WO2017042099A1 - Efflux-pump inhibitors and therapeutic uses thereof - Google Patents

Efflux-pump inhibitors and therapeutic uses thereof Download PDF

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WO2017042099A1
WO2017042099A1 PCT/EP2016/070727 EP2016070727W WO2017042099A1 WO 2017042099 A1 WO2017042099 A1 WO 2017042099A1 EP 2016070727 W EP2016070727 W EP 2016070727W WO 2017042099 A1 WO2017042099 A1 WO 2017042099A1
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methyl
formula
compounds
compound
asc
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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
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/16—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring not being further substituted
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/48—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/50—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/08—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups

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 describes 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
  • ASC is -N(R8)ASC-l ;
  • AR1, AR2 represent phenyl
  • Rl, R2, R3 represent independently hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, CpCealkoxy, or Cp Cehaloalkoxy;
  • R4 represents hydrogen, halogen, CpCealkyl, CpCehaloalkyl or O-RIO;
  • R5, R6, R7 represent independently hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, CpCealkoxy or Cp Cehaloalkoxy;
  • R8 represents hydrogen, methyl or ASC-1 ;
  • R9a represents hydrogen or methyl
  • R10 represents CpCealkyl, CpCehaloalkyl, C2-Cealkenyl, CpCealkylene-Cycle-P, CpCealkylene-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 R12, or a saturated or partially unsaturated C 5 -C6 heterocyclic ring optionally substituted by 1 to 3 R12 containing carbon atoms as ring members and one or two ring members independently selected from N(R11) and O;
  • Cycle-Q represents independently at each occurrence phenyl optionally substituted by 1 to 3 Rl 3 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 R13;
  • Rl l represents hydrogen or Ci-Cealkyl
  • R12 and R13 represent independently at each occurrence halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy, or Ci-C 4 haloalkoxy;
  • L2 represents -0-C 2 -C 6 alkylene-
  • the compound of formula I is generally 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 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.
  • the subject will have received, is receiving or will receive additionally an antimicrobial agent in order to complete the treatment of the microbial infection.
  • 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 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.
  • 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 subject will have received, is receiving or will receive additionally an antimicrobial agent in order to complete the treatment of the microbial infection.
  • 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.
  • the subject will have received, is receiving or will receive additionally an antimicrobial agent in order to complete the treatment of the microbial infection.
  • 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 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.
  • R8 is ASC-1 ;
  • Rl , R2, and R3 independently is Br, CF 3 or C 2 -Cealkyl or at least R4 is 0-C 2 -C 4 alkenyl or at least R8 is ASC-1 ;
  • Acetamide, 2-amino-N-[[4-[(4-bromophenyl)methoxy]phenyl]methyl]- e.g. CAS 155720-39-1
  • Acetamide, 2-amino-N-[4-[4-(phenylmethoxy)phenoxy]butyl]- e.g. CAS 1606700-82-6)
  • Propanamide, 3-amino-N-methyl-N-[2-[4-(phenylmethoxy)phenoxy]ethyl]- e.g. CAS1587398-66-
  • Acetamide 2-amino-N-methyl-N-[2-[4-(phenylmethoxy)phenoxy]ethyl]- (e.g. CAS1585355-41-4) ; Acetamide, N-methyl-2-(methylamino)-N-[2-[4-(phenylmethoxy)phenoxy]ethyl]- (e.g.
  • Butanamide 4-amino-N-[[3-(phenoxymethyl)phenyl]methyl]- (e.g. CAS1601670-04-5) ;
  • Butanamide N-[[2-[(2-chlorophenoxy)methyl]phenyl]methyl]-4-(methylamino)- (e.g. CAS1601633-) ;
  • Butanamide 4-amino-N-[[4-(phenoxymethyl)phenyl]methyl]- (e.g. CAS1601607-19-5) ;
  • Butanamide 4-(methylamino)-N-[[4-(phenoxymethyl)phenyl]methyl]- (e.g. CAS 1590685-95-2) ;
  • Propanamide 3-amino-N-[[2-(phenoxymethyl)phenyl]methyl]- (e.g. CAS 1590654-54-8) ;
  • Butanamide 4-amino-N-[[2-[(2-chlorophenoxy)methyl]phenyl]methyl]- (e.g. CAS 1584944-96-6) ;
  • Propanamide 3-amino-N-[[3-(phenoxymethyl)phenyl]methyl]- (e.g. CAS1579382-57-2) ;
  • Acetamide 2-amino-N-[[2-[(2-chlorophenoxy)methyl]phenyl]methyl]- (e.g. CAS 1577291-71-4) ; Butanamide, 4-(methylamino)-N-[[3-(phenoxymethyl)phenyl]methyl]- (e.g. CAS1576389-49-5) ; Propanamide, 3-amino-N-[[4-(phenoxymethyl)phenyl]methyl]- (e.g. CAS 1575930-24-3) ;
  • Acetamide, 2-arruno-N-[[2-(phenoxymethyl)phenyl]methyl]- e.g. CAS1570795-81-1) ;
  • Butanamide 4-(methylamino)-N-[[2-(phenoxymethyl)phenyl]methyl]- (e.g. CAS1570773-38-4) ; Acetamide, 2-(methylamino)-N-[[4-(phenoxymethyl)phenyl]methyl]- (e.g. CAS 1570627-43-8) ;
  • R8 is ASC-1 ;
  • Each alkyl moiety either alone or as part of a larger group such as alkoxy is a straight or branched chain and is preferably CpCealkyl, more preferably Ci-C 4 alkyl.
  • Examples include methyl, ethyl, ⁇ -propyl, prop-2-yl, n- butyl, but-2-yl, 2-methyl-prop-l-yl or 2-methyl-prop-2-yl.
  • Examples of an alkoxy include methoxy, ethoxy, 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.
  • 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 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 include, if applicable, 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 alkynyl moiety either alone or as part of a larger group such as alkynyloxy is a straight or branched chain and is preferably C 2 -Cealkynyl, more preferably C 2 -C 4 alkynyl. Examples are ethynyl and propargyl.
  • 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 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.
  • depictions of moieties given for LI the bond on the left hand side of each moiety as depicted is connected to AR1 and the bond on the right hand side is connected to AR2.
  • the left hand side of each moiety as depicted is connected to AR2 and the right hand side is connected to ASC.
  • 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 methane-sulfonic 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.
  • Rl preferably represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy, or CpCehaloalkoxy, more preferably Rl represents hydrogen, halogen, CpCealkyl or Ci-Cehaloalkyl.
  • Rl include hydrogen, F, CI, Br, I, CF 3 , -O-methyl, -O-ethyl, -O-propyl, O-butyl, methyl, ethyl, propyl, and tert- butyl.
  • R2 preferably represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy, CpCehaloalkoxy, more preferably R2 represents hydrogen, halogen, CpCealkyl or Ci-Cehaloalkyl.
  • R2 include hydrogen, F, CI, Br, I, CF 3 , -O-methyl, -O-ethyl, -O-propyl, O-butyl, methyl, ethyl, propyl, and tert- butyl.
  • R3 preferably represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy, CpCehaloalkoxy, more preferably R3 represents hydrogen, halogen, CpCealkyl or Ci-Cehaloalkyl, even more preferably hydrogen.
  • Specific examples of R3 include hydrogen, F, CI, Br, I, CF 3 , -O-methyl, -O-ethyl, -O-propyl, O- butyl, methyl, ethyl, propyl, and teri-butyl.
  • R4 preferably represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or O-RIO, wherein RIO represents Ci-Cealkyl, C 2 -Cealkenyl, Ci-Cehaloalkyl, CpCealkylene-Cycle-P, or CpCealkylene-Cycle-Q, and preferably wherein Cycle-P represents independently at each occurrence cyclopentyl or cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, or morpholinyl, each optionally substituted by 1 to 3 R12, and wherein preferably R12 represents independently at each occurrence halogen, Ci-C 4 alkyl, Cp
  • 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 R13, and wherein more preferably Cycle-Q represents independently at each occurrence phenyl, pyridinyl, thiazolyl, or thiophenyl, each optionally substituted by 1 to 3 R13, and preferably wherein
  • Cycle-Q represents phenyl, pyridinyl or thiazolyl, each optionally substituted by 1 to 3 R13, and wherein preferably R13 represents independently at each occurrence halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy, or Cp C 4 haloalkoxy; and wherein more preferably R13 represents independently at each occurrence halogen, methyl, halomethyl, methoxy, or halomethoxy.
  • Cycle-Q represents phenyl or pyridinyl, each optionally substituted by 1 to 3 R13, and wherein preferably R13 represents independently at each occurrence halogen, Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 alkoxy, or Ci-C 4 haloalkoxy; and wherein more preferably R13 represents independently at each occurrence halogen, methyl, halomethyl, methoxy, or halomethoxy.
  • R4 further preferably represents hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, or O-RIO wherein R10 represents CpCealkyl, C 2 -Cealkenyl, CpCealkylene-phenyl, or Ci-Cealkylene-morpholinyl, more preferably hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, or O-RIO wherein R10 represents CpCealkyl or C 2 - Cealkenyl.
  • R5 preferably represents hydrogen, halogen, CpCealkyl, CpCehaloalkyl, CpCealkoxy or CpCehaloalkoxy, more preferably R5 represents hydrogen, halogen, CpCealkyl or Ci-Cehaloalkyl, and again more preferably R5 represents hydrogen.
  • Specific examples of R5 include hydrogen, F, CI, Br, I, CF 3 , -O-methyl, -O-ethyl, - O-propyl, O-butyl, methyl, ethyl, propyl, and butyl.
  • R6 preferably represents hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, CpCealkoxy or CpCehaloalkoxy, more preferably R6 represents hydrogen, halogen, CpCealkyl or Ci-Cehaloalkyl, and again more preferably R6 represents hydrogen.
  • Specific examples of R6 include hydrogen, F, CI, Br, I, CF 3 , -O-methyl, -O-ethyl, - O-propyl, O-butyl, methyl, ethyl, propyl, and butyl.
  • R7 preferably represents hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, CpCealkoxy or CpCehaloalkoxy, more preferably R7 represents hydrogen, halogen, CpCealkyl or Ci-Cehaloalkyl, and again more preferably R7 represents hydrogen.
  • Specific examples of R7 include hydrogen, F, CI, Br, I, CF 3 , -O-methyl, -O-ethyl, - O-propyl, O-butyl, methyl, ethyl, propyl, and butyl.
  • R8 represents hydrogen, methyl or ASC-1, preferably R8 represents hydrogen or ASC-1.
  • R8 is hydrogen or methyl
  • R8 is ASC-1.
  • ASC-1 is -(CH 2 ) 2 -N(R9a)R9b.
  • ASC-1 is -(CH 2 ) 3 -N(R9a)R9b.
  • ASC-1 is -(CH 2 ) 4 -N(R9a)R9b.
  • ASC-1 is -CH 2 -CH(CH 3 )-CH 2 -N(R9a)R9b.
  • ASC-1 is -(CH 2 ) 2 -NH-(CH 2 ) 2 -N(R9a)R9b.
  • At least one R9a is hydrogen.
  • each R9a is methyl.
  • At least one R9b is hydrogen.
  • each R9b is methyl.
  • Rl is F.
  • Rl is CI
  • Rl is Br
  • Rl is CF 3 .
  • Rl is C 2 -C 6 alkyl.
  • Rl is C palkyl, preferably feri-butyl.
  • R2 is H.
  • R2 is CI
  • R2 is Br.
  • R3 is H.
  • At least one of Rl , R2 and R3 is not H.
  • LI is -CH 2 -0-.
  • LI is -0-CH 2 -.
  • LI is -C(CH 3 ) 2 -.
  • R4 is H.
  • R4 is CI
  • R4 is CF 3 .
  • R4 is C 2 -C 6 alkyl. In one embodiment R4 is C palkyl, preferably teri-butyl.
  • R4 is O-RIO, wherein RIO is C 2 -C 6 alkenyl.
  • R4 is O-RIO, wherein RIO is allyl.
  • R4 is O-RIO, wherein RIO is C 2 -Cealkyl, wherein RIO is preferably C 4 alkyl.
  • R4 is O-RIO, wherein RIO is iso-butyl.
  • R4 is O-RIO, wherein RIO is benzyl.
  • R4 is O-RIO, wherein RIO is (CH 2 ) 2 -morpholine.
  • R4 is 0-CH 3 .
  • R4 is not H.
  • RIO represents C 2 -Cealkyl, CpCehaloalkyl, C 2 -Cealkenyl, CpCealkylene-Cycle-P, or Cp C 6 alkylene-Cycle-Q.
  • At least one of Rl , R2 and R3 is not H and R4 is not H.
  • L2 is -CH 2 -.
  • L2 is -0-(CH 2 ) 2 -.
  • L2 is -0-(CH 2 )3-.
  • L2 is -0-(CH 2 ) r.
  • L2 is -0-(CH 2 ) 2 -, -0-(CH 2 ) 3 -, -0-(CH 2 ) 4 -, -0-(CH 2 ) 5 - or -0-(CH 2 ) 6 -.
  • R8 is ASC-1 ;
  • L2 is at the meta 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 is not -0-(CH 2 ) 3 - when ASC-1 is -(CH 2 ) 2 -NH 2 ; or (iii) L2 is not -0-(CH 2 ) 2 - or -0-(CH 2 ) 3 - when ASC-1 is -(CH 2 ) 2 -
  • L2 and R4 are at the meta positions on AR2 with respect to the position of LI and R4 is not hydrogen.
  • L2 and R4 are at the meta positions on AR2 with respect to the position of LI and R4 is not hydrogen
  • R5, R6, 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.
  • R5, R6, 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, and
  • R3, R5, R6 and R7 are hydrogen.
  • R3, R5, R6, 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.
  • R3, R5, R6, 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, and
  • R4 is not -OCH 3 .
  • 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
  • R3, R5, R6, 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, R5, R6, 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, R4, R5, R6, 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, R7 are hydrogen and L2 is at the para position on AR2 with respect to the position of LI, and wherein when LI is -CH 2 -0-, then Rl is not F.
  • Rl is not hydrogen and is at the meta position on AR1 with respect to LI
  • R2, R3, R4, R5, R6, R7 are hydrogen and L2 is at the para position on AR2 with respect to the position of LI, and wherein when L2 is -CH 2 -, then Rl is not F.
  • Rl , R2 and R3 are hydrogen and L2 is at the meta position on AR2 with respect to the position of LI, and wherein when LI is -CH 2 -0-, then R4 is not -OCH 3 .
  • Rl , R2 and R3 are hydrogen and L2 is at the meta position on AR2 with respect to the position of LI, and wherein when L2 is -CH 2 -, then R4 is not -OCH 3 .
  • R3 is hydrogen
  • R4 represents hydrogen, halogen, Ci-C 6 alkyl, Ci-C 6 haloalkyl, or O-RIO wherein R10 represents Ci-C 6 alkyl, C 2 -C 6 alkenyl, CpCealkylene-phenyl, or Ci-Cealkylene-morpholinyl;
  • R5, R6, R7 are hydrogen
  • R8 represents hydrogen or ASC-1 ;
  • R9a represents hydrogen or methyl
  • the compound of the invention is a compound of formula 1-19.
  • Rl and R2 represent independently hydrogen, halogen, CpCealkyl or CpCehaloalkyl
  • R4 represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or O-RIO wherein RIO represents Ci-Cealkyl, C2-C 6 alkenyl, CpCealkylene-phenyl, or Ci-Cealkylene-morpholinyl;
  • R8 represents hydrogen or ASC-1 ;
  • R9a represents hydrogen or methyl
  • L2 represents -0-C 2 -C 6 alkylene-.
  • the compound of the invention is a compound of formula 1-19, wherein
  • ASC-1 is -(CH 2 ) 2 -N(R9a)R9b, -(CH 2 ) 3 -N(R9a)R9b, -(CH 2 ) 4 -N(R9a)R9b, -CH 2 -CH(CH 3 )-CH 2 -N(R9a)R9b, -
  • Rl and R2 represent independently hydrogen, halogen, CpCealkyl or CpCehaloalkyl
  • R4 represents hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, or O-RIO wherein R10 represents CpCealkyl or C 2 -C 6 alkenyl;
  • R8 represents hydrogen or ASC-1 ;
  • R9a represents hydrogen or methyl
  • L2 represents -0-C2-C 6 alkylene-.
  • the compound of the invention is a compound of formula 1-19, wherein
  • Rl and R2 represent independently hydrogen, halogen, CpCealkyl or CpCehaloalkyl
  • R4 represents hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, or O-RIO, wherein RIO represents CpCealkyl or C 2 -C 6 alkenyl;
  • R8 represents hydrogen or ASC-1 ;
  • R9a represents hydrogen or methyl
  • the compound of the invention is a compound of formula 1-19, wherein
  • Rl and R2 represent independently hydrogen, halogen, Ci-C 4 alkyl or Ci-C 2 haloalkyl, wherein preferably Rl and R2 represent independently halogen, Ci-C 4 alkyl or Cihaloalkyl;
  • R4 represents hydrogen, halogen, Ci-C 2 haloalkyl, or O-RIO wherein R10 represents Ci-C 4 alkyl or C 2 - C 3 alkenyl, wherein preferably R4 represents hydrogen, halogen, Ci-C 2 haloalkyl, or O-RIO wherein R10 represents Ci-C 4 alkyl or C 3 alkenyl;
  • R8 represents hydrogen or ASC-1 ;
  • R9a and R9b are independently hydrogen or methyl
  • L2 represents -0-C 2 -C 6 alkylene-.
  • the compound of the invention is a compound of formula 1-19, wherein
  • Rl and R2 represent independently hydrogen, halogen, Ci-C 4 alkyl or Ci-C 2 haloalkyl, wherein preferably Rl and R2 represent independently halogen, Ci-C 4 alkyl or Cihaloalkyl;
  • R4 represents hydrogen, halogen, Ci-C 2 haloalkyl, or O-RIO wherein RIO represents Ci-C 4 alkyl or C 2 - C 3 alkenyl, wherein preferably R4 represents hydrogen, halogen, Ci-C 2 haloalkyl, or O-RIO wherein RIO represents Ci-C 4 alkyl or C 3 alkenyl;
  • R8 represents hydrogen or ASC-1 ;
  • R9a and R9b are independently hydrogen or methyl
  • L2 represents -0-C 2 -C 6 alkylene-.
  • the compound of the invention is a compound of formula 1-19, wherein
  • Rl and R2 represent independently hydrogen, halogen, Ci-C 4 alkyl or Ci-C 2 haloalkyl, wherein preferably Rl and R2 represent independently halogen, Ci-C 4 alkyl or Cihaloalkyl;
  • R4 represents hydrogen, halogen, Ci-C 2 haloalkyl, or O-RIO wherein R10 represents Ci-C 4 alkyl or C 2 - C 3 alkenyl, wherein preferably R4 represents hydrogen, halogen, Ci-C 2 haloalkyl, or O-RIO wherein R10 represents Ci-C 4 alkyl or C 3 alkenyl;
  • R8 represents hydrogen or ASC-1 ;
  • R9a and R9b are independently hydrogen or methyl
  • the compound of the invention is a compound of formula 1-19, wherein
  • Rl and R2 represent independently hydrogen, F, CI, Br, ⁇ -Bu or CF 3 ;
  • R8 represents hydrogen or ASC-1 ;
  • R9a and R9b are independently hydrogen or methyl
  • L2 represents -0-C 2 -C 6 alkylene-.
  • the compound of the invention is a compound of formula 1-19, wherein
  • ASC-1 is -(CH 2 ) 2 -N(R9a)R9b, -(CH 2 ) 3 -N(R9a)R9b, -(CH 2 ) 4 -N(R9a)R9b, -CH 2 -CH(CH 3 )-CH 2 -N(R9a)R9b, -
  • Rl and R2 represent independently hydrogen, F, CI, Br, ⁇ -Bu or CF 3 ;
  • R8 represents hydrogen or ASC-1 ;
  • R9a and R9b are independently hydrogen or methyl
  • L2 represents -0-C2-C 6 alkylene-.
  • the compound of the invention is a compound of formula 1-19, wherein
  • ASC-1 is -(CH 2 ) 2 -N(R9a)R9b, -(CH 2 ) 3 -N(R9a)R9b, -(CH 2 ) 4 -N(R9a)R9b, -CH 2 -CH(CH 3 )-CH 2 -N(R9a)R9b,
  • Rl and R2 represent independently hydrogen, F, CI, Br, ⁇ -Bu or CF 3 ;
  • R8 represents hydrogen or ASC-1 ;
  • R9a and R9b are independently hydrogen or methyl
  • the compound of the invention is a compound of formula 1-19, wherein
  • Rl and R2 represent independently hydrogen, halogen, Ci-C 4 alkyl or Ci-C 2 haloalkyl, wherein preferably Rl and R2 represent independently halogen, Ci-C 4 alkyl or Cihaloalkyl;
  • R4 represents hydrogen, halogen, Ci-C 2 haloalkyl, or O-RIO wherein R10 represents Ci-C 4 alkyl or C 2 - C 3 alkenyl, wherein preferably R4 represents hydrogen, halogen, Ci-C 2 haloalkyl, or O-RIO wherein R10 represents Ci-C 4 alkyl or C 3 alkenyl;
  • R8 represents hydrogen or ASC-1 ;
  • R9a and R9b are independently hydrogen or methyl
  • the compound of the invention is a compound of formula 1-19, wherein
  • Rl and R2 represent independently hydrogen, F, CI, Br, ⁇ -Bu or CF 3 ;
  • R8 represents hydrogen or ASC-1 ;
  • R9a and R9b are independently hydrogen or methyl
  • the compound of the invention is a compound of formula 1-19, wherein
  • Rl and R2 represent independently hydrogen, F, CI, Br, ⁇ -Bu or CF 3 ;
  • R8 represents hydrogen or ASC- 1 ;
  • R9a and R9b are independently hydrogen or methyl
  • the compound of the invention is a compound of formula 1-19, wherein
  • Rl and R2 represent independently hydrogen, F, CI, Br, ⁇ -Bu or CF 3 ;
  • R8 represents hydrogen or ASC-1 ;
  • R9a and R9b are independently hydrogen or methyl
  • the compound of the invention is a compound of formula 1-20 to 1-23
  • RI and R2 represent independently hydrogen, halogen, CpCealkyl or CpCehaloalkyl
  • R4 represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or O-RIO wherein RIO represents Ci-Cealkyl, C2-C 6 alkenyl, CpCealkylene-phenyl, or Ci-Cealkylene-morpholinyl;
  • R8 represents hydrogen or ASC-1 ;
  • R9a represents hydrogen or methyl
  • preferably R9a and R9b are independently hydrogen or methyl
  • L2 represents -0-C2-C 6 alkylene-.
  • the compound of the invention is a compound of formula 1-20 to 1-23, wherein
  • RI and R2 represent independently hydrogen, halogen, CpCealkyl or CpCehaloalkyl;
  • R4 represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or O-RIO wherein RIO represents CpCealkyl or C 2 -C 6 alkenyl;
  • R8 represents hydrogen or ASC-1 ;
  • R9a represents hydrogen or methyl
  • preferably R9a and R9b are independently hydrogen or methyl
  • L2 represents -0-C 2 -C 6 alkylene-.
  • the compound of the invention is a compound of formula 1-20 to 1-23, wherein
  • Rl and R2 represent independently hydrogen, halogen, CpCealkyl or CpCehaloalkyl
  • R4 represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or O-RIO, wherein R10 represents CpCealkyl or C 2 -C 6 alkenyl;
  • R8 represents hydrogen or ASC-1 ;
  • R9a represents hydrogen or methyl
  • preferably R9a and R9b are independently hydrogen or methyl
  • the compound of the invention is a compound of formula 1-20 to 1-23, wherein
  • Rl and R2 represent independently hydrogen, halogen, Ci-C 4 alkyl or Ci-C 2 haloalkyl, wherein preferably Rl and R2 represent independently halogen, Ci-C 4 alkyl or Cihaloalkyl;
  • R4 represents hydrogen, halogen, Ci-C 2 haloalkyl, or O-RIO wherein R10 represents Ci-C 4 alkyl or C 2 -
  • R4 represents hydrogen, halogen, Ci-C 2 haloalkyl, or O-RIO wherein R10 represents Ci-C 4 alkyl or C 3 alkenyl;
  • R8 represents hydrogen or ASC-1 ;
  • L2 represents -0-C2-C 6 alkylene-.
  • the compound of the invention is a compound of formula 1-20 to 1-23, wherein
  • Rl and R2 represent independently hydrogen, halogen, Ci-C 4 alkyl or Ci-C 2 haloalkyl, wherein preferably Rl and R2 represent independently halogen, Ci-C 4 alkyl or Cihaloalkyl;
  • R4 represents hydrogen, halogen, Ci-C 2 haloalkyl, or O-RIO wherein R10 represents Ci-C 4 alkyl or C 2 -
  • R4 represents hydrogen, halogen, Ci-C 2 haloalkyl, or O-RIO wherein R10 represents Ci-C 4 alkyl or C 3 alkenyl;
  • R8 represents hydrogen or ASC-1 ;
  • R9a and R9b are independently hydrogen or methyl
  • L2 represents -0-C 2 -C 6 alkylene-.
  • the compound of the invention is a compound of formula 1-20 to 1-23, wherein
  • Rl and R2 represent independently hydrogen, halogen, Ci-C 4 alkyl or Ci-C 2 haloalkyl, wherein preferably Rl and R2 represent independently halogen, Ci-C 4 alkyl or Cihaloalkyl;
  • R4 represents hydrogen, halogen, Ci-C 2 haloalkyl, or O-RIO wherein R10 represents Ci-C 4 alkyl or C 2 - C 3 alkenyl, wherein preferably R4 represents hydrogen, halogen, Ci-C 2 haloalkyl, or O-RIO wherein R10 represents Ci-C 4 alkyl or C 3 alkenyl;
  • R8 represents hydrogen or ASC-1 ;
  • the compound of the invention is a compound of formula 1-20 to 1-23, wherein
  • Rl and R2 represent independently hydrogen, F, CI, Br, ⁇ -Bu or CF 3 ;
  • R8 represents hydrogen or ASC-1 ;
  • R9a and R9b are independently hydrogen or methyl
  • L2 represents -0-C 2 -C 6 alkylene-.
  • the compound of the invention is a compound of formula 1-20 to 1-23, wherein
  • Rl and R2 represent independently hydrogen, F, CI, Br, ⁇ -Bu or CF 3 ;
  • R8 represents hydrogen or ASC-1 ;
  • R9a and R9b are independently hydrogen or methyl
  • L2 represents -0-C2-C 6 alkylene-.
  • the compound of the invention is a compound of formula 1-20 to 1-23, wherein
  • ASC-1 is -(CH 2 ) 2 -N(R9a)R9b, -(CH 2 ) 3 -N(R9a)R9b, -(CH 2 ) 4 -N(R9a)R9b, -CH 2 -CH(CH 3 )-CH 2 -N(R9a)R9b,
  • Rl and R2 represent independently hydrogen, F, CI, Br, ⁇ -Bu or CF 3 ;
  • R8 represents hydrogen or ASC-1 ;
  • R9a and R9b are independently hydrogen or methyl
  • the compound of the invention is a compound of formula 1-20 to 1-23, wherein
  • Rl and R2 represent independently hydrogen, halogen, Ci-C 4 alkyl or Ci-C 2 haloalkyl, wherein preferably Rl and R2 represent independently halogen, Ci-C 4 alkyl or Cihaloalkyl;
  • R4 represents hydrogen, halogen, Ci-C 2 haloalkyl, or O-RIO wherein R10 represents Ci-C 4 alkyl or C 2 - C 3 alkenyl, wherein preferably R4 represents hydrogen, halogen, Ci-C 2 haloalkyl, or O-RIO wherein R10 represents Ci-C 4 alkyl or C 3 alkenyl;
  • R8 represents hydrogen or ASC-1 ;
  • R9a and R9b are independently hydrogen or methyl
  • the compound of the invention is a compound of formula 1-20 to 1-23, wherein
  • Rl and R2 represent independently hydrogen, F, CI, Br, ⁇ -Bu or CF 3 ;
  • R8 represents hydrogen or ASC-1 ;
  • R9a and R9b are independently hydrogen or methyl
  • the compound of the invention is a compound of formula 1-20 to 1-23, wherein
  • Rl and R2 represent independently hydrogen, F, CI, Br, ⁇ -Bu or CF 3 ;
  • R8 represents hydrogen or ASC- 1 ;
  • R9a and R9b are independently hydrogen or methyl
  • the compound of the invention is a compound of formula 1-20 to 1-23, wherein
  • ASC-1 is -(CH 2 ) 2 -N(R9a)R9b, -(CH 2 ) 3 -N(R9a)R9b, -CH 2 -CH(CH 3 )-CH 2 -N(R9a)R9b, -(CH 2 ) 2 -NH-(CH 2 ) 2 -
  • Rl and R2 represent independently hydrogen, F, CI, Br, ⁇ -Bu or CF 3 ;
  • R8 represents hydrogen or ASC- 1 ;
  • R9a and R9b are independently hydrogen or methyl
  • a further embodiment A34 of compounds of the invention is represented by any one of the embodiments Al to A16, wherein LI represents -C(CH 3 ) 2 -, and in particular embodiment Al wherein LI represents -C(CH 3 ) 2 -
  • a further embodiment A35 of compounds of the invention is represented by any one of the embodiments Al to A16, wherein LI represents -CH 2 -0-, and in particular embodiment Al wherein LI represents -CH 2 -0-.
  • a further embodiment A36 of compounds of the invention is represented by any one of the embodiments Al to A16, wherein LI represents -0-CH 2 -, and in particular embodiment Al wherein LI represents -0-CH 2 -.
  • a further embodiment A37 of compounds of the invention is represented by any one of the embodiments Al to A36, wherein ASC is -N(ASC-1) 2 , and in particular embodiment Al wherein ASC is -N(ASC-1) 2 .
  • the compound of the invention is a compound of formula 1-20, wherein Rl, R2, R4, L2 and ASC are preferably defined as in any one of embodiments A17 to A32.
  • the compound of the invention is a compound of formula 1-21, wherein Rl, R2, R4, L2 and ASC are preferably defined as in any one of embodiments A17 to A32.
  • the compound of the invention is a compound of formula 1-22, wherein Rl , R2, R4, L2 and ASC are preferably defined as in any one of embodiments A17 to A32.
  • the compound of the invention is a compound of formula 1-23, wherein Rl, R2, R4, L2 and ASC are preferably defined as in any one of embodiments A17 to A32.
  • the compound of the invention is a compound of formula 1-20, wherein ASC is -N(ASC-1) 2 and Rl, R2, R4 and L2 are preferably defined as in any one of embodiments A17 to A32.
  • the compound of the invention is a compound of formula 1-21, wherein ASC is -N(ASC-1) 2 and Rl, R2, R4 and L2 are preferably defined as in any one of embodiments A17 to A32.
  • the compound of the invention is a compound of formula 1-22, wherein ASC is -N(ASC-1)2 and Rl, R2, R4 and L2 are preferably defined as in any one of embodiments A17 to A32.
  • the compound of the invention is a compound of formula 1-23, wherein ASC is -N(ASC-1)2 and Rl, R2, R4 and L2 are preferably defined as in any one of embodiments A17 to A32.
  • embodiments B 1 to B26 wherein, in each case, Rl, R2, R4, R8, R9a, R9b and LI are as defined as in any one of the embodiments Al to A60.
  • embodiments Bal-Ba26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment Al .
  • embodiments Bbl-Bb26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A2.
  • embodiments Bcl-Bc26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A3.
  • embodiments Bdl-Bd26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A4.
  • embodiments of compounds of the invention are represented by embodiments Bel-Be26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A5.
  • embodiments Bfl-Bf26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A6.
  • embodiments Bgl-Bg26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A7.
  • embodiments Bhl-Bh26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A8.
  • embodiments Bil -Bi26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A9.
  • embodiments Bjl -Bj26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A10.
  • embodiments Bkl-Bk26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment Al 1.
  • embodiments Bll -B126 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A12.
  • embodiments Bml-Bm26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment Al 3.
  • embodiments Bnl-Bn26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A14.
  • embodiments Bpl-Bp26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A16.
  • embodiments Bql-Bq26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A17.
  • embodiments Bsl-Bs26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A19.
  • embodiments Bvl -Bv26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A22.
  • embodiments Bwl -Bw26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A23.
  • embodiments Bxal-Bx26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A24.
  • embodiments of compounds of the invention are represented by embodiments Byl -By26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A25.
  • embodiments Bzl-Bz26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A26.
  • embodiments Baal-Baa26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A27.
  • embodiments Bbbl-Bbb26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A28.
  • embodiments Bccl -Bcc26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A29.
  • embodiments Bddl -Bdd26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A30.
  • embodiments of compounds of the invention are represented by embodiments Beel -Bee26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A31.
  • embodiments Bffl -Bff26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A32.
  • embodiments Bggl -Bgg26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A33.
  • embodiments Bhhl -Bhh26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A34.
  • embodiments of compounds of the invention are represented by embodiments Biil-Bii26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A35.
  • embodiments Bjj 1 -Bjj26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A36.
  • embodiments Bkkl -Bkk26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A37.
  • embodiments of compounds of the invention are represented by embodiments Bill -B1126, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A38.
  • embodiments Bmml -Bmm26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A39.
  • embodiments Bnnl -Bnn26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A40.
  • embodiments of compounds of the invention are represented by embodiments Bool -Boo26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A41.
  • embodiments Bppl-Bpp26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A42.
  • embodiments Bqql -Bqq26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A43.
  • embodiments Bttl-Btt26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A46.
  • embodiments Bwl -Bw26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A48.
  • embodiments Bwwl -Bww26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A49.
  • embodiments Bxxl-Bxx26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A50.
  • embodiments of compounds of the invention are represented by embodiments Byyl -Byy26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A51.
  • embodiments Bzzl -Bzz26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A52.
  • embodiments Baaal-Baaa26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A53.
  • embodiments Bbbbl-Bbbb26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A54.
  • embodiments Bdddl -Bddd26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A56.
  • embodiments Beeel-Beee26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A57.
  • embodiments Bfffl -Bfff26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A58.
  • embodiments Bgggl -Bggg26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A59.
  • embodiments Bhhhl -Bhhh26 which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A60.
  • embodiments Cbl-Cb26 which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A2.
  • embodiments Cdl-Cd26 which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A4.
  • embodiments Chl-Ch26 which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A8.
  • embodiments C11-C126 which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A12.
  • embodiments Col-Co26 which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A15.
  • embodiments of compounds of the invention are represented by embodiments Cql-Cq26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A17.
  • embodiments of compounds of the invention are represented by embodiments Crl-Cr26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment Al 8.
  • embodiments of compounds of the invention are represented by embodiments Cxl-Cx26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A24.
  • embodiments Czl-Cz26 which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A26.
  • embodiments of compounds of the invention are represented by embodiments Caal-Caa26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A27.
  • embodiments of compounds of the invention are represented by embodiments Cddl -Cdd26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A30.
  • embodiments of compounds of the invention are represented by embodiments CU1-CU26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A35.
  • embodiments of compounds of the invention are represented by embodiments Cjj l-Cjj26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A36.
  • embodiments C111-C1126 which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A38.
  • embodiments Cmml-Cmm26 which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A39.
  • embodiments of compounds of the invention are represented by embodiments Cnnl -Cnn26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A40.
  • Cool -Coo26 which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A41.
  • embodiments of compounds of the invention are represented by embodiments Cppl-Cpp26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A42.
  • embodiments of compounds of the invention are represented by embodiments Cuul-Cuu26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A47.
  • embodiments of compounds of the invention are represented by embodiments Czzl-Czz26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A52.
  • embodiments of compounds of the invention are represented by embodiments Caaal -Caaa26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A53.
  • embodiments of compounds of the invention are represented by embodiments Cdddl -Cddd26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A56.
  • embodiments of compounds of the invention are represented by embodiments Cgggl -Cggg26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A59.
  • embodiments of compounds of the invention are represented by embodiments Chhhl -Chhh26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A60.
  • embodiments Dbl-Db35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A2.
  • embodiments Dcl-Dc35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A3.
  • embodiments Ddl-Dd35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A4.
  • embodiments of compounds of the invention are represented by embodiments Del-De35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A5.
  • embodiments Dfl-Df35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A6.
  • embodiments Dil-Di35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A9.
  • embodiments Djl-Dj35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A10.
  • embodiments Dkl-Dk35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment Al 1.
  • embodiments Dml-Dm35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A13.
  • embodiments Dnl-Dn35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A14.
  • embodiments of compounds of the invention are represented by embodiments Dol-Do35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A15.
  • embodiments Dpl-Dp35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A16.
  • embodiments Dql-Dq35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A17.
  • embodiments Drl-Dr35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A18.
  • embodiments Dul-Du35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A21.
  • embodiments Dvl-Dv35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A22.
  • embodiments Dwl-Dw35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A23.
  • embodiments Dxl-Dx35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A24.
  • embodiments of compounds of the invention are represented by embodiments Dyl-Dy35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A25.
  • embodiments Dzl-Dz35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A26.
  • embodiments Daal-Daa35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A27.
  • embodiments Dbbl-Dbb35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A28.
  • embodiments Dccl-Dcc35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A29.
  • embodiments Dddl-Ddd35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A30.
  • embodiments Dggl-Dgg35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A33.
  • embodiments Dhhl-Dhh35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A34.
  • embodiments of compounds of the invention are represented by embodiments Diil-Dii35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A35.
  • embodiments Djjl-Djj35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A36.
  • embodiments Dkkl-Dkk35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A37.
  • embodiments D111-D1135 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A38.
  • embodiments Dmml -Dmm35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A39.
  • embodiments Dnnl-Dnn35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A40.
  • embodiments of compounds of the invention are represented by embodiments Dool-Doo35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A41.
  • embodiments Dppl-Dpp35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A42.
  • embodiments Dssl-Dss35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A45.
  • embodiments Dttl-Dtt35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A46.
  • embodiments Dwl-Dw35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A48.
  • embodiments Dwwl -Dww35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A49.
  • embodiments Dzzl-Dzz35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A52.
  • embodiments Daaal-Daaa35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A53.
  • embodiments Dbbbl-Dbbb35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A54.
  • embodiments Dfffl-Dfff35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A58.
  • embodiments Dgggl-Dggg35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A59.
  • embodiments Dhhhl-Dhhh35 which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A60.
  • embodiments of compounds of the invention are represented by embodiments El, E2, E3, E5, E6, E9, E10, El l, E12, E13, E14, E16, E18, E19, E27, E28, E30, E31, E50, E51 or E52, wherein, in each case, the compound of the invention is a compound of formula 1-20, and wherein Rl is at the para position on AR1 with respect to LI, and wherein R2 is at the ortho position on AR1 with respect to LI .
  • embodiments of compounds of the invention are represented by embodiments E4, E7, E8, 32, E33, E34, E37, E38, E41, E42, E45, E46, E47, E48, E49, E53 or E55, 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 .
  • embodiments E39 or E54 wherein, in each case, the compound of the invention is a compound of formula 1-22, and wherein Rl is at the ortho position on ARl with respect to LI .
  • embodiments of compounds of the invention are represented by embodiments El 5, E20 or E35, wherein, in each case, 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 include 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 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. In a further embodiment 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.
  • the 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, or 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),
  • Cefazaflur Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole,
  • Macrolides 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, PD131628, PD138312, PD140248, Q-35, AM-1155, NM394, T-3761, rufloxacin, OPC-17116, DU-6859a (AAC 37: 1419), J J-Q2, or DV- 7751a (AAC 37: 14
  • Tetracyclines and glycylcyc lines Tetracyclines and glycylcyc lines 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.
  • Pleuromutilms 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, thiolactomycin, 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.
  • compositions may comprise the compound of formula I and two or more antimicrobial agents.
  • antimicrobial agents examples 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 s
  • 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,
  • Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus are examples of Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus .
  • 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,
  • EUCAST European Committee on Antimicrobial Susceptibility Testing
  • 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.
  • 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 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.
  • 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) or (c) 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, Ri, R 2 , R 3 , R5, Re, R7 are as in formula I,
  • n 1 or 2
  • n 0 or 1
  • Yl is -OH, a halogen atom or a leaving group like mesylate, tosylate, inflate,
  • Al is -0-
  • PG1 is a hydrogen atom or a hydroxyl protecting group (such as allyl, benzyl, tetrahydropyranyl or silyl ethers),
  • A2 is -(CH 2 ) o -Y2
  • Y2 is -OH, a halogen atom, a leaving group like mesylate, tosylate, triflate, -COOH, -CHO, -C(0)-CH 2 -X or -NH-PG2,
  • X is a halogen atom and PG2 is a hydrogen atom or an amino protecting group (such as allyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethylcarbonyl, teri-butoxycarbonyl or benzyl),
  • A3 is as R4 in formula I or is a halogen atom or -OH.
  • R4 is O-RIO, with RIO defined as in formula I.
  • A4 is -NHE or -NH 2 , E being an amino protecting group, to generate compound of formula 1-1 wherein L2 is -(CH 2 ) 0 -, -(CH 2 ) P -, -(CH 2 ) 0 -C(0)-CH 2 -, -(CH 2 ) 0 -C(0)-, respectively, wherein p is 1, 2, 3, or 4.
  • Y2 is -NH-PG2
  • PG2 amino protecting group is removed and the deprotected intermediate is reacted with a compound of formula VII wherein A4 is -CH 2 -X or -CHO, with X as a halogen atom or a leaving group like mesylate, tosylate, or triflate, to generate a compound of formula 1-1 wherein L2 is -(CH 2 ) 0 -.
  • PG2 amino protecting group can be removed and the deprotected intermediate is reacted with a compound of formula VII wherein A4 is -COOH, to generate a compound of formula 1-1 wherein L2 is -(CH 2 ) 0 -.
  • the amino protecting group PG2 can be removed after reaction of a compound of formula VI-1 with a compound of formula VII.
  • the compound of formula IV- 1 can be converted to the corresponding halide, mesylate, tosylate, triflate compound, and further react with a compound of formula VII wherein A4 is -NHE or -NH 2 , E being an amino protecting group, to generate a compound of formula 1-1 wherein L2 is -(CH 2 ) 0 -.
  • the compound of formula IV- 1 can react with a compound compound of VII wherein A4 is -(CH 2 ) q -X, with X as a halogen atom or a leaving group like mesylate, tosylate, or triflate and q being comprised between 1 and 4, to generate a compound of formula 1-1 wherein L2 is -(CH 2 ) 0 -0-(CH 2 ) q .
  • Y2 may require appropriate activation to allow a reaction of compounds of formulae VI-1 and VII as described in more detail below.
  • AR1 , AR2, Ri, R 2 , R 3 , R5, Re, R7 are as in formula I,
  • n 0, 1 or 2
  • Al is -O-
  • PG1 is a hydrogen atom or a hydroxyl protecting group
  • Y is -OH, a halogen atom or a leaving group like mesylate, tosylate, triflate,
  • R4 is as in formula I.
  • AR1 , AR2, Ri, R 2 , R 3 , R5, Re, R7 are as in 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.
  • 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- 1.
  • the benzyl group is removed by hydrogeno lysis 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 tetrahydroiuran 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.
  • Compounds of formula IV- 1 can be obtained from compounds of formula II- 1 wherein Yl is -OH via a Mitsunobu coupling (as reviewed in O. Mitsunobu, Synthesis 1981, 1) with compounds of formula III for which Al-PGl is a hydroxyl group.
  • 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-dimethoxy ethane or dichloromethane and within a wide range of temperatures (between -20 °C and 60 °C).
  • the reaction might also be performed using polymer-supported triphenylphosphine.
  • An alternative route to form compounds of formula IV- 1 consists of reacting compounds of formula III wherein Al-PGl is a hydroxyl group with compounds of formula II-l for which Yl is a hydroxyl group, which needs to be activated prior to the reaction as described below, or a halogen atom in presence of an inorganic base such as sodium hydride, potassium carbonate or the like in a solvent such as dichloromethane or NN-dimethylformamide at a temperature ranging between -20 °C and 80 °C.
  • an inorganic base such as sodium hydride, potassium carbonate or the like
  • a solvent such as dichloromethane or NN-dimethylformamide
  • Activation of the hydroxyl group of compounds of formula II-l 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, respectively, 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
  • 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 O-RIO.
  • an inorganic base such as sodium hydride or the like
  • a solvent such as tetrahydrofuran or NN-dimethylformamide
  • compounds of formula IV- 1 can react with compounds 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 O-RIO.
  • compounds of formula VI- 1 can react with compounds of formula VII for which A4 is -NH 2 or -NHE, E being an amino protecting group, via a substitution reaction as previously described above, to generate compounds of formula 1-1 wherein L2 is -(CH 2 ) 0 - or -(CH 2 )o-C(0)-CH 2 -, respectively.
  • the amino protecting group is introduced by reacting the corresponding free amine with allyl, fluorenylmethyl or benzyl chloroformate or with di-tert-butyl dicarbonate in presence of a base such as sodium hydroxide, sodium hydrogen carbonate, triethylamine, 4-dimethylaminopyridine or imidazole.
  • the free amine can also be protected as N-benzyl derivatives by reaction with benzyl bromide or chloride in presence of a base such as sodium carbonate or triethylamine.
  • N-benzyl derivatives can be obtained through reductive amination in presence of benzaldehyde.
  • 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 can react with compounds of formula VII for which A4 is - NH 2 or -NHE, E being an amino protecting group, 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 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 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 derivative is further reduced into its corresponding alcohol. 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 VI- 1 can react with compounds of formula VII for which A4 is - NH 2 or -NHE, E being an amino protecting group, via a peptidic coupling reaction, to generate compounds of formula 1-1 wherein L2 is -(CH 2 ) 0 -C(0)-.
  • 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- 1 -yl)-N,NN',N'-tetramethyluronium hexafluorophosphate, 2-ethoxy- 1 - 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 compound of formula VII in an aprotic solvent like dichloromethane, chloroform, acetonitrile, NN-dimethylformamide and tetrahydrofuran to generate compound of formula 1-1.
  • an aprotic solvent like dichloromethane, chloroform, acetonitrile, NN-dimethylformamide and tetrahydrofuran
  • a base like triethylamine, NN-diisopropylethylamine, pyridine, sodium hydroxide, sodium carbonate, potassium carbonate can be added to perform the coupling.
  • the protecting group can first be removed under standard conditions as previously described above
  • the corresponding free amine can then react with a compound of formula VII for which A4 is -CH 2 -X or - CHO via a substitution or a reductive amination, respectively, to generate a compound of formula 1-1 wherein L2 is -(CH 2 ) 0 -.
  • the corresponding free amine can also react with a compound of formula VII for which A4 is -COOH via a peptidic coupling, to generate a compound of formula 1-1 wherein L2 is -(CH 2 ) 0 -.
  • amino protecting group PG2 can also be removed only after the substitution, the reductive amination or the peptidic coupling reactions, following standard procedure described above.
  • compounds of formula VI- 1 wherein Y2 is a hydroxyl group can be converted to the corresponding halide, mesylate, tosylate or triflate compound and react with compounds of formula VII for which A4 is -NH 2 or -NHE, E being an amino protecting group, via a substitution reaction as previously described above.
  • compounds of formula 1-1 for which L2 is -(CH 2 ) 0 -0-(CH 2 ) q - can be obtained by reacting compounds of formula VI- 1 wherein Y2 is a hydroxyl group with compounds of formula VII for which A4 is -(CH 2 ) q -X, X being a halogen atom or a leaving group and q being comprised between 1 and 4.
  • 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 solvent such as diethyl ether or tetrahydrofuran 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 tetrahydrofuran, 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.
  • 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:
  • Mass spectra are generated using a q-Tof Ultima (Waters AG) mass spectrometer in the positive ESI mode.
  • the system is equipped with the standard Lockspray interface;
  • 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;
  • CDCI 3 Deuterated chloroform
  • Example numbers used in the leftmost column are used in the whole application text for identifying the respective compounds.
  • Methanesulfonyl chloride (687 ⁇ L, 8.88 mmol, 1.2 eq) [124-63-0] is added at 0°C to a stirred solution of 3- [4-(l-methyl-l -phenyl-ethyl)phenoxy]propan-l-ol (2.0 g, 7.40 mmol, 1.0 eq) and NN-diisopropylethylamine (1.94 mL, 11.10 mmol, 1.5 eq) in dichloromethane (25 mL).
  • N - [3 - [4-( 1 -methyl- 1 -phenyl-ethyl)phenoxy]propyl] ethane- 1 ,2-diamine Trifluoroacetic acid (1.0 mL, 13.06 mmol, 16.3 eq) is added at room temperature to a stirred solution of tert- butyl N-[2-[3-[4-(l -methyl-l-phenyl-ethyl)phenoxy]propylamino]ethyl]carbamate (330 mg, 0. 8 mmol, 1.0 eq) in dichloromethane (5 mL).
  • reaction mixture is extracted with dichloromethane (3 x 10 mL) and water (10 mL) and the pH is adjusted to 9 by the addition of a saturated sodium hydrogen carbonate aqueous solution.
  • the combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is dissolved in a 2N hydrochloric acid solution in ethyl acetate (3 mL).
  • the titled compound is prepared as a white solid (1.30 g, 90% yield) following Scheme 1 and in analogy to Example 1 using 2,4-dichloro-l-(chloromethyl)benzene (1.0 g, 5.12 mmol, 1.0 eq) [94-99-5] and 4- hydroxybenzaldehyde (625 mg, 5.12 mmol, 1.0 eq) [123-08-0] as starting materials.
  • N-[[4-[(2,4-dichlorophenyl)methoxy]phenyl]methyl]-N',N'-dimethyl-propane-L3-diamine N',N'-dimethylpropane-l,3-diamine (200 ⁇ L, 1.60 mmol, 1.5 eq) [109-55-7] is added at room temperature to a stirred solution of 4-[(2,4-dichlorophenyl)methoxy]benzaldehyde (300 mg, 1.07 mmol, 1.0 eq) in dichloromethane (7 mL), followed by one drop of acetic acid.

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Abstract

The present invention relates to compounds of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof wherein ASC is -N(R8)ASC-1; ASC-1 is C 2-C 5alkylene-N(R9a)R9b or C(=O)-C 1-C 4alkylene-N(R9a)R9b, wherein in alkylene in both cases one -CH 2- moiety is optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH 3)-; AR1, AR2 represent phenyl; L1 represents -CH=CH-, -CH 2-0-, -(CH 2) 2-O-, -0-CH 2-, -C(CH 3) 2-, -(CH 2) 2- or -CH=CH-CH 2-; L2 represents C1-C 7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=O)-, wherein within L2 there are no adjacent -C(=O)-moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or L2 represents -O-C 2-C 6alkylene-; the other definitions are as defined in the claims; and their use in methods of treating a subject with a microbial infection or susceptible to a microbial infection.

Description

Efflux-pump inhibitors and therapeutic uses thereof
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. Early on, 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. Nowadays, 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. Gootz T.D. 2010. Critical Rev. Immunol. 30(l):79-93; Silver L.L. 2011. Clin. Microbiol. Rev. 24(1): 71-109; Denis G.A. and Relich R.F. Clin Lab Med 2014. 34: 257- 270).
Bacteria achieve resistance by different mechanisms. Some mechanisms are specific for a drug or a class of antibiotics whereas other mechanisms are non-specific and affect several unrelated classes of antibiotics. Specific mechanisms can be modification of the drug target or inactivation of the drug by degradation or by enzymatic alteration. Non-specific mechanisms can be reduced uptake of a drug by lower permeability, by transport of drugs out of the bacterial cell or by combinations of both. The result is that drug concentrations that would normally kill bacterial cells are reduced at the target site to levels that allow the survival of the bacteria (Enzyme-Mediated Resistance to Antibiotics. Bonomo R.A. and Tolmasky M. Eds. ASM Press 2007; Martinez and Baquero 2014. Upsala J. Med. Sci. 119: 68-77; Piddock L.J.V. 2006. Clin. Microbiol. Rev. 19(2):382-402; Olivares et al. 2013. Front. Microbiol. 4, 103: doi 10.3389/fmicb.2013.00103).
Active transport of antibiotics out of a bacterial cell can confer resistance and contribute significantly to high-level resistances. 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.
Chemother. 56: 20-51 ; Olivares et al. 2013. Front. Microbiol. 4:103).
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. 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 (PMF) 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. 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. Top Med. Chem. 13(24):3079-100). Models for the structure of a complete RND complex were published on the example of AcrAB-TolC and for MexAB-OprM (Kim et al. 2015. Mol. Cells. 38(2): 180-186; Du et al. 2015. Trends Microbiol. 23: 311-319; Du et al. 2014. Nature 509:512-515; Trepout et al. 2010. Biochim. Biophys. Acta 1798: 1953-1960; Symmons et al. 2009. Proc. Natl. Acad. Sci. 106:7173-7178). Pathways for substrate translocation through the assembled pump complex were described on the basis of X-ray crystal structures. 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).
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 β-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).
Increased resistance occurrence and the fact that the number of new antibiotics that are developed dramatically declined in the recent years led to a need for new treatment options. Combination therapy is a proven approach to combat resistant pathogens. Efflux pumps are considered to be targets for inhibitors that can boost the activity of existing antimicrobial agents. Molecules of different sources like natural products (e.g. Piddock L. et al. 2010 J. Antimicrob. Chemother. 65:1215-1223; Starvi et al. 2007 J. Antimicrob. Chemother. 59(6): 1247-60; Li et al. 2015. Clin. Microbiol. Rev. 28(2): 337-418), inhibitors of human efflux pumps or new chemical entities were tested and described (reviewed in Van Bambeke et al. 2010. Frontiers in Anti-infective Drug Discovery 1 : 138-175; Van Bambeke et al. 2006. Recent Patents on Anti-infective Drug Discovery; Zechini B. and Versace I. 2009. 4:37-50; Opperman and Nguyen 2015. Front. Microbiol. 6, 421 : doi 10.3389/fmicb.2015.00421). 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 describes drug efflux pump inhibitors.
The present invention provides new compounds and methods for treating bacterial infections.
In a first aspect 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
Figure imgf000004_0001
wherein
ASC is -N(R8)ASC-l ;
ASC-1 is C2-C5alkylene-N(R9a)R9b or C(=0)-CrC4alkylene-N(R9a)R9b, wherein in alkylene in both cases one -CH2- moiety is optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH3)-;
AR1, AR2 represent phenyl;
Rl, R2, R3 represent independently hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, CpCealkoxy, or Cp Cehaloalkoxy;
R4 represents hydrogen, halogen, CpCealkyl, CpCehaloalkyl or O-RIO;
R5, R6, R7 represent independently hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, CpCealkoxy or Cp Cehaloalkoxy;
R8 represents hydrogen, methyl or ASC-1 ;
R9a represents hydrogen or methyl;
R9b represents hydrogen, methyl or -C(=NH)NH2;
R10 represents CpCealkyl, CpCehaloalkyl, C2-Cealkenyl, CpCealkylene-Cycle-P, CpCealkylene-Cycle-Q; Cycle-P represents independently at each occurrence a saturated or partially unsaturated C5-C6 carbocyclic ring optionally substituted by 1 to 3 R12, or a saturated or partially unsaturated C5-C6 heterocyclic ring optionally substituted by 1 to 3 R12 containing carbon atoms as ring members and one or two ring members independently selected from N(R11) and O; Cycle-Q represents independently at each occurrence phenyl optionally substituted by 1 to 3 Rl 3 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 R13;
Rl l represents hydrogen or Ci-Cealkyl;
R12 and R13 represent independently at each occurrence halogen, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy, or Ci-C4haloalkoxy;
LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-;
L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or
L2 represents -0-C2-C6alkylene-;
including pharmaceutically acceptable salts, solvates, and hydrates of said compounds.
The compound of formula I is generally 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.
In a further aspect 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. In this case the subject will have received, is receiving or will receive additionally an antimicrobial agent in order to complete the treatment of the microbial infection.
In a further aspect 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.
In a further aspect 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.
In a further aspect 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.
In a further aspect 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. In this case the subject will have received, is receiving or will receive additionally an antimicrobial agent in order to complete the treatment of the microbial infection.
In a further aspect 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.
In a further aspect 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. In a further aspect the invention provides a pharmaceutical product comprising a compound of formula I and an antimicrobial agent.
In a further aspect 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. In this case the subject will have received, is receiving or will receive additionally an antimicrobial agent in order to complete the treatment of the microbial infection.
In a further aspect 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.
In a further aspect 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.
Although many compounds of formula I are new, some compounds of formula I are known for uses other than as compounds for use in preventing or treating a microbial infection, and in particular for uses other than as compounds for use in combination treatments with antimicrobial agents, and thus as anti-bacterial efflux pump inhibitors, and in a further aspect the invention provides compounds of formula I as described above with the following provisos, which apply to all embodiments of the invention in the context of this aspect of the invention, which provides compounds per se:
wherein
when L2 is C(=0), then R8 is ASC-1 ;
when LI is -CH2-0- and L2 is Ci-C7alkylene as defined above, then at least one of Rl , R2, and R3 independently is Br, CF3 or C2-Cealkyl or at least R4 is 0-C2-C4alkenyl or at least R8 is ASC-1 ;
and wherein the compound of formula I is not
1 ,2-Ethanediamine, N 1 ,N1 ,N2-trimethyl-N2- [4- [2-(2-phenylethenyl)phenoxy]butyl] - (e.g.
CAS758641 -30-4);
Acetamide, 2-amino-N-[[4-[(4-bromophenyl)methoxy]phenyl]methyl]- (e.g. CAS 155720-39-1) ; Acetamide, 2-amino-N-[4-[4-(phenylmethoxy)phenoxy]butyl]- (e.g. CAS 1606700-82-6) ; Propanamide, 3-amino-N-methyl-N-[2-[4-(phenylmethoxy)phenoxy]ethyl]- (e.g. CAS1587398-66-
0) ;
Acetamide, 2-amino-N-methyl-N-[2-[4-(phenylmethoxy)phenoxy]ethyl]- (e.g. CAS1585355-41-4) ; Acetamide, N-methyl-2-(methylamino)-N-[2-[4-(phenylmethoxy)phenoxy]ethyl]- (e.g.
CAS 1581931-93-2) ;
l,2-Ethanediamine, Nl-[4-[4-(phenylmethoxy)phenoxy]butyl]- (e.g. CAS434287-26-0) ;
l,2-Ethanediamine, Nl-[3-[4-(phenylmethoxy)phenoxy]propyl]- (e.g. CAS435287-50-6) ;
1 ,2-Ethanediamine, Nl,Nl-dimethyl-N2-[3-[4-(phenylmethoxy)phenoxy]propyl]- (e.g.
CAS 1003082-47-0) ;
1,2-Ethanediamine, Nl,Nl-dimethyl-N2-[[4-(2-phenylethoxy)phenyl]methyl]- (e.g. CAS1182123- 01-8) ;
1,2-Ethanediamine, Nl,Nl-dimethyl-N2-[[3-(2-phenylethoxy)phenyl]methyl]- (e.g. CAS1182123- 00-7) ;
1.2- Ethanediamine, Nl,Nl-dimethyl-N2-[[2-(2-phenylethoxy)phenyl]methyl]- (e.g. CAS1182122- 99-1) ;
1.3- Propanediamine, Nl -[[3-methoxy-4-(2-phenylethoxy)phenyl]methyl]-N3-methyl- (e.g.
CAS892609-92-6) ;
1 ,3-Propanediamine, N3-[[3-methoxy-4-(2-phenylethoxy)phenyl]methyl]-Nl ,N1 -dimethyl- (e.g. CAS892609-60-8) ;
1 ,2-Ethanediamine, N2-[[3-methoxy-4-(2-phenylethoxy)phenyl]methyl]-Nl ,N1 -dimethyl- (e.g. CAS892609-86-8) ;
Acetamide, N-[[2-[(2-chlorophenoxy)methyl]phenyl]methyl]-2-(methylamino)- (e.g. CAS1606740-) ;
Butanamide, 4-amino-N-[[3-(phenoxymethyl)phenyl]methyl]- (e.g. CAS1601670-04-5) ;
Butanamide, N-[[2-[(2-chlorophenoxy)methyl]phenyl]methyl]-4-(methylamino)- (e.g. CAS1601633-) ;
Butanamide, 4-amino-N-[[4-(phenoxymethyl)phenyl]methyl]- (e.g. CAS1601607-19-5) ;
Acetamide, 2-(methylamino)-N-[[3-(phenoxymethyl)phenyl]methyl]- (e.g. CAS 1597732-69-8) ; Acetamide, 2-amino-N-[[4-(phenoxymethyl)phenyl]methyl]- (e.g. CAS 1595479-82-5) ;
Butanamide, 4-(methylamino)-N-[[4-(phenoxymethyl)phenyl]methyl]- (e.g. CAS 1590685-95-2) ; Propanamide, 3-amino-N-[[2-(phenoxymethyl)phenyl]methyl]- (e.g. CAS 1590654-54-8) ;
Propanamide, 3-amino-N-[[2-[(2-chlorophenoxy)methyl]phenyl]methyl]- (e.g. CAS1589175-80-3) ; Acetamide, 2-amino-N-[[3-(phenoxymethyl)phenyl]methyl]- (e.g. CAS1588738-84-4) ;
Butanamide, 4-amino-N-[[2-[(2-chlorophenoxy)methyl]phenyl]methyl]- (e.g. CAS 1584944-96-6) ; Propanamide, 3-amino-N-[[3-(phenoxymethyl)phenyl]methyl]- (e.g. CAS1579382-57-2) ;
Acetamide, 2-amino-N-[[2-[(2-chlorophenoxy)methyl]phenyl]methyl]- (e.g. CAS 1577291-71-4) ; Butanamide, 4-(methylamino)-N-[[3-(phenoxymethyl)phenyl]methyl]- (e.g. CAS1576389-49-5) ; Propanamide, 3-amino-N-[[4-(phenoxymethyl)phenyl]methyl]- (e.g. CAS 1575930-24-3) ;
Acetamide, 2-arruno-N-[[2-(phenoxymethyl)phenyl]methyl]- (e.g. CAS1570795-81-1) ;
Butanamide, 4-(methylamino)-N-[[2-(phenoxymethyl)phenyl]methyl]- (e.g. CAS1570773-38-4) ; Acetamide, 2-(methylamino)-N-[[4-(phenoxymethyl)phenyl]methyl]- (e.g. CAS 1570627-43-8) ;
1,2-Ethanediamine, N/,N/-dimethyl-N2-[2-[4-(phenylmethoxy)phenoxy]ethyl]- (e.g. CAS1004699-
07-3);
1,2-Ethanediamine, N;-[2-[4-(phenylmethoxy)phenoxy]ethyl]- (e.g. CAS435284-12-1);
1,2-Ethanediamine, N;-[3-[4-(phenoxymethyl)phenyl]propyl]- (e.g. CAS101418-48-8);
1,2-Ethanediamine, N;,N;-dimethyl-N2-[3-[4-(l-methyl-l-phenylethyl)phenoxy]propyl]- (e.g.
CAS1002594-67-3);
1,2-Ethanediamine, N;-[2-[4-(l-methyl-l-phenylethyl)phenoxy]ethyl]- (e.g. CAS435288-22-5);
1.2- Ethanediamine, N;-[3-[4-(l-methyl-l-phenylethyl)phenoxy]propyl]- (e.g. CAS435283-85-5);
1.3 - Propanediamine, N1- [3 -(dimethylamino)propyl] -N1- [[4-methoxy-3 -(phenylmethoxy)phenyl] - methyl] -N3,N3-dimethyl- (e.g. CAS415925-59-6);
1 ,3 -Propanediamine, N1- [3 -(dimethylamino)propyl] -N1- [[3 -methoxy-4-(phenylmethoxy)phenyl] - methyl] -N3,N3-dimethyl- (e.g. CAS415923-22-7);
1,3-Propanediamine, N3-[[4-[(4-bromophenyl)methoxy]-3-methoxyphenyl]methyl]-N;,N;-dimethyl- (e.g. CAS 1624037-31-5).
In another aspect the invention provides compounds of formula I as described above with the following provisos:
wherein
when L2 is C(=0), then R8 is ASC-1 ;
when LI is -CH2-0- and L2 is Ci-C7alkylene as defined above, then at least one of Rl, R2, and R3 independently is Br, CF3 or tert-butyl or at least R4 is 0-CH2-CH=CH2 or at least R8 is ASC-1 ;
and wherein the compound of formula I is not any of the known compounds named above.
Each alkyl moiety either alone or as part of a larger group such as alkoxy is a straight or branched chain and is preferably CpCealkyl, more preferably Ci-C4alkyl. Examples include methyl, ethyl, ^-propyl, prop-2-yl, n- butyl, but-2-yl, 2-methyl-prop-l-yl or 2-methyl-prop-2-yl. Examples of an alkoxy include methoxy, ethoxy, propoxy, z' o-propoxy, n-butoxy, eobutoxy, teri-butoxy, n-pentoxy, neo-pentoxy, n-hexoxy. As described herein, alkoxy may include further substitutents such as halogen atoms leading to haloalkoxy moieties. Each alkylene moiety is a straight or branched chain and is, for example, -CH2-, -CH2-CH2-, -CH(CH3)-, - CH2-CH2-CH2-, -CH(CH3)-CH2-, or -CH(CH2CH3)-. Each alkenyl moiety either alone or as part of a larger group such as alkenyloxy is a straight or branched chain and is preferably C2-Cealkenyl, more preferably C2-C4alkenyl. 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 include, if applicable, 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 alkynyl moiety either alone or as part of a larger group such as alkynyloxy is a straight or branched chain and is preferably C2-Cealkynyl, more preferably C2-C4alkynyl. Examples are ethynyl and propargyl. 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. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl and cyclohexyl.
Halogen is fluorine, chlorine, bromine, or iodine.
The term "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.
The term "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.
Where a group is said to be optionally substituted, preferably there are optionally 1 -5 substituents, more preferably optionally 1 -3 substituents.
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. In respect of depictions of moieties given for LI the bond on the left hand side of each moiety as depicted is connected to AR1 and the bond on the right hand side is connected to AR2. Likewise, in respect of depictions of moieties given for L2, the left hand side of each moiety as depicted is connected to AR2 and the right hand side is connected to ASC.
Reference to "the terminal moiety of L2" refers to both termini of L2.
When a moiety is said to be optionally substituted the moiety is substituted or unsubstituted with said optional substituents.
Reference to compounds of the invention includes pharmaceutically acceptable salts of said compounds. Examples of 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 methane-sulfonic acid, / toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. Further examples of 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.
The following preferred substituent definitions may be combined in any combination.
ASC-1 prefreably represents C2-C5alkylene-N(R9a)R9b or C(=0)-CrC4alkylene-N(R9a)R9b, wherein in alkylene in both cases one, preferably one or two, -CH2- moieties are optionally replaced by - CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH3)-, wherein R9a represents hydrogen or methyl, and wherein R9b represents hydrogen, methyl or -C(=NH)NH2. Preferably, ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3- N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, -(CH2)2-NH-(CH2)2-N(R9a)R9b, - C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b, -C(=0)-CH(CH3)-N(R9a)R9b, -C(=0)-
CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)- (CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b; wherein preferably R9a represents hydrogen or methyl, and wherein R9b represents hydrogen, methyl or -C(=NH)NH2. More preferably ASC-1 is -(CH2)2- N(R9a)R9b, -(CH2)3-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, -(CH2)2-NH-(CH2)2-N(R9a)R9b, - C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b, -C(=0)-
CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b, wherein preferably R9a represents hydrogen or methyl, and wherein R9b represents hydrogen, methyl or -C(=NH)NH2.
Rl preferably represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy, or CpCehaloalkoxy, more preferably Rl represents hydrogen, halogen, CpCealkyl or Ci-Cehaloalkyl. Specific examples of Rl include hydrogen, F, CI, Br, I, CF3, -O-methyl, -O-ethyl, -O-propyl, O-butyl, methyl, ethyl, propyl, and tert- butyl. R2 preferably represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy, CpCehaloalkoxy, more preferably R2 represents hydrogen, halogen, CpCealkyl or Ci-Cehaloalkyl. Specific examples of R2 include hydrogen, F, CI, Br, I, CF3, -O-methyl, -O-ethyl, -O-propyl, O-butyl, methyl, ethyl, propyl, and tert- butyl.
R3 preferably represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy, CpCehaloalkoxy, more preferably R3 represents hydrogen, halogen, CpCealkyl or Ci-Cehaloalkyl, even more preferably hydrogen. Specific examples of R3 include hydrogen, F, CI, Br, I, CF3, -O-methyl, -O-ethyl, -O-propyl, O- butyl, methyl, ethyl, propyl, and teri-butyl.
R4 preferably represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or O-RIO, wherein RIO represents Ci-Cealkyl, C2-Cealkenyl, Ci-Cehaloalkyl, CpCealkylene-Cycle-P, or CpCealkylene-Cycle-Q, and preferably wherein Cycle-P represents independently at each occurrence cyclopentyl or cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl, or morpholinyl, each optionally substituted by 1 to 3 R12, and wherein preferably R12 represents independently at each occurrence halogen, Ci-C4alkyl, Cp
C4haloalkyl, Ci-C4alkoxy, or Ci-C4haloalkoxy; and wherein more preferably R12 represents independently at each occurrence halogen, methyl, halomethyl, methoxy, or halomethoxy; and preferably wherein 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 R13, and wherein more preferably Cycle-Q represents independently at each occurrence phenyl, pyridinyl, thiazolyl, or thiophenyl, each optionally substituted by 1 to 3 R13, and preferably wherein R13 represents independently at each occurrence halogen, Ci-C4alkyl, Cp C4haloalkyl, Ci-C4alkoxy, or Ci-C4haloalkoxy; and wherein more preferably R13 represents independently at each occurrence halogen, methyl, halomethyl, methoxy, or halomethoxy. More preferably Cycle-Q represents phenyl, pyridinyl or thiazolyl, each optionally substituted by 1 to 3 R13, and wherein preferably R13 represents independently at each occurrence halogen, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy, or Cp C4haloalkoxy; and wherein more preferably R13 represents independently at each occurrence halogen, methyl, halomethyl, methoxy, or halomethoxy. Even more preferably Cycle-Q represents phenyl or pyridinyl, each optionally substituted by 1 to 3 R13, and wherein preferably R13 represents independently at each occurrence halogen, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy, or Ci-C4haloalkoxy; and wherein more preferably R13 represents independently at each occurrence halogen, methyl, halomethyl, methoxy, or halomethoxy.
R4 further preferably represents hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, or O-RIO wherein R10 represents CpCealkyl, C2-Cealkenyl, CpCealkylene-phenyl, or Ci-Cealkylene-morpholinyl, more preferably hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, or O-RIO wherein R10 represents CpCealkyl or C2- Cealkenyl. In a preferred embodiment, R4 is hydrogen, F, CI, CF3, or O-z'-Bu or 0-CH2-CH=CH2. In another preferred embodiment, R4 is hydrogen. In another preferred embodiment, R4 is F. In another preferred embodiment, R4 is CI. In another preferred embodiment, R4 is CF3. In another preferred embodiment, R4 is O-z'-Bu. In another preferred embodiment, R4 is 0-CH2-CH=CH2.
Specific examples of R4 include hydrogen, F, CI, Br, I, methyl, ethyl, propyl, butyl, -O-methyl, -O-ethyl, -O- propyl, -O-butyl, -CF3, -O-allyl, -O-benzyl, -0-CH2-(2-aminothiazolyl), -0-CH2-(2-methylthiazolyl), -O- CH2-(3H-l,3,4-oxadiazol-2-onyl), -0-CH2-(5-methylisoxazolyl), -0-CH2-(p-chloro-o-bromo-phenyl), -O- CH2 -C(=0)OH-phenyl), -0-CH2-(p-C(=0)0(methyl)-phenyl), -0-CH2-CH2-(3,5-dimethyl-/H- pyrazolyl), -0-CH2-CH2-(3,5-dimethylisoxazolyl), -0-CH2-CH2-(3H-l,3,4-oxadiazol-2-onyl), -0-CH2-CH2- imidazolyl, -0-CH2-CH2-morpholinyl, -0-CH2-CH2-pyridinyl, -0-CH2-CH2-tetrazolyl, -0-CH2-imidazolyl, -0-CH2-N-methyl-imidazolyl, and -0-CH2-pyridinyl.
R5 preferably represents hydrogen, halogen, CpCealkyl, CpCehaloalkyl, CpCealkoxy or CpCehaloalkoxy, more preferably R5 represents hydrogen, halogen, CpCealkyl or Ci-Cehaloalkyl, and again more preferably R5 represents hydrogen. Specific examples of R5 include hydrogen, F, CI, Br, I, CF3, -O-methyl, -O-ethyl, - O-propyl, O-butyl, methyl, ethyl, propyl, and butyl.
R6 preferably represents hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, CpCealkoxy or CpCehaloalkoxy, more preferably R6 represents hydrogen, halogen, CpCealkyl or Ci-Cehaloalkyl, and again more preferably R6 represents hydrogen. Specific examples of R6 include hydrogen, F, CI, Br, I, CF3, -O-methyl, -O-ethyl, - O-propyl, O-butyl, methyl, ethyl, propyl, and butyl.
R7 preferably represents hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, CpCealkoxy or CpCehaloalkoxy, more preferably R7 represents hydrogen, halogen, CpCealkyl or Ci-Cehaloalkyl, and again more preferably R7 represents hydrogen. Specific examples of R7 include hydrogen, F, CI, Br, I, CF3, -O-methyl, -O-ethyl, - O-propyl, O-butyl, methyl, ethyl, propyl, and butyl.
R8 represents hydrogen, methyl or ASC-1, preferably R8 represents hydrogen or ASC-1.
LI preferably represents -CH=CH- (Z, E or ZIE), -CH2-0-, -0-CH2-, -CH=CH-CH2- (Z, E or Z/E), or -C(CH3)2-, more preferably -CH=CH- (Z, E or Z/E), -CH2-0-, -0-CH2- or
-C(CH3)2-, further preferably -CH=CH- (E), -CH2-0-, -0-CH2- or -C(CH3)2-.
L2 preferably represents -CH2-, -(CH2)2-, -(CH2)3-, -CH(CH3)-, -CH2-NH-CH2-, -CH2-NH-(CH2)2-, -C(=0)-, -C(=0)-CH2-, -C(=0)-NH-CH2-C(=0)-, -C(=0)-NH-(CH2)2-, -CH2-NH-C(=0)-CH2-, -CH2-NH-CH2-C(=0)- , -CH2-NH-C(=0)-CH(N(CH3)2)-(CH2)2-C(=0)-, -CH2-NH-C(=0)-CH(NH(CH3))-(CH2)2-C(=0)-, -CH2- NH-C(=0)-CH(NH2)-(CH2)2-C(=0)-, -CH2-NH-C(=0)-CH(NH2)-CH2-C(=0)-, -CH2-NH-C(=0)-CH(NH2)- (CH2)3-C(=0)-, -0-(CH2)2-, -0-(CH2)3-, -0-(CH2)4-, -0-(CH2)5-, or -0-(CH2)6-,more preferably -CH2-, -
(CH2)2-, -CH(CH3)-, -(CH2)3-, -CH2-NH-(CH2)2-, -C(=0)-, -0-(CH2)2-, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH- C(=0)-CH(NH2)-(CH2)2-C(=0)-, and L2 further preferably represents -CH2-, -C(=0)-, -0-(CH2)2-, -O- (CH2)3-, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2-C(=0)-.
All of the following embodiments set out below apply to each aspect of the invention and may be combined with each other and with any of the substituent definitions set out above. In one embodiment R8 is hydrogen or methyl.
In one embodiment R8 is ASC-1.
In one embodiment ASC-1 is -(CH2)2-N(R9a)R9b.
In one embodiment ASC-1 is -(CH2)3-N(R9a)R9b.
In one embodiment ASC-1 is -(CH2)4-N(R9a)R9b.
In one embodiment ASC-1 is -CH2-CH(CH3)-CH2-N(R9a)R9b.
In one embodiment ASC-1 is -(CH2)2-NH-(CH2)2-N(R9a)R9b.
In one embodiment ASC-1 is -C(=0)-CH2-N(R9a)R9b.
In one embodiment ASC-1 is -C(=0)-(CH2)2-N(R9a)R9b.
In one embodiment ASC-1 is -C(=0)-CH(CH3)-N(R9a)R9b.
In one embodiment ASC-1 is -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b.
In one embodiment ASC-1 is or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b.
In one embodiment at least one R9a is hydrogen.
In one embodiment each R9a is methyl.
In one embodiment at least one R9b is hydrogen.
In one embodiment each R9b is methyl.
In one embodiment Rl is F.
In one embodiment Rl is CI.
In one embodiment Rl is Br.
In one embodiment Rl is CF3.
In one embodiment Rl is C2-C6alkyl.
In one embodiment Rl is C palkyl, preferably feri-butyl.
In one embodiment R2 is H.
In one embodiment R2 is CI.
In one embodiment R2 is Br.
In one embodiment R3 is H.
In one embodiment at least one of Rl , R2 and R3 is not H.
In one embodiment LI is -CH=CH-.
In one embodiment LI is -CH2-0-.
In one embodiment LI is -0-CH2-.
In one embodiment LI is -C(CH3)2-.
In one embodiment LI is -CH=CH-CH2-.
In one embodiment R4 is H.
In one embodiment R4 is CI.
In one embodiment R4 is CF3.
In one embodiment R4 is C2-C6alkyl. In one embodiment R4 is C palkyl, preferably teri-butyl.
In one embodiment R4 is O-RIO, wherein RIO is C2-C6alkenyl.
In one embodiment R4 is O-RIO, wherein RIO is allyl.
In one embodiment R4 is O-RIO, wherein RIO is C2-Cealkyl, wherein RIO is preferably C4alkyl.
In one embodiment R4 is O-RIO, wherein RIO is iso-butyl.
In one embodiment R4 is O-RIO, wherein RIO is benzyl.
In one embodiment R4 is O-RIO, wherein RIO is (CH2)2-morpholine.
In one embodiment R4 is 0-CH3.
In one embodiment R4 is not H.
In one embodiment RIO represents C2-Cealkyl, CpCehaloalkyl, C2-Cealkenyl, CpCealkylene-Cycle-P, or Cp C6alkylene-Cycle-Q.
In one embodiment at least one of Rl , R2 and R3 is not H and R4 is not H.
In one embodiment L2 is -CH2-.
In one embodiment L2 is -C(=0)-.
In one embodiment L2 is -0-(CH2)2-.
In one embodiment L2 is -0-(CH2)3-.
In one embodiment L2 is -0-(CH2) r.
In one embodiment L2 is -CH2-NH-C(=0)-CH(NH2)-(CH2)2-C(=0)-.
In one embodiment L2 is -0-(CH2)2-, -0-(CH2)3-, -0-(CH2)4-, -0-(CH2)5- or -0-(CH2)6-.
In one embodiment L2 is -CH2-, -(CH2)2-, -(CH2)3-, -CH(CH3)-, -CH2-NH-CH2-, -CH2-NH-(CH2)2-, -C(=0)-, -C(=0)-CH2-, -C(=0)-NH-CH2-C(=0)-, -C(=0)-NH-(CH2)2-, -CH2-NH-C(=0)-CH2-, -CH2-NH-CH2-C(=0)- , -CH2-NH-C(=0)-CH(N(CH3)2)-(CH2)2-C(=0)-, -CH2-NH-C(=0)-CH(NH(CH3))-(CH2)2-C(=0)-, -CH2- NH-C(=0)-CH(NH2)-(CH2)2-C(=0)-, -CH2-NH-C(=0)-CH(NH2)-CH2-C(=0)- or -CH2-NH-C(=0)- CH(NH2)-(CH2)3-C(=0)-.
In one embodiment when L2 is C(=0), then R8 is ASC-1 ; when LI is -CH2-0- and L2 is Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, - CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent - N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, then at least one of Rl, R2, and R3 independently is Br, CF3 or tert-butyl or at least R4 is 0-CH2-CH=CH2 or at least R8 is ASC-1 ; and when LI is -CH2-0- or -0-CH2-, then ASC-1 is C2-C5alkylene-N(R9a)R9b, wherein in alkylene in both cases one -CH2- moiety is optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH3)-; and optionally R8 represents hydrogen or ASC-1 and/or at least one of Rl, R2 and R3 is not hydrogen.
In one embodiment L2 is at the meta position on AR2 with respect to the position of LI .
In one embodiment L2 is at the meta position on AR2 with respect to the position of LI, and LI is -CH=CH-, -CH2-O-, -(CH2)2-0-, -O-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-, wherein when LI is -CH2-0-, then (i) not each of Rl, R2 and R3 is hydrogen and (ii) L2 is not - CH2- and R4 is not OCH3, preferably wherein when LI is -CH2-0-, then (i) not each of Rl, R2 and R3 is hydrogen and (ii) L2 is not -CH2- or R4 is not OCH3.
In one embodiment L2 is at the para position on AR2 with respect to the position of LI .
In one embodiment L2 is at the para position on AR2 with respect to the position of LI, and LI is -CH=CH-,
-CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-,
wherein when LI is -C(CH3)2-, then (i) the compound of formula I is not 1 ,2-Ethanediamine, N7-[3- [4-(l -methyl- l -phenylethyl)phenoxy]propyl]- (e.g. CAS435283-85-5) and preferably also not any of the other known compounds named above in which LI is -C(CH3)2-; or (ii) L2 is not -0-(CH2)3- when ASC-1 is -(CH2)2-NH2; or (iii) L2 is not -0-(CH2)2- or -0-(CH2)3- when ASC-1 is -(CH2)2-
NH2;
and
wherein when LI is -CH2-0-, then (i) the compound of formula I is not 1,3-Propanediamine, N -[3- (dimethylamino)propyl]-N -[[4-methoxy-3-(phenylmethoxy)phenyl]methyl]-N3,N3-dimethyl- (e.g.
CAS415925-59-6); 1,3-Propanediamine, N7-[3-(dimethylamino)propyl]-N7-[[3-methoxy-4-
(phenylmethoxy)phenyl]methyl]-N3,N3-dimethyl- (e.g. CAS415923-22-7); 1 ,2-Propanediamine, N2-[[4-[(3- fluorophenyl)methoxy]phenyl]methyl]-, (2S)- (e.g. CAS1376621-40-7); or 1,3-Propanediamine, N3-[[4-[(4- bromophenyl)methoxy]-3-methoxyphenyl]methyl]-N;,N;-dimethyl- (e.g. CAS 1624037-31-5) and preferably also not any of the other known compounds named above in which LI is -CH2-0-; or (ii) L2 is not -CH2- when Rl is F or when R4 is -OCH3.
In one embodiment L2 and R4 are at the meta positions on AR2 with respect to the position of LI and R4 is not hydrogen.
In one embodiment L2 and R4 are at the meta positions on AR2 with respect to the position of LI and R4 is not hydrogen, and
wherein when LI is -CH2-0-, then R4 is not -OCH3.
In one embodiment R5, R6, 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.
In one embodiment R5, R6, 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, and
wherein when LI is -CH2-0-, then R4 is not -OCH3.
In one embodiment R3, R5, R6 and R7 are hydrogen.
In one embodiment R3, R5, R6, 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.
In one embodiment R3, R5, R6, 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, and
wherein when LI is -CH2-0-, then R4 is not -OCH3. In one embodiment 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, R3, R5, R6, 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 .
In one embodiment Rl is not hydrogen and is at the para position on AR1 with respect to LI,
R2, R3, R5, R6, 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 .
In one embodiment Rl is not hydrogen and is at the para position on AR1 with respect to LI, and R2, R3, R4, R5, R6, R7 are hydrogen and L2 is at the meta position on AR2 with respect to the position of LI . In one embodiment Rl is not hydrogen and is at the meta position on AR1 with respect to LI, and R2, R3, R4, R5, R6, R7 are hydrogen and L2 is at the para position on AR2 with respect to the position of LI, and wherein when LI is -CH2-0-, then Rl is not F.
In one embodiment Rl is not hydrogen and is at the meta position on AR1 with respect to LI, and R2, R3, R4, R5, R6, R7 are hydrogen and L2 is at the para position on AR2 with respect to the position of LI, and wherein when L2 is -CH2-, then Rl is not F.
In one embodiment Rl , R2 and R3 are hydrogen and L2 is at the meta position on AR2 with respect to the position of LI, and wherein when LI is -CH2-0-, then R4 is not -OCH3.
In one embodiment Rl , R2 and R3 are hydrogen and L2 is at the meta position on AR2 with respect to the position of LI, and wherein when L2 is -CH2-, then R4 is not -OCH3.
In one embodiment, LI represents -CH=CH-, -CH2-0-, -0-CH2-, -C(CH3)2- or -CH=CH-CH2-.
In another embodiment, L2 represents -CH2-, -C(=0)-, -0-(CH2)2-, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH- C(=0)-CH(NH2)-(CH2)2-C(=0)-.
In one embodiment, ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2- CH(CH3)-CH2-N(R9a)R9b, -(CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-CH(CH3)- N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)- (CH2)2-N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b; Rl and R2 represent independently hydrogen, halogen, CpCealkyl or CpCehaloalkyl;
R3 is hydrogen;
R4 represents hydrogen, halogen, Ci-C6alkyl, Ci-C6haloalkyl, or O-RIO wherein R10 represents Ci-C6alkyl, C2-C6alkenyl, CpCealkylene-phenyl, or Ci-Cealkylene-morpholinyl;
R5, R6, R7 are hydrogen;
R8 represents hydrogen or ASC-1 ;
R9a represents hydrogen or methyl, and wherein R9b represents hydrogen, methyl or -C(=NH)NH2, wherein preferably R9a and R9b are independently hydrogen or methyl;
LI represents -CH=CH-, -CH2-0-, -0-CH2-, -C(CH3)2 - or -CH=CH-CH2-; and
L2 represents -CH2-, -C(=0)-, -0-(CH2)2-, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2- C(=0)-. In embodiment Al, the compound of the invention is a compound of formula 1-19.
Figure imgf000017_0001
(1-19) wherein
ASC-1 is C2-C5alkylene-N(R9a)R9b or C(=0)-CrC4alkylene-N(R9a)R9b, wherein in alkylene in both cases one -CH2- moiety is optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH3)-;
Rl and R2 represent independently hydrogen, halogen, CpCealkyl or CpCehaloalkyl;
R4 represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or O-RIO wherein RIO represents Ci-Cealkyl, C2-C6alkenyl, CpCealkylene-phenyl, or Ci-Cealkylene-morpholinyl;
R8 represents hydrogen or ASC-1 ;
R9a represents hydrogen or methyl, and wherein R9b represents hydrogen, methyl or -C(=NH)NH2, wherein preferably R9a and R9b are independently hydrogen or methyl;
LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-; and L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or
L2 represents -0-C2-C6alkylene-.
In embodiment A2 the compound of the invention is a compound of formula 1-19, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, -
(CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b, -C(=0)-CH(CH3)- N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b, -C(=0)-
CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
Rl and R2 represent independently hydrogen, halogen, CpCealkyl or CpCehaloalkyl;
R4 represents hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, or O-RIO wherein R10 represents CpCealkyl or C2-C6alkenyl;
R8 represents hydrogen or ASC-1 ;
R9a represents hydrogen or methyl, and wherein R9b represents hydrogen, methyl or -C(=NH)NH2, wherein preferably R9a and R9b are independently hydrogen or methyl;
LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-; and L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or
L2 represents -0-C2-C6alkylene-.
In embodiment A3 the compound of the invention is a compound of formula 1-19, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, -(CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b, -C(=0)- CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)- (CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
Rl and R2 represent independently hydrogen, halogen, CpCealkyl or CpCehaloalkyl;
R4 represents hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, or O-RIO, wherein RIO represents CpCealkyl or C2-C6alkenyl;
R8 represents hydrogen or ASC-1 ;
R9a represents hydrogen or methyl, and wherein R9b represents hydrogen, methyl or -C(=NH)NH2, wherein preferably R9a and R9b are independently hydrogen or methyl;
LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-; and
L2 represents -CH2-, -C(=0)-, -0-(CH2)2-, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2-
C(=0)-.
In embodiment A4 the compound of the invention is a compound of formula 1-19, wherein
ASC-1 is C2-C5alkylene-N(R9a)R9b or C(=0)-CrC4alkylene-N(R9a)R9b, wherein in alkylene in both cases one -CH2- moiety is optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH3)-;
Rl and R2 represent independently hydrogen, halogen, Ci-C4alkyl or Ci-C2haloalkyl, wherein preferably Rl and R2 represent independently halogen, Ci-C4alkyl or Cihaloalkyl;
R4 represents hydrogen, halogen, Ci-C2haloalkyl, or O-RIO wherein R10 represents Ci-C4alkyl or C2- C3alkenyl, wherein preferably R4 represents hydrogen, halogen, Ci-C2haloalkyl, or O-RIO wherein R10 represents Ci-C4alkyl or C3alkenyl;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl;
LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-; and L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or
L2 represents -0-C2-C6alkylene-. In embodiment A5 the compound of the invention is a compound of formula 1-19, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, - (CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b, -C(=0)-CH(CH3)- N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b,
-C(=0)-CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
Rl and R2 represent independently hydrogen, halogen, Ci-C4alkyl or Ci-C2haloalkyl, wherein preferably Rl and R2 represent independently halogen, Ci-C4alkyl or Cihaloalkyl;
R4 represents hydrogen, halogen, Ci-C2haloalkyl, or O-RIO wherein RIO represents Ci-C4alkyl or C2- C3alkenyl, wherein preferably R4 represents hydrogen, halogen, Ci-C2haloalkyl, or O-RIO wherein RIO represents Ci-C4alkyl or C3alkenyl;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl;
LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-; and L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or
L2 represents -0-C2-C6alkylene-.
In embodiment A6 the compound of the invention is a compound of formula 1-19, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, -(CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b,
-C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b,
-C(=0)-CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
Rl and R2 represent independently hydrogen, halogen, Ci-C4alkyl or Ci-C2haloalkyl, wherein preferably Rl and R2 represent independently halogen, Ci-C4alkyl or Cihaloalkyl;
R4 represents hydrogen, halogen, Ci-C2haloalkyl, or O-RIO wherein R10 represents Ci-C4alkyl or C2- C3alkenyl, wherein preferably R4 represents hydrogen, halogen, Ci-C2haloalkyl, or O-RIO wherein R10 represents Ci-C4alkyl or C3alkenyl;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl;
LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-; and L2 represents -CH2-, -C(=0)-, -0-(CH2)2-, -0-(CH2)3-, -0-(CH2)4-, or CH2-NH-C(=0)-CH(NH2)-(CH2)2- C(=0)-. In embodiment A7 the compound of the invention is a compound of formula 1-19, wherein ASC-1, LI, L2, R8, R9a and R9b are defined as in any one of embodiments Al to A6, wherein Rl and R2 represent independently hydrogen, halogen, ί-Bu or CF3; and R4 represents hydrogen, halogen, CF3, or O-RI O wherein RI O represents CrC4alkyl or CH2-CH=CH2.
In embodiment A8 the compound of the invention is a compound of formula 1-19, wherein ASC-1 , LI , L2, R8, R9a and R9b are defined as in any one of embodiments Al to A6, wherein Rl and R2 represent independently hydrogen, halogen, ί-Bu or CF3; and R4 represents hydrogen, F, CI, CF3, or O-RI O wherein RI O represents CrC4alkyl or CH2-CH=CH2.
In embodiment A9 the compound of the invention is a compound of formula 1-19, wherein ASC-1 , LI , L2, R8, R9a and R9b are defined as in any one of embodiments Al to A6, wherein Rl and R2 represent independently hydrogen, F, CI, Br, ί-Bu or CF3-; and R4 represents F, CF3, or O-RI O wherein RI O represents z-Bu or CH2-CH=CH2.
In embodiment A10, the compound of the invention is a compound of formula 1-19, wherein
ASC-1 is C2-C5alkylene-N(R9a)R9b or C(=0)-CrC4alkylene-N(R9a)R9b, wherein in alkylene in both cases one -CH2- moiety is optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH3)-;
Rl and R2 represent independently hydrogen, F, CI, Br, ί-Bu or CF3;
R4 represents hydrogen, F, CI, CF3, or O-z-Bu or 0-CH2-CH=CH2;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl;
LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-; and L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or
L2 represents -0-C2-C6alkylene-.
In embodiment Al 1 the compound of the invention is a compound of formula 1-19, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, -
(CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b, -C(=0)-CH(CH3)- N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b,
-C(=0)-CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
Rl and R2 represent independently hydrogen, F, CI, Br, ί-Bu or CF3;
R4 represents hydrogen, F, CI, CF3, or Cw-Bu or 0-CH2-CH=CH2;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl;
LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-; and L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or
L2 represents -0-C2-C6alkylene-.
In embodiment A12 the compound of the invention is a compound of formula 1-19, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b,
-(CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b,
-C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b,
-C(=0)-CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b, or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
Rl and R2 represent independently hydrogen, F, CI, Br, ί-Bu or CF3;
R4 represents hydrogen, F, CI, CF3, or O-z-Bu or 0-CH2-CH=CH2;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl;
LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-; and
L2 represents -CH2-, -C(=0)-, -0-(CH2)2-, -0-(CH2)3-, -0-(CH2)4-, or CH2-NH-C(=0)-CH(NH2)-(CH2)2-
C(=0)-.
In embodiment A13 the compound of the invention is a compound of formula 1-19, wherein
ASC-1 is C2-C5alkylene-N(R9a)R9b or C(=0)-CrC4alkylene-N(R9a)R9b, wherein in alkylene in both cases one -CH2- moiety is optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH3)-;
Rl and R2 represent independently hydrogen, halogen, Ci-C4alkyl or Ci-C2haloalkyl, wherein preferably Rl and R2 represent independently halogen, Ci-C4alkyl or Cihaloalkyl;
R4 represents hydrogen, halogen, Ci-C2haloalkyl, or O-RIO wherein R10 represents Ci-C4alkyl or C2- C3alkenyl, wherein preferably R4 represents hydrogen, halogen, Ci-C2haloalkyl, or O-RIO wherein R10 represents Ci-C4alkyl or C3alkenyl;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl;
LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-; and L2 represents -CH2-, -C(=0)-, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2-C(=0)-.
In embodiment A14 the compound of the invention is a compound of formula 1-19, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, - (CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b, -C(=0)-CH(CH3)- N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b,
-C(=0)-CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b, or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b; Rl and R2 represent independently hydrogen, F, CI, Br, ί-Bu or CF3;
R4 represents hydrogen, F, CI, CF3, or O-z-Bu or 0-CH2-CH=CH2;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl;
LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-; and L2 represents -CH2-, -C(=0)-, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2-C(=0)-.
In embodiment A15 the compound of the invention is a compound of formula 1-19, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, -(CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b, -C(=0)-
CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b,
-C(=0)-CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b, or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
Rl and R2 represent independently hydrogen, F, CI, Br, ί-Bu or CF3;
R4 represents hydrogen, F, CI, CF3, or O-z-Bu or 0-CH2-CH=CH2;
R8 represents hydrogen or ASC- 1 ;
R9a and R9b are independently hydrogen or methyl;
LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-; and L2 represents -CH2-, -C(=0)-, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2-C(=0)-. In embodiment A16 the compound of the invention is a compound of formula 1-19, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, -(CH2)2-NH-(CH2)2- N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b,
-C(=0)-CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b, or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
Rl and R2 represent independently hydrogen, F, CI, Br, ί-Bu or CF3;
R4 represents hydrogen, CI, CF3, Cw-Bu or 0-CH2-CH=CH2;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl;
LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-; and L2 represents -CH2-, -C(=0)-, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2-C(=0)-.
In embodiment Al 7, the compound of the invention is a compound of formula 1-20 to 1-23
Figure imgf000022_0001
(1-20)
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000023_0003
wherein
ASC-1 is C2-C5alkylene-N(R9a)R9b or C(=0)-CrC4alkylene-N(R9a)R9b, wherein in alkylene in both cases one -CH2- moiety is optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH3)-;
RI and R2 represent independently hydrogen, halogen, CpCealkyl or CpCehaloalkyl;
R4 represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or O-RIO wherein RIO represents Ci-Cealkyl, C2-C6alkenyl, CpCealkylene-phenyl, or Ci-Cealkylene-morpholinyl;
R8 represents hydrogen or ASC-1 ;
R9a represents hydrogen or methyl, and wherein R9b represents hydrogen, methyl or -C(=NH)NH2, wherein preferably R9a and R9b are independently hydrogen or methyl; and
L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or
L2 represents -0-C2-C6alkylene-.
In embodiment A18 the compound of the invention is a compound of formula 1-20 to 1-23, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, - (CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b, -C(=0)-CH(CH3)- N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b, -C(=0)- CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
RI and R2 represent independently hydrogen, halogen, CpCealkyl or CpCehaloalkyl; R4 represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or O-RIO wherein RIO represents CpCealkyl or C2-C6alkenyl;
R8 represents hydrogen or ASC-1 ;
R9a represents hydrogen or methyl, and wherein R9b represents hydrogen, methyl or -C(=NH)NH2, wherein preferably R9a and R9b are independently hydrogen or methyl; and
L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or
L2 represents -0-C2-C6alkylene-.
In embodiment A19 the compound of the invention is a compound of formula 1-20 to 1-23, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, -(CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b, -C(=0)- CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)- (CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
Rl and R2 represent independently hydrogen, halogen, CpCealkyl or CpCehaloalkyl;
R4 represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or O-RIO, wherein R10 represents CpCealkyl or C2-C6alkenyl;
R8 represents hydrogen or ASC-1 ;
R9a represents hydrogen or methyl, and wherein R9b represents hydrogen, methyl or -C(=NH)NH2, wherein preferably R9a and R9b are independently hydrogen or methyl; and
L2 represents -CH2-, -C(=0)-, -0-(CH2)2-, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2- C(=0)-. In embodiment A20 the compound of the invention is a compound of formula 1-20 to 1-23, wherein
ASC-1 is C2-C5alkylene-N(R9a)R9b or C(=0)-CrC4alkylene-N(R9a)R9b, wherein in alkylene in both cases one -CH2- moiety is optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH3)-;
Rl and R2 represent independently hydrogen, halogen, Ci-C4alkyl or Ci-C2haloalkyl, wherein preferably Rl and R2 represent independently halogen, Ci-C4alkyl or Cihaloalkyl;
R4 represents hydrogen, halogen, Ci-C2haloalkyl, or O-RIO wherein R10 represents Ci-C4alkyl or C2-
C3alkenyl, wherein preferably R4 represents hydrogen, halogen, Ci-C2haloalkyl, or O-RIO wherein R10 represents Ci-C4alkyl or C3alkenyl;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl; and L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or
L2 represents -0-C2-C6alkylene-.
In embodiment A21 the compound of the invention is a compound of formula 1-20 to 1-23, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, - (CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b, -C(=0)-CH(CH3)- N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b,
-C(=0)-CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
L2 represents -CH2-, -C(=0)-, -0-(CH2)2-, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2- C(=0)-;
Rl and R2 represent independently hydrogen, halogen, Ci-C4alkyl or Ci-C2haloalkyl, wherein preferably Rl and R2 represent independently halogen, Ci-C4alkyl or Cihaloalkyl;
R4 represents hydrogen, halogen, Ci-C2haloalkyl, or O-RIO wherein R10 represents Ci-C4alkyl or C2-
C3alkenyl, wherein preferably R4 represents hydrogen, halogen, Ci-C2haloalkyl, or O-RIO wherein R10 represents Ci-C4alkyl or C3alkenyl;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl; and
L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or
L2 represents -0-C2-C6alkylene-. In embodiment A22 the compound of the invention is a compound of formula 1-20 to 1-23, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, -(CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b,
-C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b,
-C(=0)-CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
Rl and R2 represent independently hydrogen, halogen, Ci-C4alkyl or Ci-C2haloalkyl, wherein preferably Rl and R2 represent independently halogen, Ci-C4alkyl or Cihaloalkyl;
R4 represents hydrogen, halogen, Ci-C2haloalkyl, or O-RIO wherein R10 represents Ci-C4alkyl or C2- C3alkenyl, wherein preferably R4 represents hydrogen, halogen, Ci-C2haloalkyl, or O-RIO wherein R10 represents Ci-C4alkyl or C3alkenyl;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl; and L2 represents -CH2-, -C(=0)-, -0-(CH2)2-, -0-(CH2)3-, -0-(CH2)4-, or CH2-NH-C(=0)-CH(NH2)-(CH2)2- C(=0)-.
In embodiment A23 the compound of the invention is a compound of formula 1-20 to 1-23, wherein ASC-1 , L2, R8, R9a and R9b are defined as in any one of embodiments A17 to A22, wherein Rl and R2 represent independently hydrogen, halogen, ί-Bu or CF3; and R4 represents hydrogen, halogen, CF3, or O-RI O wherein RI O represents CrC4alkyl or CH2-CH=CH2.
In embodiment A24 the compound of the invention is a compound of formula 1-20 to 1-23, wherein ASC-1 , L2, R8, R9a and R9b are defined as in any one of embodiments A17 to A22, wherein Rl and R2 represent independently hydrogen, halogen, ί-Bu or CF3; and R4 represents hydrogen, F, Cl„ CF3, or O-RI O wherein R10 represents CrC4alkyl or CH2-CH=CH2.
In embodiment A25 the compound of the invention is a compound of formula 1-20 to 1-23, wherein ASC-1 , L2, R8, R9a and R9b are defined as in any one of embodiments A17 to A22, wherein Rl and R2 represent independently hydrogen, F, CI, Br, ί-Bu or CF3-; and R4 represents F, CF3, or O-RI O wherein R10 represents z-Bu or CH2-CH=CH2.
In embodiment A26, the compound of the invention is a compound of formula 1-20 to 1-23, wherein
ASC-1 is C2-C5alkylene-N(R9a)R9b or C(=0)-CrC4alkylene-N(R9a)R9b, wherein in alkylene in both cases one -CH2- moiety is optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH3)-;
Rl and R2 represent independently hydrogen, F, CI, Br, ί-Bu or CF3;
R4 represents hydrogen, F, CI, CF3, or O-z-Bu or 0-CH2-CH=CH2;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl; and
L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or
L2 represents -0-C2-C6alkylene-.
In embodiment A27 the compound of the invention is a compound of formula 1-20 to 1-23, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, - (CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b, -C(=0)-CH(CH3)- N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b,
-C(=0)-CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
Rl and R2 represent independently hydrogen, F, CI, Br, ί-Bu or CF3; R4 represents hydrogen, F, CI, CF3, or O-z-Bu or 0-CH2-CH=CH2;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl; and
L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or
L2 represents -0-C2-C6alkylene-.
In embodiment A28 the compound of the invention is a compound of formula 1-20 to 1-23, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b,
-(CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b,
-C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b,
-C(=0)-CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b, or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
Rl and R2 represent independently hydrogen, F, CI, Br, ί-Bu or CF3;
R4 represents hydrogen, F, CI, CF3, or Cw-Bu or 0-CH2-CH=CH2;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl; and
L2 represents -CH2-, -C(=0)-, -0-(CH2)2-, -0-(CH2)3-, -0-(CH2)4-, or CH2-NH-C(=0)-CH(NH2)-(CH2)2- C(=0)-.
In embodiment A29 the compound of the invention is a compound of formula 1-20 to 1-23, wherein
ASC-1 is C2-C5alkylene-N(R9a)R9b or C(=0)-CrC4alkylene-N(R9a)R9b, wherein in alkylene in both cases one -CH2- moiety is optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH3)-;
Rl and R2 represent independently hydrogen, halogen, Ci-C4alkyl or Ci-C2haloalkyl, wherein preferably Rl and R2 represent independently halogen, Ci-C4alkyl or Cihaloalkyl;
R4 represents hydrogen, halogen, Ci-C2haloalkyl, or O-RIO wherein R10 represents Ci-C4alkyl or C2- C3alkenyl, wherein preferably R4 represents hydrogen, halogen, Ci-C2haloalkyl, or O-RIO wherein R10 represents Ci-C4alkyl or C3alkenyl;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl; and
L2 represents -CH2-, -C(=0)-, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2-C(=0)-.
In embodiment A30 the compound of the invention is a compound of formula 1-20 to 1-23, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, - (CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b, -C(=0)-CH(CH3)- N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b, or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
Rl and R2 represent independently hydrogen, F, CI, Br, ί-Bu or CF3;
R4 represents hydrogen, F, CI, CF3, or O-z-Bu or 0-CH2-CH=CH2;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl; and
L2 represents -CH2-, -C(=0)-, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2-C(=0)-.
In embodiment A31 the compound of the invention is a compound of formula 1-20 to 1-23, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, -(CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b, -C(=0)-
CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b,
-C(=0)-CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b, or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
Rl and R2 represent independently hydrogen, F, CI, Br, ί-Bu or CF3;
R4 represents hydrogen, F, CI, CF3, or O-z-Bu or 0-CH2-CH=CH2;
R8 represents hydrogen or ASC- 1 ;
R9a and R9b are independently hydrogen or methyl; and
L2 represents -CH2-, -C(=0)-, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2-C(=0)-.
In embodiment A32 the compound of the invention is a compound of formula 1-20 to 1-23, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, -(CH2)2-NH-(CH2)2-
N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b,
-C(=0)-CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b, or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
Rl and R2 represent independently hydrogen, F, CI, Br, ί-Bu or CF3;
R4 represents hydrogen, CI, CF3, O-z-Bu or 0-CH2-CH=CH2;
R8 represents hydrogen or ASC- 1 ;
R9a and R9b are independently hydrogen or methyl; and
L2 represents -CH2-, -C(=0)-, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2-C(=0)-.
A further embodiment A33 of compounds of the invention is represented by any one of the embodiments Al to A16, wherein LI represents -CH=CH-, and in particular embodiment Al wherein LI represents (E)- CH=CH-.
A further embodiment A34 of compounds of the invention is represented by any one of the embodiments Al to A16, wherein LI represents -C(CH3)2-, and in particular embodiment Al wherein LI represents -C(CH3)2- A further embodiment A35 of compounds of the invention is represented by any one of the embodiments Al to A16, wherein LI represents -CH2-0-, and in particular embodiment Al wherein LI represents -CH2-0-.
A further embodiment A36 of compounds of the invention is represented by any one of the embodiments Al to A16, wherein LI represents -0-CH2-, and in particular embodiment Al wherein LI represents -0-CH2-.
A further embodiment A37 of compounds of the invention is represented by any one of the embodiments Al to A36, wherein ASC is -N(ASC-1)2, and in particular embodiment Al wherein ASC is -N(ASC-1)2. A further embodiment A38 of compounds of the invention is represented by any one of the embodiments Al to A36, wherein R4 is -0-CH2-CH=CH2, and in particular embodiment Al wherein R4 is -0-CH2-CH=CH2.
A further embodiment A39 of compounds of the invention is represented by any one of the embodiments Al to A36, wherein L2 is -C(=0)-, and in particular embodiment Al wherein L2 is -C(=0)-.
A further embodiment A40 of compounds of the invention is represented by any one of the embodiments Al to A36, wherein L2 is -C(=0)- and R4 is -0-CH2-CH=CH2, and in particular embodiment Al wherein L2 is - C(=0)- and R4 is -0-CH2-CH=CH2. In a further embodiment A41 the compound of the invention is a compound of formula 1-20, wherein Rl, R2, R4, L2 and ASC are preferably defined as in any one of embodiments A17 to A32.
In a further embodiment A42 the compound of the invention is a compound of formula 1-21, wherein Rl, R2, R4, L2 and ASC are preferably defined as in any one of embodiments A17 to A32.
In a further embodiment A43 the compound of the invention is a compound of formula 1-22, wherein Rl , R2, R4, L2 and ASC are preferably defined as in any one of embodiments A17 to A32.
In a further embodiment A44 the compound of the invention is a compound of formula 1-23, wherein Rl, R2, R4, L2 and ASC are preferably defined as in any one of embodiments A17 to A32.
In a further embodiment A45 the compound of the invention is a compound of formula 1-20, wherein ASC is -N(ASC-1)2 and Rl, R2, R4 and L2 are preferably defined as in any one of embodiments A17 to A32. In a further embodiment A46 the compound of the invention is a compound of formula 1-21, wherein ASC is -N(ASC-1)2 and Rl, R2, R4 and L2 are preferably defined as in any one of embodiments A17 to A32. In a further embodiment A47 the compound of the invention is a compound of formula 1-22, wherein ASC is -N(ASC-1)2 and Rl, R2, R4 and L2 are preferably defined as in any one of embodiments A17 to A32. In a further embodiment A48 the compound of the invention is a compound of formula 1-23, wherein ASC is -N(ASC-1)2 and Rl, R2, R4 and L2 are preferably defined as in any one of embodiments A17 to A32.
In a further embodiment A49 the compound of the invention is a compound of formula 1-20, wherein R4 is - 0-CH2-CH=CH2, and Rl, R2, L2 and ASC are preferably defined as in any one of embodiments A17 to A32.
In a further embodiment A50 the compound of the invention is a compound of formula 1-21, wherein R4 is - 0-CH2-CH=CH2, and Rl, R2, L2 and ASC are preferably defined as in any one of embodiments A17 to A32.
In a further embodiment A51 the compound of the invention is a compound of formula 1-22, wherein R4 is - 0-CH2-CH=CH2, and Rl, R2, L2 and ASC are preferably defined as in any one of embodiments A17 to A32.
In a further embodiment A52 the compound of the invention is a compound of formula 1-23, wherein R4 is - 0-CH2-CH=CH2, and Rl, R2, L2 and ASC are preferably defined as in any one of embodiments A17 to A32. In a further embodiment A53 the compound of the invention is a compound of formula 1-20, wherein L2 is - C(=0)- and Rl, R2, R4 and ASC are preferably defined as in any one of embodiments A17 to A32.
In a further embodiment A54 the compound of the invention is a compound of formula 1-21, wherein L2 is - C(=0)- and Rl, R2, R4 and ASC are preferably defined as in any one of embodiments A17 to A32.
In a further embodiment A55 the compound of the invention is a compound of formula 1-22, wherein L2 is - C(=0)- and Rl, R2, R4 and ASC are preferably defined as in any one of embodiments A17 to A32.
In a further embodiment A56 the compound of the invention is a compound of formula 1-23, wherein L2 is - C(=0)- and Rl, R2, R4 and ASC are preferably defined as in any one of embodiments A17 to A32.
In a further embodiment A57 the compound of the invention is a compound of formula 1-20, wherein L2 is - C(=0)- and R4 is -0-CH2-CH=CH2, and Rl, R2 and ASC are preferably defined as in any one of embodiments A17 to A32. In a further embodiment A58 the compound of the invention is a compound of formula 1-21, wherein L2 is - C(=0)- and R4 is -0-CH2-CH=CH2, and Rl , R2 and ASC are preferably defined as in any one of embodiments A17 to A32. In a further embodiment A59 the compound of the invention is a compound of formula 1-22, wherein L2 is - C(=0)- and R4 is -0-CH2-CH=CH2, and Rl , R2 and ASC are preferably defined as in any one of embodiments A17 to A32.
In a further embodiment A60 the compound of the invention is a compound of formula 1-23, wherein L2 is - C(=0)- and R4 is -0-CH2-CH=CH2, and Rl, R2 and ASC are preferably defined as in any one of embodiments A17 to A32.
In embodiments A39, A40 and A53 to A60 L2 is -C(=0)-, which means that when these embodiments are in the context of the aspect of the invention providing compounds per se R8 is ASC-1, as described above.
Further embodiments of compounds of the invention are represented by embodiments Bl to B26, wherein, in each case, Rl, R2, R3, R4, R5, R6, R7, R8, R9a, R9b and LI are as defined for compounds of formula I.
Embodi¬
L2 ASC-1
ment
Bl C(=0) (CH2)2-NH2
B2 C(=0) (CH2)4-NH2
B3 C(=0) (CH2)3-NH2
B4 CH2-NH-C(=0)-CH(NH2)-(CH2)2-C(=0) (CH2)2-NH2
B5 0-(CH2)2 (CH2)3-N(CH3)2
B6 0-(CH2)2 (CH2)2-N(CH3)2
B7 0-(CH2)3 (CH2)2-NH2
B8 0-(CH2)3 (CH2)3-N(CH3)2
B9 0-(CH2)4 (CH2)2-NH2
B10 CH2 C(=0)-CH(NH2)-(CH2)2-NH2
Bl l CH2 C(=0)-CH(NH2)-(CH2)3-NH2
B12 CH2 (CH2)2-N(CH3)2
B13 CH2 (CH2)2-NH-(CH2)2-NH2
B14 CH2 CH2-CH(CH3)-CH2-NH2
B15 CH2 (CH2)4-NHCH3
B16 CH2 C(=0)-CH2-NH2
B17 CH2 C(=0)-(CH2)2-NH2
B19 CH2 (CH2)4-N(CH3)2 B20 CH2 C(=0)-CH(NH2)-(CH2)3-NH-C(=NH)NH2
B21 CH2 C(=0)-CH(NH2)-CH3
B22 CH2 (CH2)3-NHCH3
B23 CH2 (CH2)3-NH2
B24 CH2 (CH2)3-N(CH3)2
B25 CH2 (CH2)2-N(CH3)2
B26 CH2 (CH2)4-NH2
Further embodiments of compounds of the invention are represented by embodiments B 1 to B26, wherein, in each case, Rl, R2, R4, R8, R9a, R9b and LI are as defined as in any one of the embodiments Al to A60. Further embodiments of compounds of the invention are represented by embodiments Bal-Ba26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment Al .
Further embodiments of compounds of the invention are represented by embodiments Bbl-Bb26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A2.
Further embodiments of compounds of the invention are represented by embodiments Bcl-Bc26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A3.
Further embodiments of compounds of the invention are represented by embodiments Bdl-Bd26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A4.
Further embodiments of compounds of the invention are represented by embodiments Bel-Be26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A5.
Further embodiments of compounds of the invention are represented by embodiments Bfl-Bf26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A6.
Further embodiments of compounds of the invention are represented by embodiments Bgl-Bg26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A7.
Further embodiments of compounds of the invention are represented by embodiments Bhl-Bh26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A8. Further embodiments of compounds of the invention are represented by embodiments Bil -Bi26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A9.
Further embodiments of compounds of the invention are represented by embodiments Bjl -Bj26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A10.
Further embodiments of compounds of the invention are represented by embodiments Bkl-Bk26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment Al 1.
Further embodiments of compounds of the invention are represented by embodiments Bll -B126, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A12.
Further embodiments of compounds of the invention are represented by embodiments Bml-Bm26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment Al 3.
Further embodiments of compounds of the invention are represented by embodiments Bnl-Bn26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A14.
Further embodiments of compounds of the invention are represented by embodiments Bol-Bo26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A15.
Further embodiments of compounds of the invention are represented by embodiments Bpl-Bp26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A16.
Further embodiments of compounds of the invention are represented by embodiments Bql-Bq26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A17.
Further embodiments of compounds of the invention are represented by embodiments Brl-Br26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment Al 8.
Further embodiments of compounds of the invention are represented by embodiments Bsl-Bs26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A19.
Further embodiments of compounds of the invention are represented by embodiments Btl-Bt26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A20. Further embodiments of compounds of the invention are represented by embodiments Bul-Bu26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and R9b are as defined as for compounds of formula I in embodiment A21.
Further embodiments of compounds of the invention are represented by embodiments Bvl -Bv26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A22.
Further embodiments of compounds of the invention are represented by embodiments Bwl -Bw26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A23.
Further embodiments of compounds of the invention are represented by embodiments Bxal-Bx26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A24.
Further embodiments of compounds of the invention are represented by embodiments Byl -By26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A25.
Further embodiments of compounds of the invention are represented by embodiments Bzl-Bz26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A26.
Further embodiments of compounds of the invention are represented by embodiments Baal-Baa26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A27.
Further embodiments of compounds of the invention are represented by embodiments Bbbl-Bbb26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A28.
Further embodiments of compounds of the invention are represented by embodiments Bccl -Bcc26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A29.
Further embodiments of compounds of the invention are represented by embodiments Bddl -Bdd26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A30.
Further embodiments of compounds of the invention are represented by embodiments Beel -Bee26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A31.
Further embodiments of compounds of the invention are represented by embodiments Bffl -Bff26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A32. Further embodiments of compounds of the invention are represented by embodiments Bggl -Bgg26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A33.
Further embodiments of compounds of the invention are represented by embodiments Bhhl -Bhh26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A34.
Further embodiments of compounds of the invention are represented by embodiments Biil-Bii26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A35.
Further embodiments of compounds of the invention are represented by embodiments Bjj 1 -Bjj26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A36.
Further embodiments of compounds of the invention are represented by embodiments Bkkl -Bkk26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A37.
Further embodiments of compounds of the invention are represented by embodiments Bill -B1126, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A38.
Further embodiments of compounds of the invention are represented by embodiments Bmml -Bmm26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A39.
Further embodiments of compounds of the invention are represented by embodiments Bnnl -Bnn26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, R9b and LI are as defined as for compounds of formula I in embodiment A40.
Further embodiments of compounds of the invention are represented by embodiments Bool -Boo26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A41.
Further embodiments of compounds of the invention are represented by embodiments Bppl-Bpp26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A42.
Further embodiments of compounds of the invention are represented by embodiments Bqql -Bqq26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A43.
Further embodiments of compounds of the invention are represented by embodiments Brrl-Brr26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A44. Further embodiments of compounds of the invention are represented by embodiments Bssl-Bss26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A45.
Further embodiments of compounds of the invention are represented by embodiments Bttl-Btt26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A46.
Further embodiments of compounds of the invention are represented by embodiments Buul-Buu26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A47.
Further embodiments of compounds of the invention are represented by embodiments Bwl -Bw26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A48.
Further embodiments of compounds of the invention are represented by embodiments Bwwl -Bww26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A49.
Further embodiments of compounds of the invention are represented by embodiments Bxxl-Bxx26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A50.
Further embodiments of compounds of the invention are represented by embodiments Byyl -Byy26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A51.
Further embodiments of compounds of the invention are represented by embodiments Bzzl -Bzz26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A52.
Further embodiments of compounds of the invention are represented by embodiments Baaal-Baaa26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A53.
Further embodiments of compounds of the invention are represented by embodiments Bbbbl-Bbbb26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A54.
Further embodiments of compounds of the invention are represented by embodiments Bcccl-Bccc26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A55.
Further embodiments of compounds of the invention are represented by embodiments Bdddl -Bddd26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A56. Further embodiments of compounds of the invention are represented by embodiments Beeel-Beee26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A57.
Further embodiments of compounds of the invention are represented by embodiments Bfffl -Bfff26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A58.
Further embodiments of compounds of the invention are represented by embodiments Bgggl -Bggg26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A59.
Further embodiments of compounds of the invention are represented by embodiments Bhhhl -Bhhh26, which correspond to embodiments Bl to B26, but wherein the Rl, R2, R4, R8, R9a, and R9b are as defined as for compounds of formula I in embodiment A60.
Further embodiments of compounds of the invention are represented by embodiments CI to C26, wherein, each case, Rl, R2, R3, R4, R5, R6, R7 and LI are as defined for compounds of formula I.
Embodi¬
L2 ASC
ment
CI C(=0) N-[(CH2)2-NH2]2
C2 C(=0) NH-(CH2)4-NH2
C3 C(=0) NH-(CH2)3-NH2
C4 CH2-NH-C(=0)-CH(NH2)-(CH2)2-C(=0) N-[(CH2)2-NH2]2
C5 0-(CH2)2 NH-(CH2)3-N(CH3)2
C6 0-(CH2)2 NH-(CH2)2-N(CH3)2
C7 0-(CH2)3 NH-(CH2)2-NH2
C8 0-(CH2)3 NH-(CH2)3-N(CH3)2
C9 0-(CH2)4 NH-(CH2)2-NH2
CIO CH2 NH-C(=0)-CH(NH2)-(CH2)2-NH2
Cl l CH2 NH-C(=0)-CH(NH2)-(CH2)3-NH2
C12 CH2 NH-(CH2)2-N(CH3)2
C13 CH2 NH-(CH2)2-NH-(CH2)2-NH2
C14 CH2 NH-CH2-CH(CH3)-CH2-NH2
C15 CH2 NH-(CH2)4-NHCH3
C16 CH2 NH-C(=0)-CH2-NH2
C17 CH2 NH-C(=0)-(CH2)2-NH2
C19 CH2 NH-(CH2)4-N(CH3)2
C20 CH2 NH-C(=0)-CH(NH2)-(CH2)3-NH-C(=NH)NH2
C21 CH2 NH-C(=0)-CH(NH2)-CH3 C22 CH2 NH-(CH2)3-NHCH3
C23 CH2 NH-(CH2)3-NH2
C24 CH2 NH-(CH2)3-N(CH3)2
C25 CH2 NH-(CH2)2-N(CH3)2
C26 CH2 NH-(CH2)4-NH2
Further embodiments of compounds of the invention are represented by embodiments CI to C26, wherein, in each case, Rl, R2, R4 and LI are as defined as in any one of the embodiments Al to A60.
Further embodiments of compounds of the invention are represented by embodiments Cal-Ca26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment Al .
Further embodiments of compounds of the invention are represented by embodiments Cbl-Cb26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A2.
Further embodiments of compounds of the invention are represented by embodiments Ccl-Cc26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A3.
Further embodiments of compounds of the invention are represented by embodiments Cdl-Cd26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A4.
Further embodiments of compounds of the invention are represented by embodiments Cel-Ce26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A5.
Further embodiments of compounds of the invention are represented by embodiments Cfl-Cf26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A6.
Further embodiments of compounds of the invention are represented by embodiments Cgl-Cg26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A7.
Further embodiments of compounds of the invention are represented by embodiments Chl-Ch26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A8.
Further embodiments of compounds of the invention are represented by embodiments Cil-Ci26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A9. Further embodiments of compounds of the invention are represented by embodiments Cjl-Cj26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A10.
Further embodiments of compounds of the invention are represented by embodiments Ckl-Ck26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment Al 1.
Further embodiments of compounds of the invention are represented by embodiments C11-C126, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A12.
Further embodiments of compounds of the invention are represented by embodiments Cml-Cm26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A13.
Further embodiments of compounds of the invention are represented by embodiments Cnl -Cn26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment Al 4.
Further embodiments of compounds of the invention are represented by embodiments Col-Co26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A15.
Further embodiments of compounds of the invention are represented by embodiments Cpl-Cp26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A16.
Further embodiments of compounds of the invention are represented by embodiments Cql-Cq26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A17.
Further embodiments of compounds of the invention are represented by embodiments Crl-Cr26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment Al 8.
Further embodiments of compounds of the invention are represented by embodiments Csl-Cs26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment Al 9.
Further embodiments of compounds of the invention are represented by embodiments Ctl-Ct26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A20.
Further embodiments of compounds of the invention are represented by embodiments Cul-Cu26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A21. Further embodiments of compounds of the invention are represented by embodiments Cvl-Cv26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A22.
Further embodiments of compounds of the invention are represented by embodiments Cwl-Cw26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A23.
Further embodiments of compounds of the invention are represented by embodiments Cxl-Cx26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A24.
Further embodiments of compounds of the invention are represented by embodiments Cyl-Cy26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A25.
Further embodiments of compounds of the invention are represented by embodiments Czl-Cz26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A26.
Further embodiments of compounds of the invention are represented by embodiments Caal-Caa26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A27.
Further embodiments of compounds of the invention are represented by embodiments Cbbl-Cbb26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A28.
Further embodiments of compounds of the invention are represented by embodiments Cccl-Ccc26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A29.
Further embodiments of compounds of the invention are represented by embodiments Cddl -Cdd26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A30.
Further embodiments of compounds of the invention are represented by embodiments Ceel -Cee26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A31.
Further embodiments of compounds of the invention are represented by embodiments Cffl-Cff26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A32.
Further embodiments of compounds of the invention are represented by embodiments Cggl -Cgg26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A33. Further embodiments of compounds of the invention are represented by embodiments Chhl -Chh26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A34.
Further embodiments of compounds of the invention are represented by embodiments CU1-CU26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A35.
Further embodiments of compounds of the invention are represented by embodiments Cjj l-Cjj26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A36.
Further embodiments of compounds of the invention are represented by embodiments Ckkl -Ckk26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A37.
Further embodiments of compounds of the invention are represented by embodiments C111-C1126, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A38.
Further embodiments of compounds of the invention are represented by embodiments Cmml-Cmm26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A39.
Further embodiments of compounds of the invention are represented by embodiments Cnnl -Cnn26, which correspond to embodiments CI to C26, but wherein the Rl, R2, R4 and LI are as defined as for compounds of formula I in embodiment A40.
Further embodiments of compounds of the invention are represented by embodiments Cool -Coo26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A41.
Further embodiments of compounds of the invention are represented by embodiments Cppl-Cpp26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A42.
Further embodiments of compounds of the invention are represented by embodiments Cqql -Cqq26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A43.
Further embodiments of compounds of the invention are represented by embodiments Crrl-Crr26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A44.
Further embodiments of compounds of the invention are represented by embodiments Cssl-Css26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A45. Further embodiments of compounds of the invention are represented by embodiments Cttl-Ctt26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A46.
Further embodiments of compounds of the invention are represented by embodiments Cuul-Cuu26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A47.
Further embodiments of compounds of the invention are represented by embodiments Cwl -Cw26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A48.
Further embodiments of compounds of the invention are represented by embodiments Cwwl-Cww26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A49.
Further embodiments of compounds of the invention are represented by embodiments Cxxl-Cxx26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A50.
Further embodiments of compounds of the invention are represented by embodiments Cyyl -Cyy26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A51.
Further embodiments of compounds of the invention are represented by embodiments Czzl-Czz26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A52.
Further embodiments of compounds of the invention are represented by embodiments Caaal -Caaa26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A53.
Further embodiments of compounds of the invention are represented by embodiments Cbbbl-Cbbb26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A54.
Further embodiments of compounds of the invention are represented by embodiments Ccccl-Cccc26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A55.
Further embodiments of compounds of the invention are represented by embodiments Cdddl -Cddd26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A56.
Further embodiments of compounds of the invention are represented by embodiments Ceeel-Ceee26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A57. Further embodiments of compounds of the invention are represented by embodiments Cfffl -Cfff26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A58.
Further embodiments of compounds of the invention are represented by embodiments Cgggl -Cggg26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A59.
Further embodiments of compounds of the invention are represented by embodiments Chhhl -Chhh26, which correspond to embodiments CI to C26, but wherein the Rl, R2, and R4 are as defined as for compounds of formula I in embodiment A60.
Further embodiments of compounds of the invention are represented by embodiments Dl to D35, wherein, in each case, R3, R5, R6, R7, R8, R9a, R9b, L2 and ASC are as defined for compounds of formula I.
Embodi¬
Rl R2 LI R4
ment
Dl Br H CH2-0 H
D2 Br F CH2-0 H
D3 CI H CH2-0 H
D4 CI Br CH=CH O-Allyl
D5 CI Br CH=CH O-iBu
D6 CI Br CH=CH O-Bn
D7 CI Br CH=CH CF3
D8 CI Br CH=CH CI
D9 CI Br CH=CH H
D10 CI Br CH=CH-CH2 O-Allyl
Dl l CI Br CH=CH-CH2 CF3
D12 CI Br CH=CH-CH2 CI
D13 CI Br CH=CH-CH2 H
D14 CI Br CH=CH-CH2 O-iBu
D15 CI Br CH=CH-CH2 O-Bn
D16 CI Br CH2-0 O-Allyl
D17 CI Br CH2-0 CI
D18 CI Br CH2-0 H
D19 CI Br 0-CH2 H
D20 CF3 H CH=CH O-Allyl
D21 CF3 H CH=CH O-iBu
D22 CI CI CH2-0 H
D23 F H CH=CH O-Allyl D24 F H CH=CH O-iBu
D25 H H C(CH3)2 H
D26 H H CH2-0 H
D27 iBu H CH=CH O-Allyl
D28 iBu H CH=CH O-iBu
D29 iBu H CH2-0 iBu
D30 iBu H CH2-0 O-iBu
D31 iBu H CH2-0 H
D32 iBu H CH2-0 O-Bn
D33 iBu H CH2-0 O-Allyl
D34 iBu H CH2-0 0-CH2-CH2-Morpholine
D35 iBu H CH2-0 CF3
Further embodiments of compounds of the invention are represented by embodiments Dl to D35, wherein, in each case, R8, R9a, R9b, L2 and ASC are as defined as in any one of the embodiments Al to A60. Further embodiments of compounds of the invention are represented by embodiments Dal-Da35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment Al .
Further embodiments of compounds of the invention are represented by embodiments Dbl-Db35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A2.
Further embodiments of compounds of the invention are represented by embodiments Dcl-Dc35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A3.
Further embodiments of compounds of the invention are represented by embodiments Ddl-Dd35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A4.
Further embodiments of compounds of the invention are represented by embodiments Del-De35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A5.
Further embodiments of compounds of the invention are represented by embodiments Dfl-Df35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A6.
Further embodiments of compounds of the invention are represented by embodiments Dgl-Dg35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A7. Further embodiments of compounds of the invention are represented by embodiments Dhl-Dh35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A8.
Further embodiments of compounds of the invention are represented by embodiments Dil-Di35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A9.
Further embodiments of compounds of the invention are represented by embodiments Djl-Dj35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A10.
Further embodiments of compounds of the invention are represented by embodiments Dkl-Dk35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment Al 1.
Further embodiments of compounds of the invention are represented by embodiments D11-D135, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A12.
Further embodiments of compounds of the invention are represented by embodiments Dml-Dm35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A13.
Further embodiments of compounds of the invention are represented by embodiments Dnl-Dn35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A14.
Further embodiments of compounds of the invention are represented by embodiments Dol-Do35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A15.
Further embodiments of compounds of the invention are represented by embodiments Dpl-Dp35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A16.
Further embodiments of compounds of the invention are represented by embodiments Dql-Dq35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A17.
Further embodiments of compounds of the invention are represented by embodiments Drl-Dr35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A18.
Further embodiments of compounds of the invention are represented by embodiments Dsl-Ds35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A19. Further embodiments of compounds of the invention are represented by embodiments Dtl-Dt35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A20.
Further embodiments of compounds of the invention are represented by embodiments Dul-Du35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A21.
Further embodiments of compounds of the invention are represented by embodiments Dvl-Dv35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A22.
Further embodiments of compounds of the invention are represented by embodiments Dwl-Dw35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A23.
Further embodiments of compounds of the invention are represented by embodiments Dxl-Dx35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A24.
Further embodiments of compounds of the invention are represented by embodiments Dyl-Dy35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A25.
Further embodiments of compounds of the invention are represented by embodiments Dzl-Dz35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A26.
Further embodiments of compounds of the invention are represented by embodiments Daal-Daa35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A27.
Further embodiments of compounds of the invention are represented by embodiments Dbbl-Dbb35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A28.
Further embodiments of compounds of the invention are represented by embodiments Dccl-Dcc35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A29.
Further embodiments of compounds of the invention are represented by embodiments Dddl-Ddd35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A30.
Further embodiments of compounds of the invention are represented by embodiments Deel-Dee35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A31. Further embodiments of compounds of the invention are represented by embodiments Dffl-Dff35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A32.
Further embodiments of compounds of the invention are represented by embodiments Dggl-Dgg35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A33.
Further embodiments of compounds of the invention are represented by embodiments Dhhl-Dhh35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A34.
Further embodiments of compounds of the invention are represented by embodiments Diil-Dii35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A35.
Further embodiments of compounds of the invention are represented by embodiments Djjl-Djj35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A36.
Further embodiments of compounds of the invention are represented by embodiments Dkkl-Dkk35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A37.
Further embodiments of compounds of the invention are represented by embodiments D111-D1135, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A38.
Further embodiments of compounds of the invention are represented by embodiments Dmml -Dmm35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A39.
Further embodiments of compounds of the invention are represented by embodiments Dnnl-Dnn35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A40.
Further embodiments of compounds of the invention are represented by embodiments Dool-Doo35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A41.
Further embodiments of compounds of the invention are represented by embodiments Dppl-Dpp35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A42.
Further embodiments of compounds of the invention are represented by embodiments Dqql-Dqq35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A43. Further embodiments of compounds of the invention are represented by embodiments Drrl-Drr35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A44.
Further embodiments of compounds of the invention are represented by embodiments Dssl-Dss35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A45.
Further embodiments of compounds of the invention are represented by embodiments Dttl-Dtt35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A46.
Further embodiments of compounds of the invention are represented by embodiments Duul-Duu35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A47.
Further embodiments of compounds of the invention are represented by embodiments Dwl-Dw35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A48.
Further embodiments of compounds of the invention are represented by embodiments Dwwl -Dww35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A49.
Further embodiments of compounds of the invention are represented by embodiments Dxxl-Dxx35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A50.
Further embodiments of compounds of the invention are represented by embodiments Dyyl-Dyy35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A51.
Further embodiments of compounds of the invention are represented by embodiments Dzzl-Dzz35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A52.
Further embodiments of compounds of the invention are represented by embodiments Daaal-Daaa35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A53.
Further embodiments of compounds of the invention are represented by embodiments Dbbbl-Dbbb35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A54.
Further embodiments of compounds of the invention are represented by embodiments Dcccl-Dccc35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A55. Further embodiments of compounds of the invention are represented by embodiments Ddddl-Dddd35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A56.
Further embodiments of compounds of the invention are represented by embodiments Deeel-Deee35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A57.
Further embodiments of compounds of the invention are represented by embodiments Dfffl-Dfff35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A58.
Further embodiments of compounds of the invention are represented by embodiments Dgggl-Dggg35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A59.
Further embodiments of compounds of the invention are represented by embodiments Dhhhl-Dhhh35, which correspond to embodiments Dl to D35, but wherein the R8, R9a, R9b, L2 and ASC are as defined as for compounds of formula I in embodiment A60.
Further embodiments of compounds of the invention are represented by embodiments El to E55, wherein, in each case, R3, R5, R6, and R7 are as defined for compounds of formula I.
Figure imgf000049_0001
Figure imgf000050_0001
Morpholine
E47 iBu H CH2-0 CF3 CH2 NH-(CH2)2-N(CH3)2
E48 H H CH2-0 H C(=0) NH-(CH2)4-NH2
E49 H H CH2-0 H CH2 NH-(CH2)4-NH2
E50 CI Br CH=CH O-Bn CH2 NH-(CH2)2-N(CH3)2
NH-C(=0)-CH(NH2)-
E51 CI Br CH=CH O-Allyl CH2
CH3
E52 iBu H CH=CH O-iBu 0-(CH2)4 NH-(CH2)2-NH2
E53 CI CI CH2-0 H CH2 NH-(CH2)3-N(CH3)2
E54 CI H CH2-0 H CH2 NH-(CH2)3-NHCH3
E55 H H CH2-0 H C(=0) NH-(CH2)3-NH2
Further embodiments of compounds of the invention are represented by embodiments El, E2, E3, E5, E6, E9, E10, El l, E12, E13, E14, E16, E18, E19, E27, E28, E30, E31, E50, E51 or E52, wherein, in each case, the compound of the invention is a compound of formula 1-20.
Further embodiments of compounds of the invention are represented by embodiments El 7, E21, E24, E36, E43 or E44, wherein, in each case, the compound of the invention is a compound of formula 1-21.
Further embodiments of compounds of the invention are represented by embodiments E4, E7, E8, 32, E33, E34, E37, E38, E39, E41, E42, E45, E46, E47, E48, E49, E53, E54 or E55, wherein, in each case, the compound of the invention is a compound of formula 1-22.
Further embodiments of compounds of the invention are represented by embodiments El 5, E20 or E35, wherein, in each case, the compound of the invention is a compound of formula 1-23.
Further embodiments of compounds of the invention are represented by embodiments E22, E23, E25, E26, E29 or E40, wherein, in each case, R3, R5, R6, and R7 are H.
Further embodiments of compounds of the invention are represented by embodiments El, E2, E3, E5, E6, E9, E10, El l, E12, E13, E14, E16, E18, E19, E27, E28, E30, E31, E50, E51 or E52, wherein, in each case, the compound of the invention is a compound of formula 1-20, and wherein Rl is at the para position on AR1 with respect to LI .
Further embodiments of compounds of the invention are represented by embodiments El, E2, E3, E5, E6, E9, E10, El l, E12, E13, E14, E16, E18, E19, E27, E28, E30, E31, E50, E51 or E52, wherein, in each case, the compound of the invention is a compound of formula 1-20, and wherein Rl is at the para position on AR1 with respect to LI, and wherein R2 is at the ortho position on AR1 with respect to LI .
Further embodiments of compounds of the invention are represented by embodiments E4, E7, E8, 32, E33, E34, E37, E38, E41, E42, E45, E46, E47, E48, E49, E53 or E55, 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 AR1 with respect to LI . Further embodiments of compounds of the invention are represented by embodiments E4, E7, E8, 32, E33, E34, E37, E38, E41, E42, E45, E46, E47, E48, E49, E53 or E55, 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 .
Further embodiments of compounds of the invention are represented by embodiments E39 or E54, wherein, in each case, the compound of the invention is a compound of formula 1-22, and wherein Rl is at the ortho position on ARl with respect to LI .
Further embodiments of compounds of the invention are represented by embodiments El 5, E20 or E35, wherein, in each case, 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 .
Further embodiments of compounds of the invention are represented by embodiments El 5, E20 or E35, wherein, in each case, 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 .
Further embodiments of compounds of the invention are represented by embodiments E22, E23, E25, E26, E29 or E40, wherein, in each case, R3, R5, R6, and R7 are H, and wherein Rl is at the para position on ARl with respect to LI .
Further embodiments of compounds of the invention are represented by any one of the compounds 1-55 of Table 1.
The methods of the invention include 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
simultaneously, separately or sequentially, preferably simultaneously. 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. In one embodiment the
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. In a further embodiment 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. In a further embodiment 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.
In addition to an antibiotic, or as an alternative to, 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. The 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. Various antibacterial agents can be used in combination with the compounds of formula I, including quinolones, fluoroquionolones, tetracyclines, glycopeptides, aminoglycosides, β-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.
Bacterial Topoisomerase inhibitors: e.g. GSK2140944, Ross et al. 2014. J. Clin. Microbiol. 52(7):2629, NXL101, Reck et al. 2014. Bioorg. Med. Chem. Epub ahead of print, Surivet et al. 2013 J. Med. Chem. 56(18):7396, Singh et al. 2014. Med. Chem. Lett. 5:609.
Beta-lactams: Beta-lactam antibiotics include but are not limited to, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, or 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, Faropenem, Tomopenem, Razupenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone,
Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole,
Loracarbef, Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime,
Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, Ceftolozane (CXA-101), RWJ-54428, MC-04,546, ME 1036, BAL30072, SYN 2416, Ceftiofur, Cefquinome, Cefovecin, Aztreonam, Tigemonam, Carumonam, Tebipenem, Tomopenem, RWJ-442831, RWJ-333441, BAL30072, or RWJ-333442.
Macrolides: Macrolides include but are not limited to azithromycin, clarithromycin, erythromycin, oleandomycin, rokitamycin, rosaramicin, roxythromycin, spiramycin, or troleandomycin.
Ketolides: Ketolides include but are not limited to telithromycin, solithromycin, or cethromycin.
Quinolones: 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, PD131628, PD138312, PD140248, Q-35, AM-1155, NM394, T-3761, rufloxacin, OPC-17116, DU-6859a (AAC 37: 1419), J J-Q2, or DV- 7751a (AAC 37:2212).
Tetracyclines and glycylcyc lines: Tetracyclines and glycylcyclines include but are not limited to tetracycline, minocycline, chlortetracycline, demeclocycline, doxycycline, lymecycline, methacycline, omadacycline, oxytetracycline, tigecycline, or eravacycline.
Oxazolidinones: Oxazolidinones include but are not limited to linezolid, tedizolid, eperozolid, or radezolid. Aminoglycosides: Aminoglycosides include but are not limited to amikacin, arbekacin, butirosin, dibekacin, fortimicins, gentamicin, kanamycin, neomycin, netilmicin, plazomicin, robostamycin, sisomicin, spectinomycin, streptomycin, or tobramycin.
Lincosamides: Lincosamides include but are not limited to clindamycin, or lincomycin.
Glycopeptides: Glycopeptides include but are not limited to vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, dalbavancin, oritavancin, or decaplanin.
Pleuromutilms: Pleuromutilms include but are not limited to retapamulin, valnemulin, tiamulin, azamulin, or BC-3781
Other antibiotics: Other antibiotics include but are not limited to trimethoprim, sulfamethoxazole, rifampicin, fusidic acid, puromycin, novobiocin, coumermycin, thiamphenicol, thiolactomycin, 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 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, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii,
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,
Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus,
Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus .
Of particular interest are 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, Yersinia intermedia, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella, Bacteroides fragilis, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, or Bacteroides splanchnicus.
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. Thus, 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,
In further embodiments 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.
In general, 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.
For the preparation of such tablets, pills, semi-solid substances, coated tablets, dragees and hard gelatine capsules, 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. For the preparation of soft capsules, pharmaceutical carrier substances such as, for example, vegetable oils, petroleum, animal or synthetic oils, wax, fat and polyols may be used. 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.
For suppositories, pharmaceutical carrier substances such as, for example, vegetable oils, petroleum, animal or synthetic oils, wax, fat and polyols may be used.
For aerosol formulations, 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.
The compositions of the invention may be provided in a sterile container, e.g. as a powder for reconstitution. In this case 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.
The pharmaceutical 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.
The pharmaceutical 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) or (c) described below; followed, if necessary, by removing any protecting groups, forming a pharmaceutically acceptable salt, or forming a pharmaceutically acceptable solvate or hydrate.
Process (a):
This process variant can be used for the manufacture of compounds of formula I as defined above, wherein LI is -(Ο -0-(Ο in which formula m is 1 or 2 and n is 0 or 1, within the limits defined by the claims. In this process a compound of formula II- 1
Figure imgf000058_0001
is reacted with a compound of formula III
Figure imgf000058_0002
to generate a compound of formula IV- 1
Figure imgf000058_0003
in which formulae
AR1, AR2, Ri, R2, R3, R5, Re, R7 are as in formula I,
m is 1 or 2,
n is 0 or 1 ,
Yl is -OH, a halogen atom or a leaving group like mesylate, tosylate, inflate,
Al is -0-,
PG1 is a hydrogen atom or a hydroxyl protecting group (such as allyl, benzyl, tetrahydropyranyl or silyl ethers),
A2 is -(CH2)o-Y2,
wherein 0 is 0, 1, 2 or 3,
Y2 is -OH, a halogen atom, a leaving group like mesylate, tosylate, triflate, -COOH, -CHO, -C(0)-CH2-X or -NH-PG2,
wherein X is a halogen atom and PG2 is a hydrogen atom or an amino protecting group (such as allyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethylcarbonyl, teri-butoxycarbonyl or benzyl),
A3 is as R4 in formula I or is a halogen atom or -OH.
When A3 is a halogen atom, the compound of formula IV-1 is further reacted with a compound of formula V
RVX (V)
wherein X is -CH2-OH,
to generate a compound of formula VI- 1
Figure imgf000059_0001
wherein R4 is O-RIO, with RIO defined as in formula I.
When A3 is -OH, the compound of formula IV- 1 is further reacted with a compound of formula V wherein X is -OH, a halogen atom or a leaving group like mesylate, tosylate, triflate, to generate a compound of formula VI-1 wherein R4 is O-RIO.
When Y2 is a halogen atom, a leaving group like mesylate, tosylate, triflate,-CHO, -C(0)-CH2-X or -COOH, compound of formula VI-1 is reacted with a compound of formula VII
ASC-A4 (VII)
wherein A4 is -NHE or -NH2, E being an amino protecting group, to generate compound of formula 1-1 wherein L2 is -(CH2)0-, -(CH2)P-, -(CH2)0-C(0)-CH2-, -(CH2)0-C(0)-, respectively, wherein p is 1, 2, 3, or 4.
When Y2 is -NH-PG2, PG2 amino protecting group is removed and the deprotected intermediate is reacted with a compound of formula VII wherein A4 is -CH2-X or -CHO, with X as a halogen atom or a leaving group like mesylate, tosylate, or triflate, to generate a compound of formula 1-1 wherein L2 is -(CH2)0-.
Alternatively, when Y2 is -NH-PG2, PG2 amino protecting group can be removed and the deprotected intermediate is reacted with a compound of formula VII wherein A4 is -COOH, to generate a compound of formula 1-1 wherein L2 is -(CH2)0-. Or the amino protecting group PG2 can be removed after reaction of a compound of formula VI-1 with a compound of formula VII.
When Y2 is -OH, the compound of formula IV- 1 can be converted to the corresponding halide, mesylate, tosylate, triflate compound, and further react with a compound of formula VII wherein A4 is -NHE or -NH2, E being an amino protecting group, to generate a compound of formula 1-1 wherein L2 is -(CH2)0-.
Alternatively, when Y2 is -OH, the compound of formula IV- 1 can react with a compound compound of VII wherein A4 is -(CH2)q-X, with X as a halogen atom or a leaving group like mesylate, tosylate, or triflate and q being comprised between 1 and 4, to generate a compound of formula 1-1 wherein L2 is -(CH2)0-0-(CH2)q.
In certain cases, Y2 may require appropriate activation to allow a reaction of compounds of formulae VI-1 and VII as described in more detail below. Process (b :
This process variant can be used for the manufacture of compounds of formula I as defined above, wherein LI is -0-(CH2)n- in which formula n is 0, 1 or 2 within the limits defined by the claims. In this process a compound of formula VIII
Figure imgf000060_0001
is reacted with a compound of formula IX
Figure imgf000060_0002
to generate a compound of formula IV-2
Figure imgf000060_0003
in which formulae
AR1 , AR2, Ri, R2, R3, R5, Re, R7 are as in formula I,
n is 0, 1 or 2,
Al is -O-,
PG1 is a hydrogen atom or a hydroxyl protecting group,
Y is -OH, a halogen atom or a leaving group like mesylate, tosylate, triflate,
A2 and A3 have the same meaning as in formulae III and IV- 1. Following procedures already described in process (a), the compound of formula IV-2 can react with a compound of formula V
R'4-X (V)
to generate a compound of formula VI-2
Figure imgf000060_0004
wherein R4 is as in formula I.
Further coupling with a compound of formula VII allow the generation of a compound of formula 1-2, applying procedures already described in process (a). Process (c):
This process variant can be used for the manufacture of compounds of formula I as defined above, wherein LI is -CH=CH-(CH2)m- (double bond Z, E or ZIE) or -(CH2)m+2-, with m being 0 or 1. In this process a compound of formula II-2
Figure imgf000061_0001
is reacted with a compound of formula X
Figure imgf000061_0002
to generate a compound of formula IV-3
Figure imgf000061_0003
in which formulae
AR1 , AR2, Ri, R2, R3, R5, Re, R7 are as in formula I,
Y is a phosphonium salt or a phosphonate,
m is 0 or 1 ,
LI is -CH=CH-(CH2)m- (double bond Z, E or ZIE),
A2 and A3 have the same meaning as in formulae III and IV- 1.
Following procedures already described in process (a), the compound of formula IV-3 can react with a compound of formula V
R'4-X (V)
to generate a compound of formula VI-3
Figure imgf000061_0004
wherein R4 is as in formula I. Further coupling with a compound of formula VII allow the generation of a compound of formula 1-3, applying procedures already described in process (a). When LI is -CH=CH-(CH2)m- (double bond Z, E or Z/E), compounds of formulae IV-3, VI-3 or 1-3 can further be reduced to generate compounds of formulae IV-3, VI-3 or 1-4, respectively, wherein LI is -
The necessary starting materials for the synthetic methods as described herein, if not commercially available, may be made by procedures which are described in the scientific literature, or may be made from commercially available compounds using adaptations of processes reported in the scientific literature. The reader is further referred to Advanced Organic Chemistry, 5th Edition, by J. March and M. Smith, published by John Wiley & Sons, 2001, for general guidance on reaction conditions and reagents. Furthermore in some of the reactions mentioned herein it may be necessary or desirable to protect any sensitive groups in compounds. Conventional protecting groups may be used in accordance with standard practice (for illustration see Protective Groups in Organic Synthesis, 3rd Edition, by T.W. Greene and P.G.M. Wuts, published by John Wiley & Sons, 1999). 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 compounds of formula I wherein LI is -(CH2)m-0-(CH2)n- with m being 1 or 2 and n being 0 or 1 (within the limits defined by the claims), can be obtained as summarized in Scheme 1.
Figure imgf000062_0001
11-1
R'4-X (V)
Figure imgf000062_0002
1-1 VI-1
Scheme 1. In Scheme 1, all the symbols have the same meanings as previously described in process (a).
When Al is -O- and PG1 is a hydroxyl protecting group, introduction of the protecting group PG1 is carried out under standard conditions. For example 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. Further general methods to introduce hydroxyl protecting groups have been described in Protective Groups in Organic Synthesis, 3rd Edition, by T.W. Greene and P.G.M. Wuts, published by John Wiley & Sons, 1999.
Such hydroxyl protecting groups can be removed before reaction of compounds of formula III with compounds of formula II- 1. The benzyl group is removed by hydrogeno lysis 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 tetrahydroiuran 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. Further general methods to remove hydroxyl protecting groups have been described in Protective Groups in Organic Synthesis, 3rd Edition, by T.W. Greene and P.G.M. Wuts, published by John Wiley & Sons, 1999.
Compounds of formula IV- 1 can be obtained from compounds of formula II- 1 wherein Yl is -OH via a Mitsunobu coupling (as reviewed in O. Mitsunobu, Synthesis 1981, 1) with compounds of formula III for which Al-PGl is a hydroxyl group. 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-dimethoxy ethane or dichloromethane and within a wide range of temperatures (between -20 °C and 60 °C). The reaction might also be performed using polymer-supported triphenylphosphine.
An alternative route to form compounds of formula IV- 1 consists of reacting compounds of formula III wherein Al-PGl is a hydroxyl group with compounds of formula II-l for which Yl is a hydroxyl group, which needs to be activated prior to the reaction as described below, or a halogen atom in presence of an inorganic base such as sodium hydride, potassium carbonate or the like in a solvent such as dichloromethane or NN-dimethylformamide at a temperature ranging between -20 °C and 80 °C. Activation of the hydroxyl group of compounds of formula II-l 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, respectively, 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.
When A3 is a halogen atom, compounds of formula IV- 1 can react with compounds of formula V for which X is -CH2-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 O-RIO.
Alternatively, when A3 is a hydroxyl group, a Mitsunobu coupling between compounds of formula IV- 1 and compounds of formula V for which X is -OH can lead to the generation of compounds of formula IV- 1 wherein R4 is O-RIO.
Additionally, when A3 is a hydroxyl group, compounds of formula IV- 1 can react with compounds 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 O-RIO.
For the generation of compounds of formula 1-1, when Y2 is a halogen atom, a leaving group or -C(0)-CH2-X, with X being a halogen atom, compounds of formula VI- 1 can react with compounds of formula VII for which A4 is -NH2 or -NHE, E being an amino protecting group, via a substitution reaction as previously described above, to generate compounds of formula 1-1 wherein L2 is -(CH2)0- or -(CH2)o-C(0)-CH2-, respectively.
When A4 is -NHE, the amino protecting group is introduced by reacting the corresponding free amine with allyl, fluorenylmethyl or benzyl chloroformate or with di-tert-butyl dicarbonate in presence of a base such as sodium hydroxide, sodium hydrogen carbonate, triethylamine, 4-dimethylaminopyridine or imidazole. The free amine can also be protected as N-benzyl derivatives by reaction with benzyl bromide or chloride in presence of a base such as sodium carbonate or triethylamine. Alternatively, N-benzyl derivatives can be obtained through reductive amination in presence of benzaldehyde. Further strategies to introduce other amino protecting groups have been described in Protective Groups in Organic Synthesis, 3rd Edition, by T.W. Greene and P.G.M. Wuts, published by John Wiley & Sons, 1999.
The amino protecting group E can further be removed under standard conditions. For example 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. The N-benzyl protected amines are deprotected by hydrogenolysis over a noble metal catalyst (e.g. palladium hydroxide on activated carbon). The Fmoc protecting group is removed under mild basic conditions such as diluted morpholine or piperidine in NN-dimethylformamide or acetonitrile. Further general methods to remove amine protecting groups have been described in Protective Groups in Organic Synthesis, 3rd Edition, by T.W. Greene and P.G.M. Wuts, published by John Wiley & Sons, 1999.
When Y2 is -CHO, compounds of formula VI- 1 can react with compounds of formula VII for which A4 is - NH2 or -NHE, E being an amino protecting group, via a reductive amination reaction, to generate compounds of formula 1-1 for which L2 is -(CH2)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 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. Fleming, Eds; Pergamon Press: New York (1991), vol. 8, p. 25-78) or through hydrogenation over a noble metal catalyst such as palladium on activated carbon. The reaction is usually carried out between -10 °C and 110 °C, preferably between 0 °C and 60 °C. The reaction can also be carried out in one pot. It can also be performed in protic solvents such as methanol or water in presence of a picoline-borane complex (Tetrahedron, 2004, 60, 7899).
In certain cases, 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 derivative is further reduced into its corresponding alcohol. 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. Alternatively, 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; 2nd Edition, R. C. Larock, Wiley- VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1999. Section aldehydes and ketones, p.1235- 1236 and 1238-1246.
When Y2 is -COOH, compounds of formula VI- 1 can react with compounds of formula VII for which A4 is - NH2 or -NHE, E being an amino protecting group, via a peptidic coupling reaction, to generate compounds of formula 1-1 wherein L2 is -(CH2)0-C(0)-. 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. Other suitable coupling agents may be utilized such as, 0-(7-azabenzotriazol- 1 -yl)-N,NN',N'-tetramethyluronium hexafluorophosphate, 2-ethoxy- 1 - ethoxycarbonyl-l,2-dihydroquinoline, carbonyldiimidazole or diethylphosphorylcyanide. Optionally, 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. Alternatively, 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 compound of formula VII in an aprotic solvent like dichloromethane, chloroform, acetonitrile, NN-dimethylformamide and tetrahydrofuran to generate compound of formula 1-1. Optionally, a base like triethylamine, NN-diisopropylethylamine, pyridine, sodium hydroxide, sodium carbonate, potassium carbonate can be added to perform the coupling.
Alternatively, when Y2 is -NH-PG2, PG2 being an amino protecting group, the protecting group can first be removed under standard conditions as previously described above
The corresponding free amine can then react with a compound of formula VII for which A4 is -CH2-X or - CHO via a substitution or a reductive amination, respectively, to generate a compound of formula 1-1 wherein L2 is -(CH2)0-.
The corresponding free amine can also react with a compound of formula VII for which A4 is -COOH via a peptidic coupling, to generate a compound of formula 1-1 wherein L2 is -(CH2)0-.
Alternatively, the amino protecting group PG2 can also be removed only after the substitution, the reductive amination or the peptidic coupling reactions, following standard procedure described above.
For the generation of compounds of formula 1-1 for which L2 is -(CH2)0-, compounds of formula VI- 1 wherein Y2 is a hydroxyl group, can be converted to the corresponding halide, mesylate, tosylate or triflate compound and react with compounds of formula VII for which A4 is -NH2 or -NHE, E being an amino protecting group, via a substitution reaction as previously described above.
In addition and following substitution reaction conditions described above, compounds of formula 1-1 for which L2 is -(CH2)0-0-(CH2)q- can be obtained by reacting compounds of formula VI- 1 wherein Y2 is a hydroxyl group with compounds of formula VII for which A4 is -(CH2)q -X, X being a halogen atom or a leaving group and q being comprised between 1 and 4.
In Scheme 1, the amino protecting groups PGl, PG2 and E can be removed at any convenient step of the process.
The compounds of formula I wherein LI is -0-(CH2)n- with n being 0, 1 or 2 (within the limits defined by the claims), can be obtained as summarized in Scheme 2.
VI II IX IV-2
R'4-X (V)
Figure imgf000067_0002
1-2 VI -2
Scheme 2.
In Scheme 2, all the symbols have the same meanings as previously described in process (b). Compounds of formula IV-2 can be obtained via a substitution reaction between compounds of formula VIII for which -A1-PG1 is -OH, with compounds of formula IX for which Y is a halogen atom or a leaving group, following procedures previously described above in Scheme 1. Alternatively, compounds of formula IV-2 can be obtained from compounds of formula VIII wherein -Al- 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. Further conversion of compounds of formula IV-2 into compounds of formula 1-2 is performed following methods described above in Scheme 1 for the preparation of compounds of formula 1-1.
In Scheme 2, the amino protecting groups PGl, PG2 and E can be removed at any convenient step of the process.
The compounds of formula I wherein LI is -CH=CH-(CH2)m- (double bond Z, E or Z/E) or -(CH2)m+2-, with m being 0 or 1, can be obtained as summarized in Scheme 3.
Figure imgf000068_0001
11-2 X IV-3
R'4-X (V)
Figure imgf000068_0002
VI-3
ASC-A4 (VII)
Figure imgf000068_0003
Scheme 3.
In Scheme 3, all the symbols have the same meanings as previously described in process (c). Compounds of formula IV-3 wherein LI is -CH=CH-(CH2)m- (double bond Z, E or Z/E), with m being 0 or 1, can be obtained via a Wittig or Horner- Wadsworth-Emmons reaction between compounds of formula II-2 for which Y is a phosphonium salt or a phosphonate and compounds of formula X.
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. To form the Wittig reagent (benzyl ylide), the phosphonium salt is suspended in a solvent such as diethyl ether or tetrahydrofuran and a strong base such as n-butyl lithium is added. With simple ylides, 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.
Alternatively 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 tetrahydrofuran, between 0 °C and 50 °C. In contrast to phosphonium ylides used in the Wittig reaction, phosphonate-stabilized carbanions are more nucleophilic and more basic. Diethyl benzylphosphonates can be easily prepared from readily available benzyl halides.
Further conversion of compounds of formula IV-3 into compounds of formula 1-3 is performed following methods described above in Scheme 1 for the preparation of compounds of formula 1-1.
Compounds of formulae IV-3, VI-3 and 1-3 for which LI is -CH=CH-(CH2)m- (double bond Z, E or Z/E), with m being 0 or 1, can also be converted into compounds of formulae IV-3, VI-3 and 1-4, respectively, for which LI is or -(CH2)m+2- via hydrogenolysis over a noble metal catalyst (palladium or palladium hydroxide on activated carbon; Chem. Eur. J., 1999, 5, 1055).
In Scheme 3, the amino protecting groups PG1, PG2 and E can be removed at any convenient step of the process. Unless otherwise stated the required starting compounds of formula II, III, V, VII to X are prepared following or adapting procedures described in the scientific literature.
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 μηι, 100 A, 250 x 21.1 mm column. Alternatively, 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. Alternatively 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.
The invention will now be described by way of non- limiting examples.
Examples
Particular embodiments of the invention are described in the following Examples, which serve to illustrate the invention in more detail: All reagents and solvents are generally used as received from the commercial supplier;
reactions are routinely performed with anhydrous solvents in well-dried glassware under argon or nitrogen atmosphere;
evaporations are carried out by rotary evaporation under reduced pressure and work-up procedures are carried out after removal of residual solids by filtration;
all temperatures are given in °C; unless otherwise noted, operations are carried out at room temperature, that is typically in the range 18-25°C;
column chromatography (by the flash procedure) is used to purify compounds and is performed using Merck silica gel 60 (70-230 mesh ASTM) unless otherwise stated;
in general, the course of reactions is followed by TLC, HPLC, or LC/MS and reaction times are given for illustration only; yields are given for illustration only and are not necessarily the maximum attainable;
the structure of the final products of the invention is generally confirmed by NMR, HPLC and mass spectral techniques.
HPLC of final products are generated using a Dionex Ultimate 3000 instrument and the following conditions:
Mobile Phase A: 50 mM Ammonium acetate aqueous solution
Mobile Phase B: Acetonitrile
Column: YMC Triart C18 5μιη 12 nm 100x4.6 mm
Column Temperature: 50°C
Detection: UV 250 nm
Injection: 2 μΕ of 20 mM sample DMSO solution
Flow: 1.6 mL/min Gradient for Method 1 Time (min) %Mobile Phase B
0 5
8 95
10 95
3 min equilibration
Gradient for Method 2 Time (min) %Mobile Phase B
0 5
18 95
20 95
3 min equilibration
Proton NMR spectra are recorded on a Brucker 400 MHz spectrometer. Chemical shifts (δ) are reported in ppm relative to Me4Si as internal standard, and J values are in Hertz (Hz). Each peak is denoted as a broad singlet (br), singlet (s), doublet (d), triplet (t), quadruplet (q), doublet of doublets (dd), triplet of doublets (td) or multiplet (m).
Mass spectra are generated using a q-Tof Ultima (Waters AG) mass spectrometer in the positive ESI mode. The system is equipped with the standard Lockspray interface;
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;
analytical and preparative HPLC on non-chiral phases are performed using RP-C18 based columns;
the following abbreviations may be used:
CDCI3: Deuterated chloroform
DMSO-i 6: Deuterated dimethyl sulphoxide
D20: Deuterated water
ELSD: Evaporative light scattering detection
ESI: Electrospray ionization
HPLC: High performance liquid chromatography
J: Coupling constant
LC/MS: Liquid chromatography coupled to mass spectroscopy
Me4Si: Tetramethylsilane
MS: Mass spectroscopy
NMR: Nuclear magnetic resonance
TLC: Thin layer chromatography
The following Examples refer to the compounds of formula I as indicated in Table 1 : Table 1 : Exemplified compounds
The Examples listed in the following table can be prepared using procedures described above, and detailed synthesis methodology is described in detail below. The Example numbers used in the leftmost column are used in the whole application text for identifying the respective compounds.
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Example 1 : Ν'- [3- \4-(l -methyl-l-phenyl-ethyl)phenoxyl propyll ethane-l,2-diamine :
Preparation of 3-[4-(l -methyl- 1 -phenyl-ethyl)phenoxy]propan- 1 - ol:
Cesium carbonate (5.53 g, 16.96 mmol, 1.2 eq) is added at room temperature to a stirred solution of 4-(l- methyl-1 -phenyl- ethyl)phenol (3.0 g, 14.13 mmol, 1.0 eq) [599-64-4] and 3-bromopropan-l-ol (1.28 mL, 14.13 mmol, 1.0 eq) [627-18-9] in NN-dimethylformamide (25 mL). After 18 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3 x 50 mL) and water (50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel; petroleum ether: ethyl acetate, 10:1, v/v) to afford 3-[4- (l-methyl-l-phenyl-ethyl)phenoxy]propan-l-ol as a light yellow oil (3.90 g, 97% yield).
'H-NMR (400 MHz, DMSO-i/6) δ ppm: 7.08-7.30 (m, 7H), 6.82 (d, J= 8.7 Hz, 2H), 4.52 (t, J= 5.1 Hz, 1H), 3.99 (m, 2H), 3.55 (m, 2H), 1.84 (m, 2H), 1.61 (s, 6H). Preparation of 3-[4-(l-methyl-l-phenyl-ethyl)phenoxy]propyl methanesulfonate:
Methanesulfonyl chloride (687 μL, 8.88 mmol, 1.2 eq) [124-63-0] is added at 0°C to a stirred solution of 3- [4-(l-methyl-l -phenyl-ethyl)phenoxy]propan-l-ol (2.0 g, 7.40 mmol, 1.0 eq) and NN-diisopropylethylamine (1.94 mL, 11.10 mmol, 1.5 eq) in dichloromethane (25 mL). After 2 hours stirring at room temperature, the reaction mixture is washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to afford 3-[4-(l-methyl-l-phenyl-ethyl)phenoxy]propyl methanesulfonate as a light yellow oil (2.50g, 97% yield) that is directly engaged in the next step without further purification.
'H-NMR (400 MHz, DMSO-i/6) δ ppm: 7.10-7.30 (m, 7H), 6.85 (d, J= 8.6 Hz, 2H), 4.35 (m, 2H), 4.03 (m, 2H), 3.18 (s, 3H), 2.11 (m, 2H), 1.60 (s, 6H). Preparation of ferf-butyl N-[2-[3-[4-(l-methyl-l-phenyl-ethyl)phenoxy]propylamino]ethyl]carbamate:
Potassium carbonate (793 mg, 5.74 mmol, 2.0 eq) is added at room temperature to a stirred solution of 3-[4- (1 -methyl- 1 -phenyl- ethyl)phenoxy] propyl methanesulfonate (1.0 g, 2.87 mmol, 1.0 eq) and tert-butyl N-(2- aminoethyl)carbamate (1.36 mL, 8.61 mmol, 3.0 eq) [57260-73-8] in NN-dimethylformamide (30 mL). After 1 hour stirring at 100°C, solvent is evaporated and the residue is extracted with ethyl acetate (3 x 50 mL) and water (50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel; dichloromethane methanol, 80:1 to 50: 1, v/v) to afford tert-butyl N-[2-[3-[4-(l -methyl-l-phenyl- ethyl)phenoxy]propylamino]ethyl]carbamate as a yellow oil (350 mg, 30% yield).
MS m/z (+ESI): 413.4 [M+H]+.
Preparation of N - [3 - [4-( 1 -methyl- 1 -phenyl-ethyl)phenoxy]propyl] ethane- 1 ,2-diamine: Trifluoroacetic acid (1.0 mL, 13.06 mmol, 16.3 eq) is added at room temperature to a stirred solution of tert- butyl N-[2-[3-[4-(l -methyl-l-phenyl-ethyl)phenoxy]propylamino]ethyl]carbamate (330 mg, 0. 8 mmol, 1.0 eq) in dichloromethane (5 mL). After 2 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3 x 10 mL) and water (10 mL) and the pH is adjusted to 9 by the addition of a saturated sodium hydrogen carbonate aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is dissolved in a 2N hydrochloric acid solution in ethyl acetate (3 mL). After 2 hours stirring at room temperature, the resulting precipitate is collected by centrifugation, washed with ethyl acetate and purified by preparative HPLC to afford N- [3- [4-(l -methyl- 1 -phenyl- ethyl)phenoxy]propyl] ethane- 1,2-diamine as a white solid (195 mg, 77% yield).
Example 3: ^-[^-[(l^-dichlorophenv methoxylphenyllmethyll-^^ -dimethyl-propane-l^-diamine:
Preparation of 4-[(2,4-dichlorophenyl)methoxy]benzaldehyde:
The titled compound is prepared as a white solid (1.30 g, 90% yield) following Scheme 1 and in analogy to Example 1 using 2,4-dichloro-l-(chloromethyl)benzene (1.0 g, 5.12 mmol, 1.0 eq) [94-99-5] and 4- hydroxybenzaldehyde (625 mg, 5.12 mmol, 1.0 eq) [123-08-0] as starting materials.
'H-NMR (400 MHz, DMSO-i/6) δ ppm: 9.88 (s, 1H), 7.89 (d, J= 8.8 Hz, 2H), 7.72 (s, 1H), 7.65 (d, J= 8.4 Hz, 1H), 7.48 (d, J= 8.4 Hz, 1H), 7.23 (d, J= 8.8 Hz, 2H), 5.26 (s, 2H). Preparation of N-[[4-[(2,4-dichlorophenyl)methoxy]phenyl]methyl]-N',N'-dimethyl-propane-L3-diamine: N',N'-dimethylpropane-l,3-diamine (200 \L, 1.60 mmol, 1.5 eq) [109-55-7] is added at room temperature to a stirred solution of 4-[(2,4-dichlorophenyl)methoxy]benzaldehyde (300 mg, 1.07 mmol, 1.0 eq) in dichloromethane (7 mL), followed by one drop of acetic acid. After 30 minutes stirring at room temperature, sodium cyanoborohydride (335 mg, 5.34 mmol, 5.0 eq) is added. After 3 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3 x 20 mL) and a saturated sodium hydrogen carbonate aqueous solution (20 mL), dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford N-[[4-[(2,4-dichlorophenyl)methoxy]phenyl]methyl]-N',N'- dimethyl-propane-l,3-diamine as a white solid (136 mg, 32%> yield). Example 6: Ar-(3-aminopropyl)-4-benzyloxy-benzamide:
Preparation of ferf-butyl N-[3-[(4-benzyloxybenzoyl)amino]propyl]carbamate:
teri-Butyl N-(3-aminopropyl)carbamate (374 mg, 2.15 mmol, 1.0 eq) [75178-96-0] is added at room temperature to a stirred solution of 4-benzyloxybenzoic acid (500 mg, 2.15 mmol, 1.0 eq) [1486-51-7] in NN-dimethylformamide (10 mL), followed by N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (482 mg, 2.47 mmol, 1.15 eq), 1 -hydroxybenzotriazole (362 mg, 2.36 mmol, 1.1 eq) and NN- diisopropylethylamine (1.87 mL, 10.73 mmol, 5.0 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3 x 20 mL) and water (20 mL). The combined organic layers are washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel; dichloromethane:methanol, 9: 1, v/v) to afford teri-butyl N-[3-[(4-benzyloxybenzoyl)amino]propyl]carbamate as a white solid (700 mg, 80% yield).
MS m/z (+ESI): 385.4 [M+H]+.
Preparation of N-(3-aminopropyl)-4-benzyloxy-benzamide:
The titled compound is prepared as a white solid (294 mg, 57% yield) following Scheme 1 and in analogy to Example 1 using teri-butyl N-[3-[(4-benzyloxybenzoyl)amino]propyl]carbamate (700 mg, 1.73 mmol, 1.0 eq) as starting material.
Example 10 : N'JV -dimethy V- [ [4-(l-methyl-l-phenyl-ethyl)phenyll methyll ethane-l,2-diamine : Preparation of 4-(l-methyl-l -phenyl-ethyl)benzaldehyde:Hexamethylenetetramine (350 mg, 2.55 mmol, 1.0 eq) is added at room temperature to a stirred solution of (l-methyl-l -phenyl-ethyl)benzene (500 mg, 2.55 mmol, 1.0 eq) [778-22-3] in trifluoroacetic acid (20 mL). After 15 hours stirring under reflux conditions, the reaction mixture is diluted with ethyl acetate (200 mL), washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel; petroleum ether:ethyl acetate, 10:1, v/v) to afford 4-(l-methyl-l-phenyl-ethyl)benzaldehyde as a colorless oil (470 mg, 82% yield).
'H-NMR (400 MHz, CDC13) δ ppm: 9.99 (s, 1H), 7.20-7.80 (m, 9H), 1.69 (s, 6H).
Preparation of N',N'-dimethyl-N-[[4-(l-methyl-l -phenyl-ethyl)phenyllmethyllethane-L2-diamine:
N',N'-dimethylethane-l,2-diamine (120 mg, 1.34 mmol, 1.0 eq) [108-00-9] is added at room temperature to a stirred solution of 4-(l-methyl-l-phenyl-ethyl)benzaldehyde (300 mg, 1.34 mmol, 1.0 eq) in dichloromethane (10 mL) and methanol (1 mL), followed by one drop of acetic acid. After 30 minutes stirring at room temperature, sodium triacetoxyborohydride (600 mg, 2.68 mmol, 2.0 eq) is added. After 12 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3 x 30 mL) and a saturated sodium hydrogen carbonate aqueous solution (30 mL), dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford N',N'-dimethyl-N-[[4-(l-methyl- l-phenyl-ethyl)phenyl]methyl]ethane-l,2-diamine as a white solid (70 mg, 18%> yield).
Example 12 : N- \ [3- [(2-bromo-4-chloro-phenoxy)methyll phenyll methyll -N'JV -dimethyl-butane-1,4- diamine: Preparation of 3-[(2-bromo-4-chloro-phenoxy)methyl]benzonitrile:
The titled compound is prepared as a white solid (12.1 g, 78% yield) following Scheme 2 and in analogy to Example 1 using 2-bromo-4-chloro-phenol (10.0 g, 48.2 mmol, 1.0 eq) [695-96-5] and 3- (bromomethyl)benzonitrile (9.45 g, 48.2 mmol, 1.0 eq) [28188-41-2] as starting materials.
'H-NMR (400 MHz, CDC13) δ ppm: 7.79 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.60 (d, J= 2.5 Hz, 1H), 7.53 (m, 1H), 7.25 (dd, J= 2.5 Hz, 8.8 Hz, 1H), 6.85 (d, J= 8.8 Hz, 1H), 5.15 (s, 2H).
Preparation of 3-[(2-bromo-4-chloro-phenoxy)methyl]benzaldehyde:
Diisobutylaluminium 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 4 hours stirring at 0°C, the reaction mixture is poured in a 2N hydrochloric acid aqueous solution (150 mL). The phases are separated and the aqueous phase is extracted with ethyl acetate (3 x 150 mL). The combined organic layers are washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel; petroleum ether:ethyl acetate, 10: 1, v/v) to afford 3-[(2-bromo-4-chloro-phenoxy)methyl]benzaldehyde as a white solid (3.30 g, 82% yield).
'H-NMR (400 MHz, CDC13) δ ppm: 10.07 (s, 1H), 7.99 (s, 1H), 7.88 (d, J= 8.0 Hz, 1H), 7.78 (d, J= 8.0 Hz, 1H), 7.60 (m, 2H), 7.25 (dd, J= 2.8 Hz, 8.8 Hz, 1H), 6.88 (d, J= 8.8 Hz, 1H), 5.22 (s, 2H). Preparation of N-[[3-[(2-bromo-4-chloro-phenoxy)methyl]phenyl]methyl]-N',N'-dimethyl-butane-L4- diamine:
The titled compound is prepared as a white solid (85 mg, 22%> yield) following Scheme 2 and in analogy to Example 10 using 3-[(2-bromo-4-chloro-phenoxy)methyl]benzaldehyde (300 mg, 0.92 mmol, 1.0 eq) and N,N'-dimethylbutane-l,4-diamine (130 mg, 1.11 mmol, 1.2 eq) [3529-10-0] as starting materials.
Example 17: N'- \2- \ [3- [(E)-2-(2-bromo-4-chloro-phenyl)vinyll phenyll methylaminol ethyll ethane-1,2- diamine:
Preparation of 2-bromo-4-chloro- 1 -(diethoxyphosphorylmethyl)benzene:
Triethyl phosphite (30.03 mL, 175.82 mmol, 5.0 eq) is added at room temperature to a stirred solution of 2- bromo-l-(bromomethyl)-4-chloro-benzene (10.0 g, 35.16 mmol, 1.0 eq) [33924-45-7] in toluene (100 mL).
After 4 hours stirring under reflux conditions, solvent is evaporated and the residue is purified by column chromatography (silica gel; petroleum ether:ethyl acetate, 10:1 to 1 : 1, v/v) to afford 2-bromo-4-chloro-l-
(diethoxyphosphorylmethyl)benzene as a light yellow oil (12.0 g, 85%> yield).
'H-NMR (400 MHz, DMSO-i/6) δ ppm: 7.75 (s, 1H), 7.44 (m, 2H), 4.97 (m, 4H), 3.39 (m, 2H), 1.19 (m,
6H). MS m/z (+ESI): 341.0 [M+H]
Preparation of 3-r(£' -2-(2-bromo-4-chloro-phenyl vinyllbenzonitrile:
Sodium hydride (23 mg, 0.59 mmol, 2.0 eq) is added at 0°C to a stirred solution of 2-bromo-4-chloro-l- (diethoxyphosphorylmethyl)benzene (100 mg, 0.29 mmol, 1.0 eq) in tetrahydrofuran (4 mL), followed by 3- formylbenzonitrile (42 mg, 0.32 mmol, 1.1 eq) [24964-64-5]. After 16 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3 x 15 mL) and water (15 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel; petroleum ether:ethyl acetate, 20: 1, v/v) to afford 3-[(£')-2-(2-bromo-4-chloro-phenyl)vinyl]benzonitrile as a white solid (70 mg, 75% yield).
'H-NMR (400 MHz, DMSO-i/6) δ ppm: 8.10 (s, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.84 (d, J= 8.4 Hz, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.77 (d, J= 7.6 Hz, 1H), 7.60 (dd, J= 7.6 Hz, 8.4 Hz, 1H), 7.52 (dd, J= 1.6 Hz, 8.4 Hz, 1H), 7.46 (d, J= 16.4 Hz, 1H), 7.31 (d, J= 16.4 Hz, 1H). Preparation of N - [2- [[3 - [(E)-2-(2-bromo-4-chloro-phenyl)vinyl]phenyl] methylamino] ethyl] ethane- 1,2- diamine:
The titled compound is prepared as a white solid following Scheme 3 and in analogy to Examples 1, 10 and 12 using 3-[(£')-2-(2-bromo-4-chloro-phenyl)vinyl]benzonitrile and tert-butyl N-(2-aminoethyl)-N-[2-(tert- butoxycarbonylamino)ethyl]carbamate [120131-72-8] as starting materials.
Example 19 : (2S)-2,5-diammo-N- [ [3- [(2-bromo-4-chloro-phenyl)methoxyl phenyll methyllpentanamide :
Preparation of 3-[(2-bromo-4-chloro-phenyl)methoxy]benzaldehyde:
The titled compound is prepared as a white solid (1.28 g, 97% yield) following Scheme 1 and in analogy to Example 1 using 2-bromo-l-(bromomethyl)-4-chloro-benzene (1.24 g, 4.37 mmol, 1.1 eq) [33924-45-7] and 3-hydroxybenzaldehyde (500 mg, 3.97 mmol, 1.0 eq) [100-83-4] as starting materials.
'Η-ΝΜΡ (400 MHz, DMSO-i/6) δ ppm: 10.0 (s, 1H), 7.86 (d, J= 2.1 Hz, 1H), 7.65 (d, J= 8.3 Hz, 1H), 7.56 (m, 4H), 7.39 (m, 1H), 5.21 (s, 2H). Preparation of [3-[(2-bromo-4-chloro-phenyl)methoxy]phenyl]methanol:
Sodium borohydride (70 mg, 1.80 mmol, 2.0 eq) is added at 0°C to a stirred solution of 3-[(2-bromo-4- chloro-phenyl)methoxy]benzaldehyde (300 mg, 0.90 mmol, 1.0 eq) in tetrahydrofuran (10 mL). After 2 hours stirring at 0°C, a saturated ammonium chloride aqueous solution is cautiously added and the resulting mixture is extracted with dichloromethane (3 x 30 mL) and water (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel; cyclohexane:ethyl acetate, 3: 1, v/v) to afford [3-[(2-bromo-4-chloro- phenyl)methoxy]phenyl]methanol as a white solid (230 mg, 77% yield).
'H-NMR (400 MHz, DMSO-i/6) δ ppm: 7.84 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.53 (dd, J = 2.1 Hz, 8.3 Hz, 1H), 7.27 (t, J= 7.8 Hz, 1H), 7.00 (dd, J= 1.4 Hz, 2.6 Hz, 1H), 6.94 (m, 1H), 6.88 (m, 1H), 5.21 (t, J= 5.8 Hz, 1H), 5.11 (s, 2H), 4.49 (d, J= 5.6 Hz, 2H).
Preparation of 2-[[3-r(2-bromo-4-chloro-phenyl)methoxylphenyllmethyllisoindoline-l,3-dione:
Diisopropyl azodicarboxylate (90 L, 0.45 mmol, 1.5 eq) is added at room temperature to a stirred solution of [3-[(2-bromo-4-chloro-phenyl)methoxy]phenyl]methanol (100 mg, 0.30 mmol, 1.0 eq), triphenylphosphine (118 mg, 0.45 mmol, 1.5 eq) and phthalimide (70 mg, 0.45 mmol, 1.5 eq) [85-41-6] in tetrahydrofuran (5 mL). After 1 hour stirring at room temperature, the reaction mixture is extracted with dichloromethane (3 x 20 mL) and water (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel; cyclohexane:ethyl acetate, 4: 1, v/v) to afford 2-[[3-[(2-bromo-4-chloro- phenyl)methoxy]phenyl]methyl]isoindoline-l,3-dione as a white solid (80 mg, 57% yield).
'H-NMR (400 MHz, DMSO-i/6) δ ppm: 7.90 (m, 4H), 7.77 (d, J = 2.1 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.48 (dd, J= 2.1 Hz, 8.3 Hz, 1H), 7.28 (t, J= 8.0 Hz, 1H), 6.92 (m, 3H), 5.09 (s, 2H), 4.76 (s, 2H).
Preparation of [3-[(2-bromo-4-chloro-phenyl)methoxylphenyl]methanamine:
Hydrazine monohydrate (1 mL, 20.57 mmol, 136.0 eq) is added at room temperature to a stirred suspension of 2-[[3-[(2-bromo-4-chloro-phenyl)methoxy]phenyl]methyl]isoindoline-l,3-dione (70 mg, 0.15 mmol, 1.0 eq) in methanol (2 mL). After 3 hours stirring under reflux conditions, the reaction mixture is extracted with dichloromethane (3 x 10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel; cyclohexane: ethyl acetate, 4: 1, v/v) to afford [3-[(2-bromo-4-chloro-phenyl)methoxy]phenyl]methanamine as an off-white solid (30 mg, 62%> yield).
'H-NMR (400 MHz, DMSO-i/6) δ ppm: 7.84 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.53 (dd, J = 2.1 Hz, 8.3 Hz, 1H), 7.27 (t, J= 7.9 Hz, 1H), 7.09 (dd, J= 1.5 Hz, 2.5 Hz, 1H), 6.98 (m, 1H), 6.90 (m, 1H), 5.11 (s, 2H), 3.84 (br, 2H), 3.78 (s, 2H).
Preparation of (2S)-2,5-diamino-N-[[3-r(2-bromo-4-chloro-phenyl)methoxylphenyllmethyllpentanamide: The titled compound is prepared as a white solid following Scheme 1 and in analogy to Examples 1 and 6 using [3-[(2-bromo-4-chloro-phenyl)methoxy]phenyl]methanamine and (2S)-2,5-bis(tert- butoxycarbonylamino)pentanoic acid [57133-29-6] as starting materials. Example 25: ^-[ -fCZ/^-S-ri-bromo^-chloro-phenv allyll-S-chloro-phenyllmethyll-^^'-dimethyl- ethane-l,2-diamine:
Preparation of (2-bromo-4-chloro-phenyl methyl-triphenyl-phosphonium:
A mixture of 2-bromo-l-(bromomethyl)-4-chloro-benzene (500 mg, 1.76 mmol, 1.0 eq) [33924-45-7] and triphenylphosphine (461 mg, 1.76 mmol, 1.0 eq) in xylene (10 mL) is heated under reflux conditions at 140°C for 5 hours. The resulting precipitate is collected by filtration and washed with diethyl ether to afford (2-bromo-4-chloro-phenyl)methyl-triphenyl-phosphonium as a white solid (900 mg, 94% yield) that is directly engaged in the next step without further purification.
Preparation of methyl 3-chloro-5-(2-oxoethyl)benzoate:
Lithium diisopropylamide (1M solution in n-hexane, 2.32 mL, 2.32 mmol, 1.3 eq) is added dropwise at 0°C to a stirred solution of (methoxymethyl)triphenylphosphonium chloride (800 mg, 2.42 mmol, 1.2 eq) [4009- 98-7] in tetrahydrofuran (60 mL). After 1 hour stirring at room temperature a solution of methyl 3-chloro-5- formyl-benzoate (400 mg, 2.01 mmol, 1.0 eq) [879542-48-0] in tetrahydrofuran (60 mL) is added at room temperature to the reaction mixture. After 1 hour stirring at room temperature, a saturated ammonium chloride aqueous solution (30 mL) is added to quench the reaction. The resulting mixture is extracted with ethyl acetate (3 x 50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a yellow solid that is dissolved in tetrahydrofuran (2 mL) and a 12N hydrochloric acid aqueous solution (0.8 mL). After 1 hour stirring at room temperature, the reaction mixture is extracted with ethyl acetate (3 x 10 mL) and water (10 mL). The combined organic layers are washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel; petroleum ether:ethyl acetate, 4: 1, v/v) to afford methyl 3-chloro-5-(2- oxoethyl)benzoate as a light yellow solid (150 mg, 35% yield).
'H-NMR (400 MHz, CDC13) δ ppm: 9.80 (t, J= 1.6 Hz, 1H), 7.98 (s, 1H), 7.81 (s, 1H), 7.43 (s, 1H), 3.94 (s, 3H), 7.38 (d, J= 1.6 Hz, 2H).
Preparation of methyl 3-[(Z/£')-3-(2-bromo-4-chloro-phenyl)allyl]-5-chloro-benzoate:
Silver(I) oxide (92 mg, 0.39 mmol, 1.4 eq) is added at room temperature to a stirred solution of (2-bromo-4- chloro-phenyl)methyl-triphenyl-phosphonium (170 mg, 0.31 mmol, 1.1 eq) and methyl 3-chloro-5-(2- oxoethyl)benzoate (60 mg, 0.28 mmol, 1.0 eq) in dioxane (10 mL). After 30 minutes stirring at 60°C, the reaction mixture is filtered and the filtrate is concentrated to give a residue that is purified by column chromatography (silica gel; petroleum ether:ethyl acetate, 8: 1, v/v) to afford methyl 3-[(Z/£")-3-(2-bromo-4- chloro-phenyl)allyl]-5-chloro-benzoate as a light yellow oil (52 mg, 46%> yield, ratio Z/E = 1/0.5). 'H-NMR (400 MHz, CDC13) δ ppm: 7.15-7.90 (m, 3H + 6H), 6.77 (d, J= 15.2 Hz, 0.5H), 6.60 (d, J= 11.2 Hz, 1H), 6.22 (td, J= 7.2 Hz, 15.2 Hz, 0.5H), 5.95 (td, J= 7.6 Hz, 11.2 Hz, 1H), 3.96 (s, 1.5H + 3H), 3.61 (d, J= 7.2 Hz, 1H), 3.50 (d, J= 7.6 Hz, 2H) Preparation of [3-r(Z/£' -3-(2-bromo-4-chloro-phenyl allyll-5-chloro-phenyllmethanol:
Diisobutylaluminium hydride (1M solution in n-hexane, 2.81 mL, 2.81 mmol, 2.5 eq) is added dropwise at 0°C to a stirred solution of methyl 3-[(Z/£')-3-(2-bromo-4-chloro-phenyl)allyl]-5-chloro-benzoate (450 mg, 1.12 mmol, 1.0 eq) in dichloromethane (30 mL). After 2 hours stirring at 0°C, the reaction mixture is quenched with a 2N hydrochloric acid aqueous solution (5 mL). The resulting mixture is extracted with dichloromethane (3 x 20 mL) and water (10 mL). The combined organic layers are washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford [3-[(Z/£")-3-(2-bromo-4-chloro- phenyl)allyl]-5-chloro-phenyl]methanol as a light yellow oil (360 mg, 86% yield, ratio Z/E = 1/1.2).
'H-NMR (400 MHz, CDCI3) δ ppm: 7.62 (s, 1H), 7.55 (s, 1.2H), 7.40 (d, J= 8.4 Hz, 1.2H), 7.02-7.30 (m, 4.8H + 5H), 6.75 (d, J= 15.6 Hz, 1.2H), 6.56 (d, J= 11.2 Hz, 1H), 6.22 (td, J= 7.2 Hz, 15.6 Hz, 1.2H), 5.95 (td, J= 7.2 Hz, 11.2 Hz, 1H), 4.66 (m, 2.4H + 2H), 3.55 (d, J= 7.2 Hz, 2.4H), 3.45 (d, J= 7.2 Hz, 2H).
Preparation of 3-r(Z/£')-3-(2-bromo-4-chloro-phenyl)allyll-5-chloro-benzaldehyde:
Pyridinium chlorochromate (33 mg, 0.15 mmol, 1.2 eq) is added at room temperature to a stirred solution of [3-[(Z/£')-3-(2-bromo-4-chloro-phenyl)allyl]-5-chloro-phenyl]methanol (50 mg, 0.13 mmol, 1.0 eq) in dichloromethane (3 mL). After 2 hours stirring at room temperature, the reaction mixture is filtered and concentrated to give a residue that is purified by column chromatography (silica gel; petroleum ether:ethyl acetate, 6: 1, v/v) to afford 3-[(Z/£')-3-(2-bromo-4-chloro-phenyl)allyl]-5-chloro-benzaldehyde as a light yellow oil (31 mg, 62% yield, ratio Z/E = 0.9/1).
'H-NMR (400 MHz, CDCI3) δ ppm: 9.98 (s, 1H), 9.96 (s, 0.9H), 7.75 (m, 1H + 0.9H), 7.66 (m, 1H + 0.9H), 7.58 (m, 1H + 0.9H), 7.52 (s, 1H), 7.43 (m, 2H), 7.22-7.32 (m, 1.8H), 7.20 (d, J= 8.4 Hz, 0.9H), 6.81 (d, J = 15.6 Hz, 1H), 6.64 (d, J = 11.2 Hz, 0.9H), 6.25 (td, J = 6.8 Hz, 15.6 Hz, 1H), 5.96 (td, J = 7.6 Hz, 1 1.2 Hz, 0.9H), 3.67 (d, J= 6.8 Hz, 2H), 3.56 (d, J= 7.6 Hz, 1.8H).
Preparation of N- [[3 - \(Z/E)- -(2-bromo-4-chloro-phenyl)allyll -5-chloro-phenyllmethyll -N',N'-dimethyl- ethane- 1 ,2-diamine:
The titled compound is prepared as a white solid (98 mg, 31%> yield, ratio Z/E = 1/1) following Scheme 3 and in analogy to Example 10 using 3-[(Z/£')-3-(2-bromo-4-chloro-phenyl)allyl]-5-chloro-benzaldehyde (261 mg, 0.70 mmol, 1.0 eq) and N,N'-dimethylethane-l,2-diamine (93 mg, 1.06 mmol, 1.5 eq) [108-00-9] as starting materials. Example 29: Ar-[[3-[(Z/£)-3-(2-bromo-4-chloro-phenyl)allyll-5-(trifluoromethyl)phenyllmethyll-Arf,Arf- dimethyl-ethane-l,2-diamine:
Preparation of methyl 3-allyl-5-(trifluoromethyl)benzoate:
Tetrakis(triphenylphosphine)palladium(0) (816 mg, 0.71 mmol, 0.2 eq) is added at room temperature to a stirred solution of methyl 3-bromo-5-(trifluoromethyl)benzoate (1.0 g, 3.53 mmol, 1.0 eq) [187331-46-0] in NN-dimethylformamide (150 mL), followed by lithium chloride (449 mg, 10.6 mmol, 3.0 eq) and allyltributyltin (2.19 mL, 7.06 mmol, 2.0 eq) [24850-33-7]. After 3 hours stirring at 100°C, a solution of potassium fluoride (821 mg, 14.13 mmol, 4.0 eq) in water (100 mL) is added and the resulting mixture is stirred at room temperature for 30 minutes before extraction with ethyl acetate (3 x 200 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel; petroleum ether:ethyl acetate, 8: 1, v/v) to afford methyl 3-allyl-5-(trifluoromethyl)benzoate as a light yellow oil (863 mg, 99% yield).
'H-NMR (400 MHz, CDC13) δ ppm: 8.14 (s, 1H), 8.05 (s, 1H), 7.63 (s, 1H), 5.95 (m, 1H), 5.15 (m, 2H), 3.95 (s, 3H), 3.50 (m, 2H).
Preparation of methyl 3-(2-oxoethyl)-5-(trifluoromethyl)benzoate:
Ozone is bubbling at -78°C into a solution of 3-allyl-5-(trifluoromethyl)benzoate (660 mg, 2.7 mmol, 1.0 eq) in dichloromethane (60 mL) until a pale blue color appears. Then oxygen is bubbling to remove ozone excess. Methylsulfanylmethane (4.8 g, 13.5 mmol, 5.0 eq) is then added at room temperature to the reaction mixture and after 30 minutes stirring at room temperature, solvent is removed to afford methyl 3-(2- oxoethyl)-5-(trifluoromethyl)benzoate as a light yellow oil (640 mg, 96% yield) that is directly engaged in the next step without further purification. Preparation of N- [[3 - \(Z/E)- -(2-bromo-4-chloro-phenyl)allyl] -5-(trifluoromethyl)phenyl]methyl] -Ν',Ν'- dimethyl- ethane- 1 ,2-diamine:
The titled compound is prepared as a white solid (ratio Z/E = 1/1) following Scheme 3 and in analogy to Examples 10 and 25 using methyl 3-(2-oxoethyl)-5-(trifluoromethyl)benzoate and (2-bromo-4-chloro- phenyl)methyl-triphenyl-phosphonium as starting materials.
Example 48 : (2S)-N- \ [3-allyloxy-5- [(2-bromo-4-chloro-phenyl)methoxyl phenyll methyll -2,4-diamino- butanamide:
Preparation of [3-allyloxy-5-[(2-bromo-4-chloro-phenyl)methoxy]phenyl]methanamine: The titled compound is prepared as a white solid following Scheme 1 and in analogy to Examples 1 , 19 and 25 using methyl 3,5-dihydroxybenzoate [2150-44-9], allylbromide [106-35-6] and 2-bromo-l -(bromomethyl)-4- chloro-benzene [33924-45-7] as starting materials. Preparation of ferf-butyl N-[(3S)-4-[[3-allyloxy-5-[(2-bromo-4-chloro- phenly methoxy]phenyl]methylamino]-3-(fer?-butoxycarbonylamino -4-oxo-butyl]carbamate:
(2S)-2,4-^z,y(tert-butoxycarbonylamino)butanoic acid (333 mg, 1.04 mmol, 1.0 eq) [34404-27-8] is added at room temperature to a stirred solution of [3-allyloxy-5-[(2-bromo-4-chloro- phenyl)methoxy]phenyl]methanamine (400 mg, 1.04 mmol, 1.0 eq) in ethyl acetate (10 mL), followed by 4- (4,6-dimethoxy-l ,3,5-triazin-2-yl)-4-methylmorpholinium chloride (434 mg, 1.57 mmol, 1.5 eq). After 15 hours stirring at room temperature, solvent is removed to give a residue that purified by column chromatography (silica gel; petroleum ether:ethyl acetate, 1 : 1 , v/v) to afford teri-butyl N-[(3S)-4-[[3- allyloxy-5-[(2-bromo-4-chloro-phenly)methoxy]phenyl]methylamino]-3-(ter/-butoxycarbonylamino)-4-oxo- butyl]carbamate as a colorless gum (610 mg, 85% yield).
'H-NMR (400 MHz, DMSO-i/6) δ ppm: 8.24 (m, 1H), 7.81 (d, J= 2.0 Hz, 1H), 7.57 (m, 1H), 7.50 (m, 1H), 6.95 (m, 1H), 6.72 (m, 1H), 6.48 (m, 3H), 5.99 (m, 1H), 5.37 (m, 1H), 5.23 (m, 1H), 5.05 (s, 2H), 4.51 (m, 2H), 4.22 (m, 2H), 3.97 (m, 1H), 2.95 (m, 2H), 1.75 (m, 1H), 1.60 (m, 1H), 1.36 (m, 18H).
MS m/z (+ESI): 682.1 , 684.2 [M+H]+. Preparation of (2S)-N-[[3-allyloxy-5-[(2-bromo-4-chloro-phenyl)methoxy]phenyl]methyl]-2^-diamino- butanamide:
The titled compound is prepared as a white solid (150 mg, 40% yield) following Scheme 1 and in analogy to Example 1 using fe^butyl N-^iS^-fP-allyloxy-S-^-bromo^-chloro- phen^methoxyJphenylJmethylaminoJ-S-^e^butoxycarbonylamn^^ (500 mg, 0.73 mmol, 1.0 eq) as starting material.
Example 50 : (2S)-N- \ [3-allyloxy-5- [ E)-2-(2-bromo-4-chloro-phenyl)vinyll phenyll methyll-2,4-diamino- butanamide: Preparation of dimethyl 5-allyloxybenzene-l ,3-dicarboxylate:
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
(1.0 g, 4.66 mmol, 1.0 eq) [13036-02-7] and allyl bromide (620 mg, 5.13 mmol, 1.1 eq) [106-95-6] as starting materials.
'H-NMR (400 MHz, CDC13) δ ppm: 8.30 (d, J = 1.6 Hz, 1H), 7.79 (d, J = 1.6 Hz, 2H), 6.07 (m, 1H), 5.46 (m, 1H), 5.35 (m, 1H), 4.65 (m, 2H), 3.96 (s, 6H). MS m/z (+ESI): 251.1 [M+H]
Preparation of [3-allyloxy-5-(hydroxymethyl)phenyl1methanol:
Lithium aluminium hydride (310 mg, 8.27 mmol, 3.0 eq) is added at 0°C to a stirred solution of dimethyl 5- allyloxybenzene-l,3-dicarboxylate (690 mg, 2.76 mmol, 1.0 eq) in tetrahydrofuran (15 mL). After 2 hours stirring at 0°C, the reaction mixture is quenched with brine (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford [3- allyloxy-5-(hydroxymethyl)phenyl]methanol as a colorless oil (490 mg, 91% yield) that is directly engaged in the next step without further purification.
'H-NMR (400 MHz, CDC13) δ ppm: 6.75-6.95 (m, 3H), 6.05 (m, IH), 5.42 (m, IH), 5.30 (m, IH), 4.50-4.70 (m, 6H).
MS m/z (+ESI): 195.2 [M-iBu+H]+.
Preparation of 3-allyloxy-5-(hydroxymethyl)benzaldehyde:
Manganese dioxide (45 mg, 0.51 mmol, 1.0 eq) is added at room temperature to a stirred solution of [3- allyloxy-5-(hydroxymethyl)phenyl]methanol (100 mg, 0.51 mmol, 1.0 eq) in tetrahydrofuran (10 mL). After 16 hours stirring at 40°C, manganese dioxide is removed by filtration and the solution is evaporated to give a residue that is purified by column chromatography (silica gel; petroleum ethenethyl acetate, 2: 1, v/v) to afford 3-allyloxy-5-(hydroxymethyl)benzaldehyde as a colorless oil (62 mg, 63% yield).
'H-NMR (400 MHz, CDC13) δ ppm: 9.95 (s, IH), 7.47 (s, IH), 7.32 (s, IH), 7.23 (s, IH), 6.08 (m, IH), 5.45 (m, IH), 5.32 (m, IH), 4.76 (s, 2H), 4.62 (m, 2H).
Preparation of (2S)-N-[[3-allyloxy-5-r(£')-2-(2-bromo-4-chloro-phenyl)vinyllphenyllmethyll-2,4-diamino- butanamide:
The titled compound is prepared as a white solid following Scheme 3 and in analogy to Examples 1, 17, 19 and 48 using 3-allyloxy-5-(hydroxymethyl)benzaldehyde and (2S)-2,4-^w(tert-butoxycarbonylamino)butanoic acid [34404-27-8] as starting materials.
Example 53: (2 -Ar-[[3-allyloxy-5-[(.£')-2-(2-bromo-4-chloro-phenyl)vinyllphenyllmethyll-2-amino- A^A^-bisri-aminoethvDpentanediamide:
Preparation of methyl (2S)-5-r >;.yr2-(fer?-butoxycarbonylamino)ethyllaminol-2-(fer?-butoxycarbonylamino)- 5-oxo-pentanoate:
The titled compound is prepared as a white solid (145 mg, 69%> yield) following Scheme 3 and in analogy to Example 48 using (4S)-4-(tert-butoxycarbonylamino)-5-methoxy-5-oxo-pentanoic acid (100 mg, 0.38 mmol, 1.0 eq) [72086-72-7] and feri-butyl N-[2-[2-(teri-butoxycarbonylamino)ethylamino]ethyl]carbamate (1 16 mg, 0.38 mmol, 1.0 eq) [117499-16-8] as starting materials.
'H-NMR (400 MHz, CDC13) δ ppm: 5.36 (br, 2H), 5.02 (br, 1H), 4.35 (m, 1H), 3.76 (s, 3H), 3.51 (m, 2H), 3.34 (m, 4H), 3.25 (m, 2H), 2.52 (m, 1H), 2.41 (m, 1H), 2.29 (m, 1H), 1.90 (m, 1H), 1.45 (m, 27H).
MS m/z (+ESI): 547.3 [M+H]+.
Preparation of (2S)-5-[Z>;.y[2-(fer?-butoxycarbonylamino)ethyl]amino]-2-(fer?-butoxycarbonylamino)-5-oxo- pentanoic acid:
Lithium hydroxide (31 mg, 1.28 mmol, 5.0 eq) is added at room temperature to a stirred solution of methyl (2S)-5-[^z,y[2-(tert-butoxycarbonylamino)ethyl]amino]-2-(tert-butoxycarbonylamino)-5-oxo-pentanoate (140 mg, 0.26 mmol, 1.0 eq) in methanol (3 mL). After 3 hours stirring at 40°C, the reaction mixture is quenched with a 2M hydrochloric acid aqueous solution (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford (2S)-5-[^w[2-(teri- butoxycarbonylamino)ethyl]amino]-2-(teri-butoxycarbonylamino)-5-oxo-pentanoic acid as a white semi- solid (135 mg, 99% yield) that is directly engaged in the next step without further purification.
'H-NMR (400 MHz, CDCI3) δ ppm: 5.73 (br, 1H), 5.56 (br, 1H), 5.23 (br, 1H), 4.23 (m, 1H), 3.58 (m, 2H), 3.30-3.45 (m, 6H), 2.95 (m, 1H), 2.54 (m, 1H), 2.17 (m, 1H), 2.11 (m, 1H), 1.45 (m, 27H).
Preparation of (2S)-N-[[3-allyloxy-5-[(-E)-2-(2-bromo-4-chloro-phenyl)vinyl]phenyl]methyl]-2-amino-N',N'- bis(2-aminoethyl)pentanediamide:
The titled compound is prepared as a white solid following Scheme 3 and in analogy to Examples 1, 17, 19, 48 and 50 using dimethyl 5-hydroxybenzene-l,3-dicarboxylate [13036-02-7], allyl bromide [10695-6] and (25)- 5-[^z,y[2-(tert-butoxycarbonylamino)ethyl]amino]-2-(tert-butoxycarbonylamino)-5-oxo-pentanoic acid as starting materials.
Biological Examples
Efflux inhibition assay:
In vitro efflux-pump inhibition was measured with P. aeruginosa based on Alamar Blue accumulation following a published procedure (F. Vidal-Aroca et al. 2009. J. Microbiol. Methods 79: 232-237).
P. aeruginosa PAOl was grown on Muller-Hinton agar plates. Bacteria were resuspended in Dulbecco's phosphate buffered saline to OD625 = 1. Assays were performed in 96-well microtiter plates. Each well contained 100 μΕ assay mixture with 84 μΕ bacteria suspension, 5 μΐ succinic acid 40 mM, 10 μΕ Alamar Blue (Biosource DALl 100) and 1 μΕ test compound in DMSO. Fluorescence was measured every 5 minutes for 1 h with a Spectramax microtiter plate reader (ex at 530 nm, em at 590 nm). Inhibition of efflux pumps caused increased accumulation of Alamar Blue compared to controls without inhibitor (i.e. uninhibited control). Results were expressed as relative fluorescence intensity (% of uninhibited control). Efflux inhibition caused increased relative fluorescence. Antibacterial activity in combination with minocycline or with linezolid:
Inhibition of growth was measured with E. coli ATCC25922 and P. aeruginosa PAOl in a 96-well plate format. Cation-adjusted Muller-Hinton broth (caMHB) was inoculated with an overnight culture and incubated at 37°C on a shaker until OD625 reached 0.6 to 0.7. Density was adjusted to OD600 = 0.5 by addition of caMHB. 35 L of the suspension were diluted to 35 mL with caMHB and supplemented with minocycline at the subinhibitory doses of 0.25 μg/mL for E. coli and 8 μg/mL for P. aeruginosa or with linezolid at the subinhibitory dose of 128 μg/mL for E. coli and P. aeruginosa. Each well contained 1 μΕ of test compound in 100 μΕ caMHB with minocycline or with linezolid.
Plates were incubated at 37°C on a plate shaker. OD625 was measured at lh, 6h, and at 23h.
The difference between OD at 23 h and at lh was taken as measure for cell density and compared to controls without inhibitor (i.e. uninhibited control). Results were expressed as residual growth (% of uninhibited control). Enhancement of minocycline activity caused reduced residual growth.
The following compounds provide at least 115% accumulation in the efflux inhibition assay when the compound of formula I is present at 50μΜ or less:
1-55 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 minocycline when the compound is present at 50 μΜ:
1, 2, 3, 4, 5, 7, 8, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54 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 minocycline when the compound is present at 50 μΜ:
1, 2, 3, 7, 8, 11, 12, 13, 14, 15, 16, 17, 18, 21, 22, 23, 24, 25, 26, 27, 29, 30, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54 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 minocycline when the compound is present at 50 μΜ: 1, 4, 5, 7, 1 1, 13, 16, 17, 18, 19, 21, 22, 23, 24, 25, 27, 29, 30, 32, 35, 36, 37, 38, 44, 45, 46, 48, 49, 50, 53, 54 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 minocycline when the compound is present at 50 μΜ:
1, 4, 13, 16, 17, 18, 19, 21, 22, 23, 24, 27, 36, 37, 38, 44, 45, 46, 48, 50, 53, 54 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 minocycline when the compound is present at 25 μΜ:
1, 3, 4, 5, 7, 8, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 33, 34, 36, 37, 38, 39, 40, 41, 42, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54 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 minocycline when the compound is present at 25 μΜ:
I, 3, 7, 8, 13, 14, 17, 18, 19, 21, 22, 23, 24, 25, 26, 27, 29, 33, 34, 36, 37, 38, 40, 41 , 42, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54 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 minocycline when the compound is present at 25 μΜ:
I I, 16, 17, 18, 19, 21, 23, 24, 27, 36, 37, 38, 45, 48, 50, 53, 54 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 minocycline when the compound is present at 25 μΜ:
17, 18, 21, 23, 24, 27, 37, 38, 45, 48, 50, 53, 54 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 50 μΜ: 1 , 2, 3, 4, 5, 7, 8, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 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 50 μΜ: 1, 2, 3, 4, 5, 7, 8, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54 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 50 μΜ: 17, 18, 21, 37, 38, 44, 45, 46, 48, 50, 53, 54 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 50 μΜ: 17, 18, 21, 37, 38, 44, 45, 46, 48, 50, 53, 54 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 μΜ: 1, 2, 3, 4, 5, 7, 8, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,
34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54 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 μΜ: 1, 2, 3, 4, 5, 7, 8, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,
35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54 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 μΜ: 21, 37, 45, 50, 53, 54 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 μΜ: 21, 37, 45, 50, 53, 54 of Table 1.

Claims

Claims
1. A compound of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof
Figure imgf000099_0001
wherein
ASC is -N(R8)ASC-l ;
ASC-1 is C2-C5alkylene-N(R9a)R9b or C(=0)-CrC4alkylene-N(R9a)R9b, wherein in alkylene in both cases one -CH2- moiety is optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH3)-;
AR1, AR2 represent phenyl;
Rl, R2, R3 represent independently hydrogen, halogen, Ci-Cealkyl, CpCehaloalkyl, CpCealkoxy, or Cp Cehaloalkoxy;
R4 represents hydrogen, halogen, Ci-Cealkyl, CpCehaloalkyl or O-RIO;
R5, R6, R7 represent independently hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy or Cp Cehaloalkoxy;
R8 represents hydrogen, methyl or ASC-1 ;
R9a represents hydrogen or methyl;
R9b represents hydrogen, methyl or -C(=NH)NH2;
RIO represents Ci-Cealkyl, Ci-Cehaloalkyl, C2-C6alkenyl, CpCealkylene-Cycle-P, CpCealkylene-Cycle-Q;
Cycle-P represents independently at each occurrence a saturated or partially unsaturated C5-C6 carbocyclic ring optionally substituted by 1 to 3 R12, or a saturated or partially unsaturated C5-C6 heterocyclic ring optionally substituted by 1 to 3 Rl 2 containing carbon atoms as ring members and one or two ring members independently selected from N(R11) and O;
Cycle-Q represents independently at each occurrence phenyl optionally substituted by 1 to 3 Rl 3 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 R13;
Rl l represents hydrogen or Ci-Cealkyl;
R12 and R13 represent independently at each occurrence halogen, Ci-C4alkyl, Ci-C ihaloalkyl, Ci-C4alkoxy, or Ci-C4haloalkoxy;
LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-; L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or
L2 represents -0-C2-C6alkylene-;
wherein
when L2 is C(=0), then R8 is ASC-1 ;
when LI is -CH2-0- and L2 is Ci-C7alkylene as defined above, then at least one of Rl , R2, and R3 independently is Br, CF3 or C2-Cealkyl or at least R4 is 0-C2-C4alkenyl or at least R8 is ASC-1 ;
and wherein the compound of formula I is not
1 ,2-Ethanediamine, Nl ,Nl ,N2-trimethyl-N2-[4-[2-(2-phenylethenyl)phenoxy]butyl]- ;
Acetamide, 2-amino-N-[[4-[(4-bromophenyl)methoxy]phenyl]methyl]-;
Acetamide, 2-amino-N-[4-[4-(phenylmethoxy)phenoxy]butyl]-;
Propanamide, 3 -amino-N-methyl-N- [2- [4-(phenylmethoxy)phenoxy] ethyl] -;
Acetamide, 2-amino-N-methyl-N-[2-[4-(phenylmethoxy)phenoxy]ethyl]-;
Acetamide, N-methyl-2-(methylamino)-N-[2-[4-(phenylmethoxy)phenoxy]ethyl]-;
1 ,2-Ethanediamine, Nl -[4-[4-(phenylmethoxy)phenoxy]butyl]-;
1 ,2-Ethanediamine, Nl -[3-[4-(phenylmethoxy)phenoxy]propyl]-;
1 ,2-Ethanediamine, Nl ,Nl -dimethyl-N2-[3-[4-(phenylmethoxy)phenoxy]propyl]-;
1 ,2-Ethanediamine, Nl ,Nl -dimethyl-N2-[[4-(2-phenylethoxy)phenyl]methyl]-;
1 ,2-Ethanediamine, Nl ,Nl -dimethyl-N2-[[3-(2-phenylethoxy)phenyl]methyl]-;
1.2- Ethanediamine, Nl ,Nl -dimethyl-N2-[[2-(2-phenylethoxy)phenyl]methyl]-;
1.3- Propanediamine, Nl -[[3-methoxy-4-(2-phenylethoxy)phenyl]methyl]-N3-methyl-;
1 ,3-Propanediamine, N3-[[3-methoxy-4-(2-phenylethoxy)phenyl]methyl]-Nl ,N1 -dimethyl-;
1 ,2-Ethanediamine, N2-[[3-methoxy-4-(2-phenylethoxy)phenyl]methyl]-Nl ,N1 -dimethyl-;
Acetamide, N-[[2-[(2-chlorophenoxy)methyl]phenyl]methyl]-2-(methylamino)-;
Butanamide, 4-amino-N-[[3-(phenoxymethyl)phenyl]methyl]-;
Butanamide, N-[[2-[(2-chlorophenoxy)methyl]phenyl]methyl]-4-(methylamino)-;
Butanamide, 4-amino-N-[[4-(phenoxymethyl)phenyl]methyl]-;
Acetamide, 2-(methylamino)-N-[[3-(phenoxymethyl)phenyl]methyl]-;
Acetamide, 2-amino-N-[[4-(phenoxymethyl)phenyl]methyl]-;
Butanamide, 4-(methylamino)-N-[[4-(phenoxymethyl)phenyl]methyl]-;
Propanamide, 3-amino-N-[[2-(phenoxymethyl)phenyl]methyl]-;
Propanamide, 3 -amino-N- [[2- [(2-chlorophenoxy)methyl]phenyl]methyl] -;
Acetamide, 2-amino-N- [ [3 - (phenoxymethyl)phenyl] methyl] - ;
Butanamide, 4-amino-N-[[2-[(2-chlorophenoxy)methyl]phenyl]methyl]- ;
Propanamide, 3-amino-N-[[3-(phenoxymethyl)phenyl]methyl]-; Acetamide, 2-amino-N-[[2-[(2-chlorophenoxy)methyl]phenyl]methyl]-;
Butanamide, 4-(methylamino)-N-[[3-(phenoxymethyl)phenyl]methyl]-;
Propanamide, 3-amino-N-[[4-(phenoxymethyl)phenyl]methyl]-;
Acetamide, 2-amino-N-[[2-(phenoxymethyl)phenyl]methyl]-;
Butanamide, 4-(methylamino)-N-[[2-(phenoxymethyl)phenyl]methyl]-;
Acetamide, 2-(methylamino)-N-[[4-(phenoxymethyl)phenyl]methyl]-;
1 ,2-Ethanediamine, N/,N/-dimethyl-N2-[2-[4-(phenylmethoxy)phenoxy]ethyl]-;
1 ,2-Ethanediamine, N;-[2-[4-(phenylmethoxy)phenoxy]ethyl]-;
1 ,2-Ethanediamine, N;-[3-[4-(phenoxymethyl)phenyl]propyl]-;
1 ,2-Ethanediamine, N;,N;-dimethyl-N2- [3 - [4-( 1 -methyl- 1 -phenylethyl)phenoxy]propyl] -;
1 ,2-Ethanediamine, N;-[2-[4-(l -methyl-1 -phenylethyl)phenoxy] ethyl]-;
1.2- Ethanediamine, N;-[3-[4-(l -methyl-1 -phenylethyl)phenoxy]propyl]-;
1.3 - Propanediamine, N1- [3 -(dimethylamino)propyl] -N1- [[4-methoxy-3 -(phenylmethoxy)phenyl] - methyl]-N3,N3-dimethyl-;
1 ,3 -Propanediamine, N1- [3 -(dimethylamino)propyl] -N1- [[3 -methoxy-4-(phenylmethoxy)phenyl] - methyl]-N3,N3-dimethyl-;
1,3-Propanediamine, N3-[[4-[(4-bromophenyl)methoxy]-3-methoxyphenyl]methyl]-N;,N;-dimethyl-.
2. The compound according to claim 1 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein LI represents -CH=CH-.
3. The compound according to claim 1 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein LI represents -CH2-0-.
4. The compound according to claim 1 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein LI represents -C(CH3)2-.
5. The compound according to any one of claims 1 to 4 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein L2 represents -CH2-, -(CH2)2-, -(CH2)3-, -CH(CH3)-, -CH2-NH-CH2-, -CH2-NH- (CH2)2-, -C(=0)-, -C(=0)-CH2-, -C(=0)-NH-CH2-C(=0)-, -C(=0)-NH-(CH2)2-, -CH2-NH-C(=0)-CH2-, - CH2-NH-CH2-C(=0)-, -CH2-NH-C(=0)-CH(N(CH3)2)-(CH2)2-C(=0)-, -CH2-NH-C(=0)-CH(NH(CH3))- (CH2)2-C(=0)-, -CH2-NH-C(=0)-CH(NH2)-(CH2)2-C(=0)-, -CH2-NH-C(=0)-CH(NH2)-CH2-C(=0)-, -CH2- NH-C(=0)-CH(NH2)-(CH2)3-C(=0)-, -0-(CH2)2-, -0-(CH2)3- or -0-(CH2)4-.
6. The compound according to any one of claims 1 to 4 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein L2 represents -CH2-, -(CH2)2-, -CH(CH3)-, -(CH2)3-, -CH2-NH-(CH2)2-, -C(=0)-, - 0-(CH2)2-, -0-(CH2)3-, -0-(CH2)4- or -CH2-NH-C(=0)-CH(NH2)-(CH2)2-C(=0)-.
5 7. The compound according to any one of claims 1 to 4 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein L2 represents -0-(CH2)2-, -0-(CH2)3-, -0-(CH2)4-, -0-(CH2)5- or -0-(CH2)6-.
8. The compound according to claim 1 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein LI represents -CH=CH-, -CH2-0-, -0-CH2-, -C(CH3)2- or -CH=CH-CH2- and L2 represents -CH2-, -
10 C(=0)-, -0-(CH2)2-, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2-C(=0)-.
9. The compound according to any one of claims 1 to 8 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein ASC-1 is C2-C5alkylene-N(R9a)R9b wherein in alkylene one or two -CH2- moieties are optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH3)-.
15
10. The compound according to any one of claims 1 to 8 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein ASC-1 is C(=0)-Ci-C4alkylene-N(R9a)R9b, wherein in alkylene one or two -CH2- moieties are optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH3)-.
20 11. The compound according to any one of claims 1 to 8 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2- CH(CH3)-CH2-N(R9a)R9b, -(CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2- N(R9a)R9b, -C(=0)-CH(CH3)-N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)- (CH2)2-N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b.
25
12. The compound according to any one of claims 1 to 11, wherein at least one of Rl, R2 and R3 represents halogen, CpCealkyl, CpCehaloalkyl, CpCealkoxy, or Ci-Cehaloalkoxy.
13. The compound according to any one of claims 1 to 12, wherein R4 represents halogen, CpCealkyl, 30 Ci-Cghaloalkyl or O-RIO.
14. The compound according to claim 1 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, -(CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b, -C(=0)- CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)- (CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
Rl and R2 represent independently hydrogen, halogen, CpCealkyl or CpCehaloalkyl;
R3 is hydrogen;
R4 represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or O-RIO wherein RIO represents Ci-Cealkyl, C2-C6alkenyl, Ci-Cealkylene-phenyl, or Ci-Cealkylene-morpholinyl, preferably CpCealkyl or C2-Cealkenyl; R5, R6, R7 are hydrogen;
R8 represents hydrogen or ASC-1 ;
R9a represents hydrogen or methyl, and wherein R9b represents hydrogen, methyl or -C(=NH)NH2, wherein preferably R9a and R9b are independently hydrogen or methyl, preferably R9a and R9b are independently hydrogen or methyl;
LI represents -CH=CH-, -CH2-0-, -0-CH2-, -C(CH3)2 - or -CH=CH-CH2-;
L2 represents -CH2-, -C(=0)-, -0-(CH2)2, -0-(CH2)3, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2- C(=0)-.
15. The compound according to claim 1 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula 1-19.
Figure imgf000103_0001
wherein
ASC-1 is C2-C5alkylene-N(R9a)R9b or C(=0)-CrC4alkylene-N(R9a)R9b, wherein in alkylene in both cases one -CH2- moiety is optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH3)-;
Rl and R2 represent independently hydrogen, halogen, CpCealkyl or CpCehaloalkyl;
R4 represents hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, or O-RIO wherein RIO represents CpCealkyl,
C2-C6alkenyl, CpCealkylene-phenyl, or Ci-Cealkylene-morpholinyl;
R8 represents hydrogen or ASC-1 ;
R9a represents hydrogen or methyl, and wherein R9b represents hydrogen, methyl or -C(=NH)NH2, wherein preferably R9a and R9b are independently hydrogen or methyl;
LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-; and L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or
L2 represents -0-C2-C6alkylene-.
16. The compound according to claim 1 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula 1-20 to 1-23.
Figure imgf000104_0001
Figure imgf000104_0002
Figure imgf000104_0003
Figure imgf000104_0004
wherein
ASC-1 is C2-C5alkylene-N(R9a)R9b or C(=0)-CrC4alkylene-N(R9a)R9b, wherein in alkylene in both cases one -CH2- moiety is optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH3)-;
Rl and R2 represent independently hydrogen, halogen, CpCealkyl or CpCehaloalkyl;
R4 represents hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, or O-RIO wherein R10 represents CpCealkyl, C2-C6alkenyl, CpCealkylene-phenyl, or Ci-Cealkylene-morpholinyl, preferably CpCealkyl or C2-Cealkenyl; R8 represents hydrogen or ASC-1 ; R9a represents hydrogen or methyl, and wherein R9b represents hydrogen, methyl or -C(=NH)NH2, wherein preferably R9a and R9b are independently hydrogen or methyl, preferably R9a and R9b are independently hydrogen or methyl; and
L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or
L2 represents -0-C2-C6alkylene-.
17. The compound according to any one of claims 1 to 16, preferably claim 15 or 16, or
pharmaceutically acceptable salt, solvate or hydrate thereof, wherein ASC is -N(ASC-1)2.
18. The compound according to claim 17 wherein each ASC-1 is independently -(CH2)2-N(R9a)R9b.
19. The compound according to any one of claims 1 to 18, preferably claims 15 to 18, or
pharmaceutically acceptable salt, solvate or hydrate thereof, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, - (CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b, -C(=0)-CH(CH3)- N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b, -C(=0)- CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b; and
L2 represents -CH2-, -C(=0)-, -0-(CH2)2-, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2- C(=0)-.
20. The compound according to any one of claim 1 to 19, preferably claims 15 to 19, or
pharmaceutically acceptable salt, solvate or hydrate thereof, wherein
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, -(CH2)2-NH-(CH2)2- N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b, -C(=0)- CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b; and
L2 represents -CH2-, -C(=0)-, -0-(CH2)2-, -0-(CH2)3-, -0-(CH2)4-, or CH2-NH-C(=0)-CH(NH2)-(CH2)2- C(=0)-.
21. The compound according to any one of claims 1 to 20, preferably claims 15 to 20, or
pharmaceutically acceptable salt, solvate or hydrate thereof, wherein
Rl and R2 represent independently hydrogen, F, CI, Br, ί-Bu or CF3; and
R4 represents hydrogen, F, CI, CF3, or O-z-Bu or 0-CH2-CH=CH2.
22. The compound according to any one of claim 1 to 21, preferably claims 15 to 21, or
pharmaceutically acceptable salt, solvate or hydrate thereof, wherein
Rl and R2 represent independently hydrogen, F, CI, Br, ί-Bu or CF3;
R4 represents hydrogen, F, CI, CF3, O-z-Bu or 0-CH2-CH=CH2;
5 ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -(CH2)4-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, -(CH2)2-NH-(CH2)2-N(R9a)R9b, -C(=0)-CH2-N(R9a)R9b, -C(=0)-(CH2)2-N(R9a)R9b, -C(=0)- CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)- (CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
R8 represents hydrogen or ASC-1 ;
10 R9a and R9b are independently hydrogen or methyl; and
L2 represents -CH2-, -C(=0)-, -0-(CH2)2, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2- C(=0)-.
23. The compound according to any one of claims 1 to 22, preferably claims 15 to 22, or
15 pharmaceutically acceptable salt, solvate or hydrate thereof, wherein
Rl and R2 represent independently hydrogen, F, CI, Br, ί-Bu or CF3;
R4 represents hydrogen, CI, CF3, Cw-Bu or 0-CH2-CH=CH2;
ASC-1 is -(CH2)2-N(R9a)R9b, -(CH2)3-N(R9a)R9b, -CH2-CH(CH3)-CH2-N(R9a)R9b, -(CH2)2-NH-(CH2)2- N(R9a)R9b, -C(=0)-CH(N(R9a)R9b)-(CH2)2-N(R9a)R9b, -C(=0)-CH(NH2)-(CH2)2-N(R9a)R9b, -C(=0)- 20 CH(N(R9a)R9b)-(CH2)3-N(R9a)R9b or -C(=0)-CH(NH2)-(CH2)3-N(R9a)R9b;
R8 represents hydrogen or ASC-1 ;
R9a and R9b are independently hydrogen or methyl; and
L2 represents -CH2-, -C(=0)-, -0-(CH2)3-, -0-(CH2)4-, or -CH2-NH-C(=0)-CH(NH2)-(CH2)2-C(=0)-.
25 24. The compound according to any one of claims 16 to 23 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula of 120.
25. The compound according to any one of claims 16 to 23 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula 121.
30
26. The compound according to any one of claims 16 to 23 or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the compound is a compound of formula 122.
27. The compound according to any one of claims 16 to 23 or pharmaceutically acceptable salt, solvate 35 or hydrate thereof, wherein the compound is a compound of formula 123.
28. A compound of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof, 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
Figure imgf000107_0001
wherein
ASC is -N(R8)ASC-l ;
ASC-1 is C2-C5alkylene-N(R9a)R9b or C(=0)-CrC4alkylene-N(R9a)R9b, wherein in alkylene in both cases one -CH2- moiety is optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH3)-;
AR1, AR2 represent phenyl;
Rl, R2, R3 represent independently hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy, or Cp Cehaloalkoxy;
R4 represents hydrogen, halogen, Ci-Cealkyl, CpCehaloalkyl or O-RIO;
R5, R6, R7 represent independently hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy or Cp Cehaloalkoxy;
R8 represents hydrogen, methyl or ASC-1 ;
R9a represents hydrogen or methyl;
R9b represents hydrogen, methyl or -C(=NH)NH2;
R10 represents Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkenyl, CpCealkylene-Cycle-P, CpCealkylene-Cycle-Q; Cycle-P represents independently at each occurrence a saturated or partially unsaturated C5-C6 carbocyclic ring optionally substituted by 1 to 3 R12, or a saturated or partially unsaturated C5-C6 heterocyclic ring optionally substituted by 1 to 3 Rl 2 containing carbon atoms as ring members and one or two ring members independently selected from N(R11) and O;
Cycle-Q represents independently at each occurrence phenyl optionally substituted by 1 to 3 Rl 3 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 R13;
Rl l represents hydrogen or Ci-Cealkyl;
R12 and R13 represent independently at each occurrence halogen, Ci-C4alkyl, Ci-C ihaloalkyl, Ci-C4alkoxy, or Ci-C4haloalkoxy; LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -C(CH3)2-, -(CH2)2- or -CH=CH-CH2-;
L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a)-, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or
L2 represents -0-C2-C6alkylene-;
and wherein preferably said compound is defined as in any one of claims 2 to 27.
29. A pharmaceutical product comprising (i) a compound of formula I as defined in claim 28, preferably as defined in any one of claims 1 to 27 or pharmaceutically acceptable salt, solvate or hydrate thereof and an (ii) an antimicrobial agent.
30. 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 or pharmaceutically acceptable salt, solvate or hydrate thereof as defined in claim 28, preferably as defined in any one of claims 1 to 27, to said subject, and wherein said subject is receiving the compound of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof in combination with an antimicrobial agent.
31. A compound for use in a method according to claim 28 or pharmaceutically acceptable salt, solvate or hydrate thereof, or a pharmaceutical product according to claim 29 or method according to claim 30, wherein the antimicrobial agent is a tetracycline antibiotic.
32. A compound of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof for use in a method as according to claim 28, or a pharmaceutical product according to claim 24, or a method according to claim 25, wherein the antimicrobial agent is an oxazolidinone antibiotic, e.g. linezolid.
International application No.
INTERNATIONAL SEARCH REPORT
PCT/EP2016/070 727
Box No. IV Text of the abstract (Continuation of item 5 of the first sheet)
The present invention relates to compounds of formula I or
pharmaceutically acceptable salt, solvate or hydrate thereof
Figure imgf000109_0001
wherein
ASC is -N(R8)ASC-1;
ASC-1 is C 2-C 5alkylene-N(R9a)R9b or C(=0)-C C 4alkylene- N(R9a)R9b, wherein in alkylene in both cases one -CH 2- moiety is optionally replaced by -CH(N(R9a)R9b)- or -N(R9a)- or -CH(CH 3)-; AR1, AR2 represent phenyl;
LI represents -CH=CH-, -CH 2-0-, -(CH 2) 2-O-, -0-CH 2-, -C(CH 3) 2-, (CH 2 ) 2- or -CH=CH-CH 2-;
L2 represents C j-C yalkylene, wherein one or more -CH2- moieties in the alkylene are optionally replaced independently by -N(R9a) -, -CH(N(R9a)R9b)-, or -C(=0)-, wherein within L2 there are no adjacent -C(=0)-moieties or adjacent -N(R9a)- moieties, and wherein the terminal moiety of L2 is not -N(R9a)-, or L2 represents O-C 2-C ealkylene-;
the other definitions are as defined in the claims;
and their use in methods of treating a subject with a microbial infection or susceptible to a microbial infection.
Form PCT/ISA/210 (continuation of first sheet (3)) (July2009)
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