Cealkyl, C 2 -C 6 alkenyl or CpCealkylene-Cycle-Q;
  • Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl; and L2 represents -CH 2 -, -CH 2 -CH 2 - or -C(0)-CH 2 -.
  • the compound of the invention is a compound of formula 1-20, 1-21 , 122, 123 or 1-24 as defined in embodiment A13, wherein R8 is absent.
  • the compound of the invention is a compound of formula 1-20, 1-21 , 122, 123 or 1-24 as defined in embodiment A13, wherein R8 represents methyl.
  • the compound of the invention is a compound of formula 1-20, 1-21 , 122, 123 or 1-24 as defined in embodiment A13, wherein R8 is absent; and R9a and R9b represent hydrogen.
  • the compound of the invention is a compound of formula 1-20, 1-21 , 122, 123 or 1-24 as defined in embodiment A13, wherein R8 represents methyl; and R9a and R9b represent hydrogen.
  • the compound of the invention is a compound of formula 1-20, 1-21 , 122, 123 or 1-24 as defined in embodiment A13, wherein R8 is absent; R9a and R9b represent hydrogen; and
  • R4 represents hydrogen, halogen, C r C 4 alkyl, C 2 -C 6 alkenylene-R10b, CHO, C(0)N(R12)R13 or 0-R14.
  • the compound of the invention is a compound of formula 1-20, 1-21 , 122, 123 or 1-24 as defined in embodiment A13, wherein R8 represents methyl; R9a and R9b represent hydrogen; and
  • R4 represents hydrogen, halogen, C r C 4 alkyl, C 2 -C 6 alkenylene-R10b, CHO, C(0)N(R12)R13 or 0-R14.
  • the compound of the invention is a compound of formula 1-20, 1-21 or 122 as defined in embodiment A13, wherein ASC is ASC-a or ASC-b
  • R8 is absent; R9a and R9b represent hydrogen; Cycle-Q represents furanyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl; and L2 represents -CH 2 - or -CH 2 -CH 2 -.
  • the compound of the invention is a compound of formula 1-20, 1-21 or 122 as defined in embodiment A13, wherein ASC is ASC-a or ASC-b
  • R8 represents methyl and the respective nitrogen atom carries a positive charge
  • R9a and R9b represent hydrogen
  • Cycle-Q represents furanyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl
  • L2 represents -CH 2 - or -
  • a further embodiment A24 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 1-20.
  • a further embodiment A25 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 1-21
  • a further embodiment A26 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 1-22
  • a further embodiment A27 of compounds of the invention is represented by any one of the embodiments Al to A21, wherein the compound of formula I is a compound of formula 1-23.
  • a further embodiment A28 of compounds of the invention is represented by any one of the embodiments Al to A21, wherein the compound of formula I is a compound of formula 1-24.
  • a further embodiment A29 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 1-20 and ASC is ASC-a.
  • a further embodiment A30 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 120 and ASC is ASC-b.
  • a further embodiment A31 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 121 and ASC is ASC-a.
  • a further embodiment A32 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 121 and ASC is ASC-b.
  • a further embodiment A33 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 122 and ASC is ASC-a.
  • a further embodiment A34 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 122 and ASC is ASC-b.
  • Further embodiments of compounds of the invention are represented by embodiments B 1 to B9, wherein, in each case, Rl, R2, R3, R4, R5, R6, R7, RlOa, RlOb, Rl la, Rl lb, R12, R13, R14, R15, R16, R17a, R17b, Cycle-P, Cycle Q and LI are as defined for compounds of formula I.
  • embodiments B 1 to B9 Further embodiments of compounds of the invention are represented by embodiments B 1 to B9, wherein, in each case, Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as in any one of the embodiments Al to A34.
  • embodiments of compounds of the invention are represented by embodiments Bal-Ba9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment Al .
  • embodiments Bbl-Bb9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A2.
  • embodiments Bcl-Bc9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A3.
  • embodiments Bdl-Bd9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A4.
  • embodiments of compounds of the invention are represented by embodiments Bel-Be9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A5.
  • embodiments Bfl-Bf9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A6.
  • embodiments Bgl-Bg9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A7.
  • embodiments Bhl-Bh9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A8.
  • embodiments of compounds of the invention are represented by embodiments Bil -Bi9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A9.
  • embodiments Bj l -Bj9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A10.
  • embodiments Bkl-Bk9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment Al 1.
  • embodiments B11 -B19 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A12.
  • embodiments Bml-Bm9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A13.
  • embodiments Bnl-Bn9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A14.
  • embodiments of compounds of the invention are represented by embodiments Bol-Bo9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A15.
  • embodiments Bpl-Bp9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A16.
  • embodiments Bql-Bq9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A17.
  • embodiments Bsl-Bs9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A19.
  • embodiments Btl-Bt9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A20.
  • embodiments of compounds of the invention are represented by embodiments Bul-Bu9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A21.
  • embodiments Bvl-Bv9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A22.
  • embodiments Bwl-Bw9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A23.
  • embodiments Bxl-Bx9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A24.
  • embodiments of compounds of the invention are represented by embodiments Byl-By9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A25.
  • embodiments Bzl-Bz9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A26.
  • embodiments Baal-Baa9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A27.
  • embodiments Bbbl-Bbb9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A28.
  • embodiments Bccl -Bcc9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A29.
  • embodiments Bddl -Bdd9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A30.
  • embodiments of compounds of the invention are represented by embodiments Beel -Bee9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A31.
  • embodiments Bffl-Bff9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A32.
  • embodiments Bggl -Bgg9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A33.
  • embodiments Bhhl -Bhh9 which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A34.
  • Further embodiments of compounds of the invention are represented by embodiments CI to CI 8, wherein, in each case, R3, R5, R6, R7, R8, R9a, R9b, R17a, R17b, L2 and ASC are as defined for compounds of formula I.
  • embodiments Cal-Cal 8 which correspond to embodiments CI to C18, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment Al .
  • embodiments Cbl-Cbl 8 which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A2.
  • embodiments of compounds of the invention are represented by embodiments Cfl-Cfl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A6.
  • embodiments of compounds of the invention are represented by embodiments Cgl -Cgl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A7.
  • embodiments Chi -Chi 8 which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A8.
  • embodiments Cil -Cil 8 which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A9.
  • embodiments of compounds of the invention are represented by embodiments Cj l-Cjl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A10.
  • embodiments of compounds of the invention are represented by embodiments Ckl-Ckl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment Al 1.
  • embodiments C11-C118 which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A12.
  • embodiments of compounds of the invention are represented by embodiments Cml-Cml 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A13.
  • embodiments of compounds of the invention are represented by embodiments Cql-Cql 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A17.
  • embodiments of compounds of the invention are represented by embodiments Crl-Crl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A18.
  • embodiments of compounds of the invention are represented by embodiments Cs 1 -Cs 18, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A19.
  • embodiments of compounds of the invention are represented by embodiments Ctl-Ctl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A20.
  • embodiments Cul-Cul 8 which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A21.
  • embodiments of compounds of the invention are represented by embodiments Cvl-Cvl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A22.
  • embodiments of compounds of the invention are represented by embodiments Cwl-Cwl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A23.
  • embodiments of compounds of the invention are represented by embodiments Cxi -Cxi 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A24.
  • embodiments Czl-Czl 8 which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A26.
  • embodiments of compounds of the invention are represented by embodiments Cccl-Cccl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A29.
  • embodiments of compounds of the invention are represented by embodiments Cddl -Cddl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A30.
  • embodiments Ceel -Ceel 8 which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A31.
  • embodiments of compounds of the invention are represented by embodiments Cffl-Cffl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A32.
  • embodiments of compounds of the invention are represented by embodiments Cggl -Cggl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A33.
  • embodiments Chhl -Chhl 8 which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A34.
  • embodiments D14 wherein the compound of the invention is a compound of formula 1-23.
  • embodiments of compounds of the invention are represented by embodiments D4, D5, D6, D7, D8, D9, D10, D12, D13, D21, D22 or D23, wherein, in each case, the compound of the invention is a compound of formula 1-21, and wherein Rl is at the para position on ARl with respect to LI .
  • embodiments of compounds of the invention are represented by embodiments D4, D5, D6, D7, D8, D9, D10, D12, D13, D21, D22 or D23, wherein, in each case, the compound of the invention is a compound of formula 1-21, and wherein Rl is at the para position on ARl with respect to LI, and wherein R2 is at the ortho position on ARl with respect to LI .
  • embodiments of compounds of the invention are represented by embodiments Dl, D2 or D3, wherein, in each case, the compound of the invention is a compound of formula 1-22, and wherein Rl is at the para position on ARl with respect to LI .
  • embodiments of compounds of the invention are represented by embodiments Dl, D2 or D3, wherein, in each case, the compound of the invention is a compound of formula 1-22, and wherein Rl is at the para position on ARl with respect to LI, and wherein R2 is at the ortho position on ARl with respect to LI .
  • embodiment D14 Further embodiment of compounds of the invention are represented by embodiment D14, wherein the compound of the invention is a compound of formula 1-23, and wherein Rl is at the para position on ARl with respect to LI .
  • embodiment D14 Further embodiment of compounds of the invention are represented by embodiment D14, wherein the compound of the invention is a compound of formula 1-23, and wherein Rl is at the para position on ARl with respect to LI, and wherein R2 is at the ortho position on ARl with respect to LI .
  • the methods of the invention relate to administering the compound of formula I in combination with the antimicrobial agent.
  • Administering the compound of formula I in combination with an antimicrobial agent means, for example, that the compound of formula I and antimicrobial agent are administered
  • the compounds of formula I may be administered in combination with more than one antimicrobial agent if desired.
  • the pharmaceutical products comprising the compound of formula I and an antimicrobial agent may include instructions for simultaneous, separate or sequential administration.
  • the compound of formula I and the antimicrobial agent may be provided in different dosage units or may be combined in the same dosage unit e.g. for simultaneous administration.
  • the same dosage unit e.g. for simultaneous administration.
  • pharmaceutical product may comprise one or more than one dosage unit comprising the compound of formula I, and one or more than one dosage unit comprising the antimicrobial agent.
  • the pharmaceutical product may comprise one or more than one dosage units comprising the compound of formula I and the antimicrobial agent.
  • the invention also provides a compound of formula I for use in a method of enhancing the antimicrobial agent efficacy of an antimicrobial agent comprising contacting a microbe with the compound of formula I and said antimicrobial agent.
  • the invention provides a method for enhancing the sensitivity of a microorganism to an antimicrobial agent, which comprises the step of contacting a microorganism with a compound of formula I.
  • the compounds of formula I may be administered in combination with antifungal agent, an antiviral agent, an anti- inflammatory agent or an anti-allergic agent.
  • antimicrobial agents to be used in combination with the compounds of the invention are preferably antibiotics. Whilst antimicrobial agents are agents that are able to kill or inhibit growth of microbes in a general sense, antibiotics are agents that are able to kill or inhibit the growth of bacteria, i.e. antibacterial agents.
  • antibacterial agents can be used in combination with the compounds of formula I, including quinolones, fluoroquionolones, tetracyclines, glycopeptides, aminoglycosides, ⁇ -lactams, rifamycins, macrolides and ketolides, oxazolidinones, coumermycins, phenicols (including chloramphenicol), fusidic acid, and novel bacterial topoisomerase inhibitors (NBTI). These are described in more detail below.
  • Beta-lactam antibiotics include but are not limited to, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Talampicilli), Epicillin, Carbenicillin (Carindacillin), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G), Clometacillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propicillin, Benzathine phenoxymethylpenicillin, Pheneticillin, Cloxacillin (Dicloxacillin, Flucloxacillin), Oxacillin, Meticillin, Nafcillin, Faropene
  • Macro lides include but are not limited to azithromycin, clarithromycin, erythromycin, oleandomycin, rokitamycin, rosaramicin, roxythromycin, spiramycin or troleandomycin.
  • Ketolides include but are not limited to telithromycin, solithromycin or cethromycin.
  • Quinolones include but are not limited to amifloxacin, besifloxacin, cinoxacin, ciprofloxacin, enoxacin, finafloxacin, fleroxacin, flumequine, lomefloxacine, nalidixic acid, nemonoxacin, norfloxacin, ofloxacin, levofloxacin, oxolinic acid, pefloxacin, rosoxacin, temafloxacin, tosufloxacin, sparfloxacin, clinafloxacin, moxifloxacin, gemifloxacin, garenofloxacin, delafloxacin, PD 131628, PD 138312, PD 140248, Q-35, AM-1155, NM394, T-3761, rufloxacin, OPC-17116, DU-6859a (AAC 37: 1419), J J-Q2 or DV- 7751a
  • Tetracyclines and glycylcyclines include but are not limited to
  • tetracycline minocycline, chlortetracycline, demeclocycline, doxycycline, lymecycline, methacycline, omadacycline, oxytetracycline, tigecycline or eravacycline.
  • Oxazolidinones include but are not limited to linezolid, tedizolid, eperozolid or radezolid.
  • Aminoglycosides include but are not limited to amikacin, arbekacin, butirosin, dibekacin, fortimicins, gentamicin, kanamycin, neomycin, netilmicin, plazomicin, robostamycin, sisomicin, spectinomycin, streptomycin or tobramycin.
  • Lincosamides include but are not limited to clindamycin or lincomycin.
  • Glycopeptides include but are not limited to vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, dalbavancin oritavancin or decaplanin.
  • Pleuromutilins include but are not limited to rumblemulin, valnemulin, tiamulin, azamulin or BC-3781.
  • antibiotics include but are not limited to trimethoprim, sulfamethoxazole, rifampicin, fusidic acid, puromycin, novobiocin, coumermycin, thiamphenicol
  • ETX0914 (AZD0914) (see Huband et al. AAC 2015. 59(1): 467), VXc-486 (see Locher et al. AAC 2015. 59(3): 1455 and Grillot et al. J. Med. Chem. 2014. 57:8792).
  • compositions comprising the compound of formula I and an antimicrobial agent may comprise the compound of formula I and an antibiotic in the weight ratio of, for example, 1 :10 to 10:1, 1 :5 to 5: 1, 2:1 to 2: 1 , for example about 1 :1.
  • the compounds of the present invention may be administered in combination with two or more
  • compositions may comprise the compound of formula I and two or more antimicrobial agents.
  • antimicrobial agents as desired, and likewise, compositions may comprise the compound of formula I and two or more antimicrobial agents.
  • examples of such combinations include compounds of formula I and two or more beta lactam antibiotics, e.g. ceftolozane/tazobactam, ceftazidime/avibactam, and the corresponding triple beta lactam combinations.
  • the microorganism and microbial infections to be treated by the present invention are preferably bacteria and bacterial infections.
  • Bacteria that may be treated using the present invention include but are not limited to Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella enterica (including all subspecies and serotypes some of which are also known as Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis) Salmonella bongori (including all subspecies and serotypes), Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae,
  • Acinetobacter baumannii Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae,
  • Haemophilus haemolyticus Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus,
  • Pseudomonas aeruginosa Pseudomonas fluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacter freundii, Salmonella enterica (including all subspecies and serotypes some of which are also known as Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis), Salmonella bongori (including all subspecies and serotypes), Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis
  • a particularly suitable example of a bacterium that can be treated by the present invention is the pathogenic bacterial species Pseudomonas aeruginosa, which is intrinsically resistant to many commonly used antibiotics.
  • Co-administration of compound of formula I with an antibacterial agent can reduce the export of the antibacterial agent out of the cell leading to intracellular accumulation to levels higher than the ones otherwise maintained in the absence of the compound of formula I.
  • the compounds and compositions of the invention are particularly useful for treating subjects infected with or susceptible to infection with bacteria that are resistant to one or several antibiotics.
  • the methods of the invention may comprise administering the compound of formula I in combination with an antibiotic to which the bacteria show resistance.
  • the resistance may be intermediate or complete resistance according to guidelines such as issued by the Clinical Laboratory Standards Institute in the US and European Committee on Antimicrobial Susceptibility Testing (EUCAST) in Europe, e.g. exposure of the bacteria to the antibiotic results in reduced or in no growth inhibition,
  • the invention provides a method for eliminating resistance of a microorganism with intrinsic or acquired resistance to an antimicrobial agent, which comprises the step of contacting the microorganism, which is being exposed to the antimicrobial agent, with an effective amount of a compound of formula I.
  • the invention also provides a method for inhibiting acquisition of resistance to an antimicrobial agent by a microorganism, which is being exposed to the antimicrobial agent, which comprises the step of contacting a microorganism with an effective amount of a compound of formula I.
  • Other bacterial and microbial species may have broad substrate spectrum efflux pumps similar to Pseudomonas aeruginosa and may therefore be appropriate targets too.
  • a compound according to the invention is not only for the (prophylactic and preferably therapeutic) management of human subjects, but also for veterinary use for the treatment of other warm-blooded animals, for example of commercially useful animals, for example cattle, horses, pigs, chickens, sheep, dogs, cats, rodents, such as mice, rabbits or rats or guinea-pigs. Such a compound may also be used as a reference standard to permit a comparison with other compounds. Treatment of humans is preferred.
  • compounds of formula (I) are administered either individually, or optionally also in combination with another desired therapeutic agent as described herein, using the known and acceptable methods.
  • Such therapeutically useful agents may be administered, for example, by one of the following routes: orally, for example in the form of dragees, coated tablets, pills, semi-solid substances, soft or hard capsules, solutions, emulsions or suspensions; parenterally, for example in the form of an injectable solution; rectally in the form of suppositories; by inhalation, for example in the form of a powder formulation or a spray; transdermally or intranasally.
  • routes of administration include parenteral, enteral and topical.
  • the compositions comprise the active ingredient, preferably together with a pharmaceutically acceptable carrier, which may be selected from conventional carriers and excipients known to the person skilled in the art.
  • the therapeutically usable product may be mixed with pharmacologically inert, inorganic or organic pharmaceutical carrier substances, for example with lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talcum, stearic acid or salts thereof, skimmed milk powder, and the like.
  • pharmaceutical carrier substances such as, for example, vegetable oils, petroleum, animal or synthetic oils, wax, fat and polyols may be used.
  • liquid solutions and syrups for the preparation of liquid solutions and syrups, pharmaceutical carrier substances such as, for example, water, alcohols, aqueous saline solution, aqueous dextrose solution, polyols, glycerol, vegetable oils, petroleum and animal or synthetic oils may be used.
  • pharmaceutical carrier substances such as, for example, water, alcohols, aqueous saline solution, aqueous dextrose solution, polyols, glycerol, vegetable oils, petroleum and animal or synthetic oils may be used.
  • pharmaceutical carrier substances such as, for example, vegetable oils, petroleum, animal or synthetic oils, wax, fat and polyols may be used.
  • compressed gases that are suitable for this purpose, such as, for example, oxygen, nitrogen and carbon dioxide may be used.
  • the pharmaceutically acceptable agents may also comprise additives for preserving and stabilizing, emulsifiers, sweeteners, flavourings, salts for altering the osmotic pressure, buffers, encapsulation additives and antioxidants.
  • compositions of the invention may be provided in a sterile container, e.g. as a powder for reconstitution.
  • the invention provides a method of preparing a pharmaceutical composition for administration, comprising reconstituting the contents of the sterile container using a pharmaceutically acceptable diluent.
  • the reconstituted solution may be administered intravenously to a patient.
  • compositions of the invention comprise the compound of formula I and/or the antimicrobial agent in a pharmaceutically effective amount, and the methods of the invention comprise administering the active compounds in pharmaceutically effective amounts.
  • the pharmaceutical compositions may comprise from approximately 1% to approximately 95% active ingredient.
  • the dosage of the active ingredient depends upon the disease to be treated and upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, and the mode of administration.
  • compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes.
  • the compositions may be provided in solid or liquid form.
  • the activity of antibacterial agents to treat infections caused by drug-resistant pathogens can be restored and enhanced by co-administration with efflux-pump inhibitor compounds.
  • the invention provides methods to overcome antibiotic resistance of bacteria that express efflux pumps, which transport antibiotics out of the cell.
  • the compounds according to the present invention, as well as pharmaceutically acceptable salts, solvates, hydrates thereof can be prepared e.g. by one of the processes (a), (b), (c) or (d) described below; followed, if necessary, by removing any protecting groups, forming a pharmaceutically acceptable salt, or forming a pharmaceutically acceptable solvate or hydrate.
  • AR1, AR2, Rl, R2, R3, R5, R6 and R7 are as in formula I,
  • Yl is -OH, a halogen atom or a leaving group like mesylate, tosylate, triflate,
  • Al is -O- or -S-
  • PG1 is a hydrogen atom or a hydroxyl protecting group (such as allyl, benzyl, tetrahydropyranyl or silyl ethers),
  • A2 is -(CH 2 ) 0 -Y2
  • o 0, 1, 2 or 3
  • Y2 is -OH, a halogen atom, a leaving group like mesylate, tosylate, triflate, -COOH, -CHO or -C(0)-CH 2 - X,
  • X is a halogen atom
  • A3 is R4, wherein R4 is as defined for compounds of formula I, or A3 is a halogen atom, -OH, -CHO or - COOH.
  • R4 is 0-R14, wherein 0-R14 is as defined for compounds of formula I.
  • the compound of formula IV- 1 can further react with a compound of formula V wherein X is a phosphonium salt or a phosphonate, to generate a compound of formula VI-1 wherein R4 is a C 2 -C6- alkenyl group.
  • the compound of formula IV- 1 can further react with a compound of formula V wherein X is -NHE or -NH 2 , E being an amino protecting group (such as allyloxycarbonyl,
  • the compound of formula VI-1 can be converted to the corresponding halide, mesylate, tosylate, triflate compound, and further react with a compound of VII
  • L2 is -(CH 2 ) 0 -, -(CH 2 ) P -, -(CH 2 ) 0 -C(0)-CH 2 - or -(CH 2 ) 0 - C(O)-, respectively, wherein p is 1, 2, 3 or 4.
  • Y2 may require appropriate activation to allow a reaction of compounds of formulae VI-1 and VII as described in more detail below.
  • ARl, AR2, Rl, R2, R3, R5, R6 and R7 are as defined for compounds of formula I,
  • n 1 or 2
  • Al is -O- or -S-
  • PG1 is a hydrogen atom or a hydroxyl protecting group
  • Y is a halogen atom, a hydroxyl group or a leaving group like mesylate, tosylate, triflate,
  • A2 and A3 have the same meaning as in formulae III and IV- 1.
  • ARl , AR2, Rl , R2, R3, R5, R6 and R7 are as defined for compounds of formula I,
  • Y is a phosphonium salt or a phosphonate
  • n 0 or 1
  • A2 and A3 have the same meaning as in formulae III and IV- 1.
  • R4 is as in formula I.
  • This process variant can be used for the manufacture of compounds of formula I as defined above, that present a quaternary amine. These molecules can be obtained by reacting a methyl halide or the
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the art, or they may be removed during a later reaction step or work-up.
  • the protecting group PG1 is carried out under standard conditions.
  • the benzyl or the allyl groups are introduced with an alkaline solution of benzyl or allyl halide, respectively; the tetrahydropyranyl group is introduced with dihydropyran under acidic conditions; the hydroxyl groups are protected as silyl ethers by reacting with the required silyl chloride reagent in presence of a base such as imidazole or pyridine.
  • a base such as imidazole or pyridine.
  • Such hydroxyl protecting groups can be removed before reaction of compounds of formula III with compounds of formula II-l .
  • the benzyl group is removed by hydrogenolysis over a noble metal catalyst (e.g. palladium or palladium hydroxide on activated carbon); the tetrahydropyranyl group is removed in presence of /jara-toluenesulfonic acid at pH 3, between 40 °C and 70 °C in a solvent such as methanol;
  • the silyl ether groups are removed either using fluoride anion sources such as tetra-n-butylammonium fluoride in a solvent such as tetrahydrofuran or NN-dimethylformamide between 0 °C and 40 °C or in hydrofluoric acid in acetonitrile between 0 °C and 40 °C or using acidic conditions such as acetic acid in tetrahydrofuran-methanol or hydrochloric acid in methanol.
  • the reaction is for example performed in the presence of diethyl or diisopropyl azodicarboxylate and triphenylphosphine, in a wide range of solvents such as NN-dimethylformamide, tetrahydrofuran, 1,2-dimethoxyethane or dichloromethane and within a wide range of temperatures (between -20 °C and 60 °C).
  • solvents such as NN-dimethylformamide, tetrahydrofuran, 1,2-dimethoxyethane or dichloromethane
  • the reaction might also be performed using polymer-supported triphenylphosphine.
  • Activation of the hydroxyl group of compounds of formula II- 1 wherein Yl is -OH as for example a mesylate, a tosylate or a triflate can be achieved by reacting the corresponding alcohol with methanesulfonyl chloride or methanesulfonic anhydride, / toluenesulfonyl chloride, trifluoromethanesulfonyl chloride or
  • trifluoromethanesulfonic anhydride in presence of a base such as triethylamine or the like in a dry aprotic solvent such as pyridine, acetonitrile, tetrahydrofuran or dichloromethane between -30 °C and 80 °C.
  • a base such as triethylamine or the like
  • a dry aprotic solvent such as pyridine, acetonitrile, tetrahydrofuran or dichloromethane between -30 °C and 80 °C.
  • compounds of formula IV-1 can react with compounds of formula V for which X is -CH 2 -OH, in presence of an inorganic base such as sodium hydride or the like in a solvent such as tetrahydrofuran or NN-dimethylformamide at a temperature ranging between -20 °C and 80 °C, to generate compounds of formula VI-1 wherein R4 is 0-R14, wherein 0-R14 is as defined for compounds of formula I.
  • compounds of formula IV-1 can react with a compound of formula V for which X is a halogen atom or a leaving group, in presence of an inorganic base such as sodium hydride or the like in a solvent such as tetrahydrofuran or NN-dimethylformamide at a temperature ranging between -20 °C and 80 °C, to generate compounds of formula VI-1 wherein R4 is 0-R14, wherein 0-R14 is as defined for compounds of formula I.
  • compounds of formula IV- 1 can react with compounds of formula V for which X is a phosphonium salt or a phosphonate via a Wittig or Horner- Wadsworth-Emmons reaction, respectively, to generate compounds of formula VI- 1 for which R4 is a C2-C6-alkenyl group.
  • the Wittig reaction is the reaction of an aldehyde with a triphenyl phosphonium ylide to afford an alkene and triphenylphosphine oxide.
  • the Wittig reagent is usually prepared from a phosphonium salt, which is, in turn, prepared by alkylation of triphenylphosphine with a benzyl halide.
  • a phosphonium salt is suspended in a solvent such as diethyl ether or tetrahydroiuran and a strong base such as n-butyl lithium is added.
  • the product is usually mainly the Z-isomer, although a lesser amount of the is-isomer also is often formed. If the reaction is performed in NN- dimethylformamide in the presence of lithium or sodium iodide, the product is almost exclusively the Z-isomer. If the Z-isomer is the desired product, the Schlosser modification may be used.
  • the Horner- Wadsworth-Emmons reaction produces predominantly is-alkenes.
  • the Horner- Wadsworth-Emmons reaction is the condensation of stabilized phosphonate carbanions with aldehydes in presence of a base such as sodium hydride or sodium methylate in a solvent such as diethyl ether or tetrahydroiuran, between 0 °C and 50 °C.
  • phosphonate-stabilized carbanions are more nucleophilic and more basic. Diethyl benzylphosphonates can be easily prepared from readily available benzyl halides.
  • compounds of formula IV- 1 can react with compounds of formula V for which X is - NH 2 or -NHE, E being an amino protecting group, via a peptidic coupling reaction, to generate compounds of formula VI- 1 for which R4 is an amide group.
  • the reaction takes place in the presence of an activating agent such as NN'-dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, with the optional addition of 1 -hydroxybenzotriazole.
  • Suitable coupling agents may be utilized such as, 0-(7-azabenzotriazol-l-yl)-N,NN',N'-tetramethyluronium hexafluorophosphate, 2-ethoxy- l-ethoxycarbonyl-l,2-dihydroquinoline, carbonyldiimidazole or diethylphosphorylcyanide.
  • a base like triethylamine, NN-diisopropylethylamine or pyridine can be added to perform the coupling.
  • the peptidic coupling is conducted at a temperature comprised between -20 °C and 80 °C, in an inert solvent, preferably a dry aprotic solvent like dichloromethane, acetonitrile or NN-dimethylformamide and chloroform.
  • an inert solvent preferably a dry aprotic solvent like dichloromethane, acetonitrile or NN-dimethylformamide and chloroform.
  • the carboxylic acid can be activated by conversion into its corresponding acid chloride or its corresponding activated ester, such as the N-hydroxysuccinimidyl ester (Org. Process Res. & Dev., 2002, 863) or the benzothiazolyl thioester (J. Antibiotics, 2000, 1071).
  • the generated activated entity can react at a temperature comprised between -20 °C and 80 °C with a compound of formula II- 1 in an aprotic solvent like dichloromethane, chloroform, acetonitrile, NN-dimethylformamide and tetrahydroiuran to generate a compound of formula 1-1.
  • a base like triethylamine, NN-diisopropylethylamine, pyridine, sodium hydroxide, sodium carbonate, potassium carbonate can be added to perform the coupling.
  • the amino protecting group E is introduced by reacting the corresponding free amine with allyl,
  • the amino protecting group E can further be removed under standard conditions.
  • the benzyl carbamates are deprotected by hydrogenolysis over a noble metal catalyst (e.g. palladium or palladium hydroxide on activated carbon).
  • the Boc group is removed under acidic conditions such as hydrochloric acid in an organic solvent such as methanol, dioxane or ethyl acetate, or trifluoroacetic acid neat or diluted in a solvent such as dichloromethane.
  • the Alloc group is removed in presence of a palladium salt such as palladium acetate or tetrakis(triphenylphosphine)palladium(0) and an allyl cation scavenger such as morpholine, pyrrolidine, dimedone or tributylstannane between 0 °C and 70 °C in a solvent such as tetrahydrofuran.
  • a palladium salt such as palladium acetate or tetrakis(triphenylphosphine)palladium(0)
  • an allyl cation scavenger such as morpholine, pyrrolidine, dimedone or tributylstannane between 0 °C and 70 °C in a solvent such as tetrahydrofuran.
  • the N-benzyl protected amines are deprotected by hydrogenolysis over a noble metal catalyst (e.g. palladium hydroxide on activated carbon).
  • compounds of formula VI- 1 wherein Y2 is a hydroxyl group can be converted to the corresponding halide, mesylate, tosylate or triflate compounds and react with compounds of formula VII via a substitution reaction as previously described above.
  • compounds of formula VI- 1 can react with compounds of formula VII via a substitution reaction as previously described above, to generate compounds of formula 1-1 wherein L2 is - (CH 2 )o- or -(CH 2 )o-C(0)-CH 2 -, respectively.
  • compounds of formula VI- 1 can react with compounds of formula VII via a reductive amination reaction, to generate compounds of formula 1-1 for which L2 is -(CH 2 ) P -, wherein p is comprised between 1 and 4.
  • the reductive amination reaction between the amine and the aldehyde to form an intermediate imine is conducted 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, magnesium sulfate or sodium sulfate).
  • Such solvent is typically toluene, n-hexane, tetrahydrofuran, dichloromethane NN-dimethylformamide, NN-dimethylacetamide, acetonitrile, 1,2- dichloroethane or mixture of solvents such as methanol- 1 ,2-dichloroethane.
  • the reaction can be catalyzed by 5 traces of acid (usually acetic acid).
  • the intermediate imine is reduced subsequently or simultaneously with a suitable reducing agent (e.g. sodium borohydride, sodium cyanoborohydride, sodiumtriacetoxyborohydride; R.O. and M.K. Hutchins, Comprehensive Organic Synthesis, B.M. Trost, I.
  • a suitable reducing agent e.g. sodium borohydride, sodium cyanoborohydride, sodiumtriacetoxyborohydride; R.O. and M.K. Hutchins, Comprehensive Organic Synthesis, B.M. Trost, I.
  • reaction is usually carried out between -10 °C and 110 °C, preferably between 0 °C and 10 60 °C.
  • the reaction can also be carried out in one pot. It can also be performed in protic solvents such as methanol or water in presence of a picoline-borane complex (Tetrahedron, 2004, 60, 7899).
  • compounds of formula VI- 1 for which Y2 is -CHO can be generated from the corresponding compounds for which Y2 is an ester group or a carboxylic acid function.
  • the ester derivatives are further reduced into their corresponding alcohols. This reduction is performed with a reducing agent like boron or aluminium hydride reducing agent such as lithium aluminium hydride, lithium borohydride, sodium borohydride in a solvent such as tetrahydrofuran between -20 °C and 80 °C.
  • the ester function is hydrolyzed into its corresponding carboxylic acid using an alkali hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide in water or in a mixture of water with polar protic or aprotic organic solvents such as dioxane, tetrahydrofuran or methanol between -10 °C and 80 °C.
  • the resulting carboxylic acid is further reduced into the corresponding alcohol using a borane derivative such as borane- tetrahydrofuran complex in a solvent such as tetrahydrofuran between -10 °C and 80 °C.
  • the generated alcohol is then transformed into its corresponding aldehyde through oxidation under Swern, Dess Martin, Sarett or Corey-Kim conditions respectively. Further methods are described in Comprehensive Organic Transformations. A guide to functionnal Group Preparations; 2 nd Edition, R. C. Larock, Wiley- VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1999. Section aldehydes and ketones, p.1235- 1236 and 1238-1246.
  • compounds of formula IV-2 wherein LI is -0-(CH 2 ) n - can be obtained from compounds of formula VIII wherein -A1-PG1 is -OH via a Mitsunobu coupling (as reviewed in O. Mitsunobu, Synthesis 1981, 1) with compounds of formula IX for which Y is a hydroxyl group, following procedures previously described above in Scheme 1.
  • an optically active form of a compound of the invention When an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure enantiomer or diastereomer as a starting material, or by resolution of a mixture of the enantiomers or diastereomers of the final product or intermediate using a standard procedure.
  • the resolution of enantiomers may be achieved by chromatography on a chiral stationary phase, such as REGIS PIRKLE COVALENT (R-R) WHELK-02, 10 ⁇ , 100 A, 250 x 21.1 mm column.
  • resolution of stereoisomers may be obtained by preparation and selective crystallization of a diastereomeric salt of a chiral intermediate or chiral product with a chiral acid, such as camphorsulfonic acid.
  • a method of stereoselective synthesis may be employed, for example by using a chiral variant of a protecting group, a chiral catalyst or a chiral reagent where appropriate in the reaction sequence.
  • Enzymatic techniques may also be used for the preparation of optically active compounds and/or intermediates.
  • evaporations are carried out by rotary evaporation under reduced pressure and work-up procedures are carried out after removal of residual solids by filtration;
  • HPLC of final products are generated using a Dionex Ultimate 3000 instrument and the following conditions:
  • each intermediate is purified to the standard required for the subsequent stage and is characterized in sufficient detail to confirm that the assigned structure is correct;
  • Example numbers used in the leftmost column are used in the whole application text for identifying the respective compounds.
  • Diisobutylalumimum hydride (1M solution in n-hexane, 18.6 mL, 18.6 mmol, 1.5 eq) is added dropwise at 0°C to a stirred solution of 3-[(2-bromo-4-chloro-phenoxy)methyl]benzonitrile (4.0 g, 12.4 mmol, 1.0 eq) in dichloromethane (40 mL). After 2 hours stirring at 0°C, the reaction mixture is poured in a 6N hydrochloric acid aqueous solution (40 mL). The phases are separated and the aqueous phase is extracted with ethyl acetate (3 x 50 mL).
  • Example 5 3-[[5-(aminomethyl)-2-oxo-l,3-oxazinan-3-yllmethyll-5-[(2-bromo-4- chloro-phenvDmethoxylbenzamide: Preparation of ferf -butyl 3 - 1 " [ [3 -
  • methyll azetidine- 1 -carboxylate
  • the titled compound is prepared as a white solid (28 mg, 12%> yield) following Scheme 1 and in analogy to Example 7 using tert-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-carbamoyl-phenyl]methyl]-tert- butoxycarbonyl-amino]methyl] azetidine- 1 -carboxylate (235 mg, 0.37 mmol) as starting material.
  • the titled compound is prepared as a white solid (30 mg, 12% yield) following Scheme 1 and in analogy to Example 7 using tert-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(3- methoxypropylcarbamoyl)phenyl]methyl-tert-butoxycarbonyl-amino]methyl]azetidine-l-carboxylate (330 mg, 0.46 mmol) as starting material.
  • Example 7 3-[[5-(aminomethyl)-2-oxo-l,3-oxazinan-3-yllmethyll-5-[(2-bromo-4-chloro- phenvDmethoxyl benzaldehyde : Preparation of dimethyl 5-r(2-bromo-4-chloro-phenyl methoxylbenzene-l,3-dicarboxylate:
  • the titled compound is prepared as a white solid following Scheme 1 and in analogy to Example 1 using 2- bromo-l-(bromomethyl)-4-chloro-benzene [33924-45-7] and dimethyl 5-hydroxybenzene-l,3-dicarboxylate [13036-02-7] as starting materials.
  • Lithium borohydride (1.26 g, 58.02 mmol, 5.0 eq) is added at room temperature to a stirred solution of dimethyl 5-[(2-bromo-4-chloro-phenyl)methoxy]benzene-l,3-dicarboxylate (4.8 g, 11.6 mmol, 1.0 eq) in tetrahydrofuran (100 mL).
  • Triethylamine (637 L, 4.56 mmol, 1.5 eq) is added at room temperature to a stirred solution of tert-butyl 3- [[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(hydroxymethyl)phenyl]methylamino]methyl]azetidine-l- carboxylate (1.6 g, 3.04 mmol, 1.0 eq) in dichloromethane (60 mL), followed by di-tert-butyl dicarbonate (797 mg, 3.65 mmol, 1.2 eq).
  • Dess Martin periodinane solution (0.75 mL, 0.74 mmol, 1.5 eq) is added at 0°C to a stirred solution of tert- butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(hydroxymethyl)phenyl]methyl-tert-butoxycarbonyl- amino]methyl]azetidine-l-carboxylate (310 mg, 0.49 mmol, 1.0 eq) in dichloromethane (20 mL). After 1 hour stirring at 0°C, the reaction mixture is quenched with a saturated sodium thiosulfate aqueous solution (20 mL).
  • Trifluoroacetic acid (2 mL, 26.12 mmol, 81.6 eq) is added at room temperature to a stirred solution of tert- butyl 3 - [[ [3 - [(2-bromo-4-chloro-phenyl)methoxy] -5-formyl-phenyl]methyl-tert-butoxycarbonyl- amino]methyl]azetidine-l-carboxylate (200 mg, 0.32 mmol, 1.0 eq) in dichloromethane (2 mL).
  • Example 8 Ethyl ( ⁇ -S- -ffS-CaminomethvD-l-oxo-l ⁇ -o azinan-S-yllmethyll-S-Kl- bromo-4-chloro-phenyl)methoxyl phenyll prop-2-enoate : Preparation of ferf-butyl 3-rrr3-r(2-bromo-4-chloro-phenyl)methoxyl-5-r(£')-3-ethoxy-3-oxo-prop-l- enyllphenyllmethyl-fer?-butoxycarbonyl-aminolmethyllazetidine-l-carboxylate:
  • the titled compound is prepared as a white solid (1.0 g, 56%> yield) following Scheme 1 and in analogy to Example 1 using 2-bromo-l-(bromomethyl)-4-chloro-benzene [33924-45-7] (1.5 g, 5.27 mmol, 1.0 eq) and l-(3-hydroxyphenyl)ethanone [121-71 -1] (0.72 g, 5.27 mmol, 1.0 eq) as starting materials.
  • feri-Butyl N-(pyrrolidin-3-ylmethyl)carbamate (280 mg, 1.42 mmol, 2.0 eq) [149366-79-0] is added at room temperature to a stirred solution of 2-bromo-l-[3-[(2-bromo-4-chloro-phenyl)methoxy]phenyl]ethanone (300 mg, 0.72 mmol, 1.0 eq) in acetonitrile (20 mL), followed by NN-diisopropylethylamine (0.24 mL, 1.42 mmol, 3.0 eq).
  • the titled compound is prepared as a light yellow oil following Scheme 1 and in analogy to Examples 1 and 7 using 2-bromo-l -(bromomethyl)-4-chloro-benzene [33924-45-7] and methyl 3-sulfanylbenzoate [32886-42- 1] as starting materials.
  • Manganese dioxide (2.38 g, 27.4 mmol, 10.0 eq) is added at room temperature to a stirred solution of 3-[(2- bromo-4-chloro-phenyl)methylsulfanyl]phenyl]methanol (940 mg, 2.74 mmol, 1.0 eq) in dichloromethane (20 mL). After 16 hours stirring at room temperature, manganese dioxide is removed by filtration and the solution is evaporated to afford 3-[(2-bromo-4-chloro-phenyl)methylsulfanyl]benzaldehyde as a light yellow oil (640 mg, 69% yield) that is directly engaged in the next step without further purification.
  • the titled compound is prepared as a white solid (110 mg, 80% yield) following Scheme 1 and in analogy to Example 7 using teri-butyl 3-[[[3-[(2-bromo-4-chloro- phenyl)methylsulfanyl]phenyl]methylamino]methyl]pyrrolidine-l-carboxylate (170 mg, 0.32 mmol) as starting material.
  • Example 15 [l-[[3-[(.£ ' )-2-(2-bromo-4-chloro-phenyl)vinyll-5-chloro- phenyll methyllpyrrolidin-3-yll methanamine :
  • the titled compound is prepared as a white solid (400 mg, 76%> yield) following Scheme 3 and in analogy to Example 16 using methyl 3-chloro-5-formyl-benzoate [879542-48-0] (280 mg, 1.41 mmol, 1.0 eq) and 2- bromo-4-chloro-l -(diethoxyphosphorylmethyl)benzene (480 mg, 1.41 mmol, 1.0 eq) as starting materials.
  • 'H-NMR 400 MHz, DMSO-i/6) ⁇ ppm: 13.48 (br, 1H), 8.09 (s, 1H), 7.81-7.97 (m, 4H), 7.37-7.55 (m, 3H).
  • Potassium carbonate (220 mg, 1.61 mmol, 1.5 eq) is added at room temperature to a stirred solution of 3- [(£ ' )-2-(2-bromo-4-chloro-phenyl)vinyl]-5-chloro-benzoic acid (400 mg, 1.07 mmol, 1.0 eq) in NN- dimethylformamide (5 mL), followed by iodomethane (100 ⁇ , 1.61 mmol, 1.5 eq). After 3 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3 x 10 mL) and water (10 mL).
  • Triethyl phosphite (30.3 niL, 175.82 mmol, 5.0 eq) is added at room temperature to a stirred solution of 2- bromo-l-(bromomethyl)-4-chloro-benzene [33924-45-7] (10.0 g, 35.16 mmol, 1.0 eq) in toluene (100 mL).
  • Lithium diisopropylamide (2M solution in tetrahydrofuran, 2.40 mL, 4.80 mmol, 3.0 eq) is added at 0°C to as stirred suspension of (methoxymethyl)triphenylphosphonium chloride (800 mg, 2.33 mmol, 1.5 eq) in tetrahydrofuran (20 mL).
  • 3-[(£)-2-(2-bromo-4-chloro- phenyl)vinyl]benzaldehyde (500 mg, 1.55 mmol, 1.0 eq) is added at room temperature to the reaction mixture.
  • Example 18 S-f -allyloxy-S-K ⁇ -l-Cl-bromo ⁇ -chloro-phenvDvinyllphenyllmethyll-S- (aminomethyl)-l,3-oxazinan-2-one:
  • the titled compound is prepared as a white solid (1.16 g, 99%> yield) following Scheme 3 and in analogy to Example 1 using dimethyl 5-hydroxybenzene-l,3-dicarboxylate [13036-02-7] (1.0 g, 4.66 mmol, 1.0 eq) and allyl bromide [106-95-6] (620 mg, 5.13 mmol, 1.1 eq) as starting materials.
  • 'H-NMR 400 MHz, CDC1 3 ) ⁇ ppm: 8.30 (s, 1H), 7.79 (s, 2H), 6.07 (m, 1H), 5.46 (m, 1H), 5.35 (m, 1H), 4.65 (m, 2H), 3.96 (s, 6H).
  • Lithium aluminium hydride (360 mg, 9.5 mmol, 0.85 eq) is added at 0°C to a stirred solution of dimethyl 5- allyloxybenzene-l,3-dicarboxylate (2.80 g, 11.2 mmol, 1.0 eq) in tetrahydrofuran (40 mL). After 2 hours stirring at 0°C, the reaction mixture is quenched with brine (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford methyl 3-allyloxy-5-(hydroxymethyl)benzoate as a colorless oil (1.0 g, 40% yield) that is directly engaged in the next step without further purification.
  • the titled compound is prepared as a white solid following Scheme 3 and in analogy to Example 7 using methyl 3-allyloxy-5-(hydroxymethyl)benzoate, methanesulfonyl chloride [124-63-0], tert-butyl 3- (aminomethyl)azetidine-l-carboxylate [325775-44-8] and di-tert-butyl dicarbonate as starting materials.
  • the titled compound is prepared as a white solid following Scheme 3 and in analogy to Examples 1 and 7 using dimethyl 5-formylbenzene-l,3-dicarboxylate [164073-80-7] and teri-butyl N-(pyrrolidin-3- ylmethyl)carbamate [325775-44-8] as starting materials.
  • Example 22 [l-[[3-[(2-bromo-4-chloro-phenyl)methoxyl-5-isobutoxy-phenyllmethyll- 1 -methyl-pyrrolidin-1 -ium-3 -yll methanamine :
  • the titled compound is prepared as a white solid following Scheme 1 and in analogy to Example 1 using 2- bromo-l-(bromomethyl)-4-chloro-benzene [33924-45-7], 3,5-dihydroxybenzaldehyde [26153-38-8], 1- bromo-2-methyl-propane [78-77-3] and teri-butyl N-(pyrrolidin-3-ylmethyl)carbamate [149366-79-0] as starting materials.
  • Potassium carbonate (126 mg, 0.91 mmol, 2.0 eq) is added at room temperature to a stirred solution of tert- butyl N- [[ 1 - [[3 - [(2-bromo-4-chloro-phenyl)methoxy] -5 -isobutoxy-phenyl]methyl]pyrrolidin-3 - yl]methyl]carbamate (265 mg, 0.46 mmol, 1.0 eq) in NN-dimethylformamide (10 mL), followed by iodomethane (57 ⁇ , 0.91 mmol, 2.0 eq).
  • the titled compound is prepared as a light yellow semi-solid following Scheme 1 and in analogy to Examples 1, 7 and 22 using teri-butyl 4-[2-[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-formyl-phenoxy]ethyl]imidazole- 35 1 -carboxylate and iodomethane as starting materials.
  • Biological Examples
  • aeruginosa or with linezolid at the subinhibitory dose of 128 ⁇ g/mL for E. coli and P. aeruginosa.
  • Each well contained 1 ⁇ of test compound in 100 ⁇ caMHB with minocycline or with linezolid.
  • OD625 was measured at lh, 6h, and at 23h.
  • the following compounds reduce growth of P. aeruginosa PAOl to no more than 10%> growth of the uninhibited control in the antibacterial activity assay with linezolid when the compound is present at 50 ⁇ : 2, 11, 15, 19, 21, 22, 24, 25 of Table 1.
  • the following compounds reduce growth of E. coli ATCC25922 to no more than 50%> growth of the uninhibited control in the antibacterial activity assay with linezolid when the compound is present at 25 ⁇ : 1, 2, 3, 4, 8, 9, 11, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25 of Table 1.
  • the following compounds reduce growth of E. coli ATCC25922 to no more than 10%> growth of the uninhibited control in the antibacterial activity assay with linezolid when the compound is present at 25 ⁇ : 1, 2, 3, 4, 8, 9, 11, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25 of Table 1.
  • the following compounds reduce growth of P. aeruginosa PAOl to no more than 50%> growth of the uninhibited control in the antibacterial activity assay with linezolid when the compound is present at 25 ⁇ : 15, 16, 22, 24, 25 of Table 1.
  • the following compounds reduce growth of P. aeruginosa PAOl to no more than 10%> growth of the uninhibited control in the antibacterial activity assay with linezolid when the compound is present at 25 ⁇ : 15, 16, 22, 24, 25 of Table 1.

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Abstract

La présente invention concerne des composés de formule I ou leurs sels, solvates ou hydrates pharmaceutiquement acceptables, ASC étant telle que le cycle A représente un cycle saturé de 4 à 6 chaînons contenant des atomes de carbones en tant que chaînons cycliques en plus de l'atome d'azote, une fraction -CH 2 -CH 2 – adjacente à l'atome d'azote étant éventuellement remplacée par une fraction -C(=O)-O- pour former un carbamate; X représente une liaison ou -CH 2 -; AR1 et AR2 représentent phényle; R1, R2 et R3 représentent indépendamment hydrogène, halogène, alkyle en C 1 -C 6, halogénure d'alkyle en C 1 -C 6, alcoxy en C 1 -C 6 ou halogéno-alcoxy en C 1 -C 6; R4 représente hydrogène, halogène, alkyle en C 1 -C 6 éventuellement substitué par 1 à 5 R10a, alcényle en C 2 -C 6 éventuellement substitué par 1 à 5 R10a, alkylène-R10b en C 1 -C 6, alcénylène-R10b en C 2 -C 6, C(O)OR11a, CHO, C(O)N(R12)R13 ou O-R14; R5, R6 et R7 représentent indépendamment hydrogène, halogène, alkyle en C 1 -C 6, halogénure d'alkyle en C 1 -C 6, alcoxy en C 1 -C 6 ou halogéno-alcoxy en C 1 -C 6; R8 représente méthyle ou est absent, et lorsque R8 est présent, l'atome d'azote respectif porte une charge positive; R9a et R9b représentent indépendamment hydrogène ou méthyle; R10a représente indépendamment à chaque occurrence halogène, hydroxyle, alcoxy en C 1 -C 6 ou halogéno-alcoxy en C 1 -C 6; R10b représente cycloakyle en C 3 -C 8, C(O)OR11a, CHO, C(O)N(R12)R13, N(R12)R13, un cycle P ou un cycle Q; R11a et R11b représentent indépendamment à chaque occurrence hydrogène ou alkyle en C 1 -C 6; R12 et R13 représentent indépendamment à chaque occurrence hydrogène, alkyle en C 1 -C 4, halogénure d'alkyle en C 1 -C 4 ou alcoxy en C 1 -C 4, alkyle en -C 1 -C 4; R14 représente alkyle en C 1 -C 6, halogénure d'alkyle en C 1 -C 6, alcényle en C 2 -C 6, halogéno-alcényle en C 2 -C 6, un cycle P d'alkylène en C 1 -C 6, un cycle Q d'alkylène en C 1 -C 6; le cycle P représente indépendamment à chaque occurrence un cycle carboxylique saturé ou partiellement insaturé en C 5 -C 6 éventuellement substitué par 1 à 3 R15 ou un cycle hétérocyclique saturé ou partiellement insaturé de 5 à 6 chaînons éventuellement substitué par 1 à 3 R15 contenant des atomes de carbones en tant que chaînons cycliques et un ou deux chaînons cycliques étant indépendamment choisis parmi N(R11b) et O; le cycle Q représente indépendamment à chaque occurrence phényle éventuellement substitué par 1 à 3 R16 ou un cycle hétéroaryle de 5 à 6 chaînons contenant de un à quatre hétéroatomes indépendamment choisis parmi O, S et N, éventuellement substitués par 1 à 3 R16; R15 et R16 représentent indépendamment à chaque occurrence halogène, alkyle en C 1 -C 4, halogénure d'alkyle en C 1 -C 4, alcoxy en C 1 -C 4 ou halogéno-alcoxy en C 1 -C 4; L1 représente -CH=CH-, -CH 2 -O-, -(CH 2 ) 2 -O-, -0-CH 2 -, -CH 2 -S-, -(CH 2 ) 2 -S-, -S-CH 2 -, -C(CH 3 ) 2 -, -(CH 2 ) 2 - ou -CH=CH-CH 2 -; L2 représente alkylène en C 1 -C 7, une ou plusieurs fractions -CH 2 – dans la fraction alkylène étant éventuellement remplacées indépendamment par -C(=O)-. L2 ne contient pas de fractions -C(=O)- adjacentes et la fraction terminale de L2 n'est pas -C(=O)-. L'invention concerne en outre leur utilisation dans des procédés de traitement d'un sujet souffrant d'une infection microbienne ou susceptible de souffrir d'une infection microbienne en association avec un agent antimicrobien.
PCT/EP2016/078938 2015-11-30 2016-11-28 Dérivés de pipéridine, de pyrrolidine et de 2-oxo-1,3-oxazinane en tant qu'inhibiteurs de pompes à efflux bactériennes pour le traitement d'infections microbiennes WO2017093157A1 (fr)

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CN108410880A (zh) * 2018-01-26 2018-08-17 昆明理工大学 一种丹波黑大豆柠檬酸转运蛋白基因及其应用
WO2023014431A1 (fr) * 2021-08-02 2023-02-09 The Regents Of The University Of Colorado Inhibiteurs de pompes d'efflux bactériennes et procédés d'utilisation

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108410880A (zh) * 2018-01-26 2018-08-17 昆明理工大学 一种丹波黑大豆柠檬酸转运蛋白基因及其应用
WO2023014431A1 (fr) * 2021-08-02 2023-02-09 The Regents Of The University Of Colorado Inhibiteurs de pompes d'efflux bactériennes et procédés d'utilisation

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