PATENTSCOPE will be unavailable a few hours for maintenance reason on Monday 03.02.2020 at 10:00 AM CET
Search International and National Patent Collections
Some content of this application is unavailable at the moment.
If this situation persists, please contact us atFeedback&Contact
1. (WO2017093157) PIPERIDINE, PYRROLIDINE AND 2-OXO-1,3-OXAZINANE DERIVATIVES AS INHIBITORS OF BACTERIAL EFFLUX-PUMPS FOR THE TREATMENT OF MICROBIAL INFECTIONS
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

PIPERIDINE, PYRROLIDINE AND 2-OXO-1 ,3-OXAZINANE DERIVATIVES AS INHIBITORS OF

BACTERIAL EFFLUX-PUMFfS FOR THE TREATMENT OF M ICROBIAL INFECTIONS

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 and WO 00/01714 describe 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


Ring A represents a 4- to 6-membered saturated ring containing carbon atoms as ring members in addition to the nitrogen atom, wherein a -CH2-CH2- moiety adjacent to the nitrogen atom is optionally replaced by a -C(=0)-0- moiety to form a carbamate;

X represents a bond or -CH2-;

AR1 and AR2 represent phenyl;

Rl, R2 and R3 represent independently hydrogen, halogen, CpCealkyl, Ci-Cehaloalkyl, CpCealkoxy or Cp Cehaloalkoxy;

R4 represents hydrogen, halogen, CpCealkyl optionally substituted by 1 to 5 RlOa, C2-Cealkenyl optionally substituted by 1 to 5 RlOa, CrC6alkylene-R10b, C2-C6alkenylene-R10b, C(0)ORl la, CHO,

C(0)N(R12)R13 or O-R14;

R5, R6 and R7 represent independently hydrogen, halogen, CpCealkyl, CpCehaloalkyl, CpCealkoxy or Cp Cehaloalkoxy;

R8 represents methyl or is absent, and when R8 is present the respective nitrogen atom carries a positive charge;

R9a and R9b represent independently hydrogen or methyl;

RlOa represents independently at each occurrence halogen, hydroxyl, CpCealkoxy or CpCehaloalkoxy; RlOb represents C3-C8cycloalkyl, C(0)ORl la, CHO, C(0)N(R12)R13, N(R12)R13, Cycle-P or Cycle-Q; Rl la and Rl lb represent independently at each occurrence hydrogen or CpCealkyl;

R12 and R13 represent independently at each occurrence hydrogen, Ci-C4alkyl, Ci-C4haloalkyl or Cp C4alkoxy-C i -C4alkyl;

R14 represents CpCealkyl, CpCehaloalkyl, C2-C6alkenyl, C2-C6haloalkenyl, CpCealkylene-Cycle-P or Cp C6alkylene-Cycle-Q;

Cycle-P represents independently at each occurrence a saturated or partially unsaturated C5-C6 carbocyclic ring optionally substituted by 1 to 3 R15, or a saturated or partially unsaturated 5- or 6-membered heterocyclic ring optionally substituted by 1 to 3 Rl 5 containing carbon atoms as ring members and one or two ring members independently selected from N(R1 lb) and O;

Cycle-Q represents independently at each occurrence phenyl optionally substituted by 1 to 3 Rl 6 or a 5- to 6-membered heteroaryl ring containing one to four heteroatoms independently selected from O, S and N, optionally substituted by 1 to 3 R16;

R15 and R16 represent independently at each occurrence halogen, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy or Ci-C4haloalkoxy;

LI represents -CH=CH-, -CH2-0-, -(CH2)2-0-, -0-CH2-, -CH2-S-, -(CH2)2-S-, -S-CH2-, -C(CH3)2-, -(CH2)2-or -CH=CH-CH2-;

L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene moiety are optionally replaced independently by -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties and wherein the terminal moiety of L2 is not -C(=0)-;

including pharmaceutically acceptable salts, solvates, and hydrates of said compounds.

The compound of formula I is administered to the subject as a component of a combined therapy with an antimicrobial agent. The subject may have been treated with the antimicrobial agent prior to administration with the compound of formula I, or the treatment with the antimicrobial agent may be simultaneous with, or after administration of the compound of formula I.

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 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 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, 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 preventing or treating a subject with a microbial infection or susceptible to a microbial infection, said method comprising administering the compound of formula I to said subject, and wherein said subject is receiving the compound of formula I in combination with an antimicrobial agent.

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. Thus, 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 LI represents -CH2-0-, L2 is Ci-C7alkylene- as defined above and Ring A is a 6-membered ring, then

at least one of Rl, R2 and R3 is independently Br, C2-Cealkyl, Ci-Cehaloalkyl, C2-Cealkoxy or Ci-Cehaloalkoxy; or

R4 represents CI, F, CpCealkyl optionally substituted by 1 to 5 RlOa, C2-Cealkenyl optionally substituted by 1 to 5 RlOa, CpCealkylene-RlOb, C2-C6alkenylene-R10b,

C(0)ORl la, CHO, C(0)N(R12)R13 or 0-R14 and R14 represents R14 C2-C6alkyl, Cr

Cehaloalkyl, C2-C6alkenyl, C2-C6haloalkenyl, Ci-Cealkylene-Cycle-P or CpCealkylene- Cycle-Q;

preferably wherein

when LI represents -CH2-0-, L2 is Ci-C7alkylene- as defined above and Ring A is a 6-membered ring, then

at least one of Rl , R2 and R3 is Br or C2-Cealkyl; or

R4 is 0-C2-C4alkenyl;

and wherein preferably at least R4 and L2 are at the meta positions on AR2 with respect to the position of LI ;

and wherein the compound of formula I is not

3-Pyrrolidinemethanamine, l-[[2-methoxy-4-(phenylmethoxy)phenyl]methyl]- (e.g. CAS1609748- 80-2);

3-Pyrrolidinemethanamine, l-[[2-[(2-chloro-6-fluorophenyl)methoxy]phenyl]methyl]- (e.g.

CAS1609743-35-2);

3-Azetidinamine, l-[[4-(phenylmethoxy)phenyl]methyl]- (e.g. CAS1479250-23-1);

3-Pyrrolidinamine, l-[[2-(phenylmethoxy)phenyl]methyl]- (e.g. CAS869747-18-2);

3-Pyrrolidinamine, 1 -[[5-bromo-2-[(4-chlorophenyl)methoxy]phenyl]methyl]-N-methyl- (e.g.

CAS851547-93-8);

3-Pyrrolidinamine, l-[[5-bromo-2-[(4-chlorophenyl)methoxy]phenyl]methyl]- (e.g. CAS851547-79-0);

2- Pyrrolidinemethanamine, l-[[3-(phenylmethoxy)phenyl]methyl]- (e.g. CAS725213-26-3);

3 - Pyrrolidinamine, 1 - [[2- [[(5-bromo-2-methoxyphenyl)methyl]thio] -3 -chlorophenyljmethyl] - (e. g. CAS325829-03-6);

3- Pyrrolidinamine, 1 -[[2-[[(5-bromo-2-methoxyphenyl)methyl]thio]phenyl]methyl]- (e.g.

CAS325823-68-5);

4- Piperidinamine, l-[[2-(2-phenylethoxy)phenyl]methyl]- (e.g. CAS1181584-15-5);

4-Piperidinamine, l-[[3-(2-phenylethoxy)phenyl]methyl]- (e.g. CAS 1181444-05-2);

4-Piperidinamine, l-[[4-(2-phenylethoxy)phenyl]methyl]- (e.g. CAS911626-70-5).

Optionally the compound of formula I is not:

e.g. CAS 2025865-79-4;




3-Azetidinamine, l-[[3-(phenylmethoxy)phenyl]methyl]-, (e.g. CAS 2008203-72-1);

2- Pyrrolidinemethanamine, N-methyl-l-[[3-(phenylmethoxy)phenyl]methyl]-, e.g. (CAS 2005132- 18-1);

5 3-Pyrrolidinemethanamine, l-[[3-(phenylmethoxy)phenyl]methyl]- e.g. (CAS 1882809-38-2);

3- Pyrrolidinamine, l-[[4-(phenylmethoxy)phenyl]methyl]- e.g. (CAS 1882732-57-1);

3-Pyrrolidinamine, l-[2-[3-(phenylmethoxy)phenyl]ethyl]- e.g. (CAS 1882168-61-7);

3-Pyrrolidinamine, l-[[3-(phenylmethoxy)phenyl]methyl]- e.g. (CAS 1881211-15-9);

3-Pyrrolidinemethanamine, l-[2-[3-(phenylmethoxy)phenyl]ethyl]- e.g. (CAS 1880758-04-2);

10 3-Pyrrolidinemethanamine, N-methyl-l-[[3-(phenylmethoxy)phenyl]methyl]- e.g. (CAS 1878947- 92-2);

3-Pyrrolidinemethanamine, N-methyl-l-[[2-(phenylmethoxy)phenyl]methyl]- e.g. (CAS 1876632- 12-0);

2- Pyrrolidinemethanamine, N-methyl-l-[[4-(phenylmethoxy)phenyl]methyl]- e.g. (CAS 1875821- 15 55-8);

3- Pyrrolidinamine, N-methyl-l-[[4-(phenylmethoxy)phenyl]methyl]- e.g. (CAS 1875326-91-2); 3-Pyrrolidinamine, N-methyl-l-[[3-(phenylmethoxy)phenyl]methyl]- e.g. (CAS 1875303-09-5);

2- Pyrrolidinemethanamine, l-[[4-(phenylmethoxy)phenyl]methyl]- e.g. (CAS 1873739-35-5);

3- Pyrrolidinamine, l-[2-[4-(phenylmethoxy)phenyl]ethyl]- e.g. (CAS 1873681-95-8);

20 3-Pyrrolidinamine, N-methyl-l-[2-[4-(phenylmethoxy)phenyl]ethyl]- e.g. (CAS 1873681-91-4);

3-Pyrrolidinemethanamine, N-methyl-l-[[4-(phenylmethoxy)phenyl]methyl]- e.g. (CAS 1873641- 33-8);

3-Pyrrolidinemethanamine, l-[2-[4-(phenylmethoxy)phenyl]ethyl]- e.g. (CAS 1872172-00-3); 3-Pyrrolidinemethanamine, l-[[4-(phenylmethoxy)phenyl]methyl]- e.g. (CAS 1871764-73-6); 25 3-Pyrrolidinamine, N-methyl-l-[[2-(phenylmethoxy)phenyl]methyl]- e.g. (CAS 1871593-19-9);

3-Pyrrolidinamine, N-methyl-l-[2-[3-(phenylmethoxy)phenyl]ethyl]- e.g. (CAS 1854313-33-9); 3-Pyrrolidinemethanamine, l-[[2-(phenylmethoxy)phenyl]methyl]- e.g. (CAS 1852302-19-2).

Optionally, when LI represents -CH2-0-, then at least one of Rl, R2, R3 and R4 is not hydrogen.

30 For the avoidance of doubt, compounds excluded by the above provisos are included in the invention in so far as the invention relates to the pharmaceutical products and use of the compoudns in methods of treating and preventing microbial infections.

Each alkyl moiety either alone or as part of a larger group such as alkoxy or alkylene is a straight or branched chain and is preferably Ci-Cealkyl, more preferably Ci-C4alkyl. Examples include methyl, ethyl, n-propyl, prop-2-yl, « -butyl, but-2-yl, 2-methyl-prop-l -yl or 2-methyl-prop-2-yl. Examples of an alkoxy include methoxy, ethoxy, n-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.

The term "alkoxyalkyl" refers to an R-O-R' moiety in which the R and R' groups are alkyl groups.

Examples include methoxymethyl, methoxyethyl, methoxypropyl and methoxybuyl.

Each alkylene moiety is a straight or branched chain and is, for example, -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 or alkenylene 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 may include either said compound with said alkenyl moiety in its (E)-configuration, said compound with said alkenyl moiety in its (^-configuration and mixtures thereof in any ratio.

Each haloalkyl moiety either alone or as part of a larger group such as haloalkoxy is an alkyl group substituted by one or more of the same or different halogen atoms. Examples include difluoromethyl, trifluoromethyl, chlorodifluoromethyl and 2,2,2-trifluoro-ethyl. Haloalkyl moieties include for example 1 to 5 halo substituents, or 1 to 3 halo substituents.

Each haloalkenyl moiety either alone or as part of a larger group such as haloalkenyloxy is an alkenyl group substituted by one or more of the same or different halogen atoms. Examples include,2-difluoro-vinyl and 1 ,2-dichloro-2-fluoro-vinyl. Haloalkenyl moieties include for example 1 to 5 halo substituents, or 1 to 3 halo substituents.

Each cycloalkyl moiety can be in mono- or bi-cyclic form, typically and preferably in mono-cyclic form, and preferably contains 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl 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 depictionns 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 the right hand side of L2 as depicted.

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 methanesulfonic 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.

Ring A represents a 4- to 6-membered saturated ring containing carbon atoms as ring members in addition to the nitrogen atom, wherein a -CH2-CH2- moiety adjacent to the nitrogen atom is optionally replaced by a -C(=0)-0- moiety to form a carbamate. Preferably, Ring A represents a ring selected from azetidine, pyrrolidine, piperidine, l,3-oxazolidin-2-one and l,3-oxazinan-2-one; more preferably, Ring A represents a ring selected from azetidine, pyrrolidine, piperidine and l,3-oxazinan-2-one; even more preferably Ring A represents a ring selected from pyrrolidine and piperidine.

X represents a bond or -CH2-. Preferably, X represents a bond when Ring A is a 6-membered ring, and -CH2-when Ring A is a 4- or 5-membered ring. Preferably X is at the 3-position on the pyrrolidine ring.

Preferably X is at the 4-position on the piperidine ring. Preferably X is at the 5-position on the 1 ,3-oxazinan-2-one ring.

R9a and R9b represent independently hydrogen or methyl. Preferably, R9a and R9b represent hydrogen. Considering ASC as a whole, preferably Ring A represents a ring selected from azetidine, pyrrolidine, piperidine, l ,3-oxazolidin-2-one and l ,3-oxazinan-2-one, wherein X is at the 3-position of the azetidine ring, at the 3-position on the pyrrolidine ring, at the 4-position on the piperidine ring, at the 4-position on the 1 ,3-oxazolidin-2-one ring, and at the 5-position on the 3-oxazinan-2-one ring. More preferably Ring A represents a ring selected from pyrrolidine, piperidine, and l ,3-oxazinan-2-one, wherein X is at the 3-position on the pyrrolidine ring, at the 4-position on the piperidine ring, at the 4-position of the 1 ,3-oxazolidin-2-one ring, and wherein X is -CH2- when Ring A is pyrrolidine or l ,3-oxazinan-2-one and a bond when the Ring A is piperidine.

Preferably, ASC is ASC-a, ASC-b, ASC-c or ASC-d


More preferably ASC is ASC-a, ASC-b or ASC-c, even more preferably ASC-a or ASC-b.

Rl represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy or CpCehaloalkoxy. Specific examples of Rl include hydrogen, F, CI, Br, I, CF3, -O-methyl, -O-ethyl, -O-propyl, O-butyl, methyl, ethyl, propyl, and butyl (e.g. i-butyl). Preferably, Rl represents hydrogen, halogen, Ci-C4alkyl, Ci-C4haloalkyl, Cp C4alkoxy or Ci-C4haloalkoxy. More preferably, Rl represents hydrogen, halogen, Ci-C4alkyl, Cihaloalkyl or Ci-C2alkoxy. Again more preferably, Rl represents hydrogen, halogen, Ci-C4alkyl or CF3. Still more preferably, Rl represents hydrogen, F, CI, Br, i-butyl or CF3.

R2 represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy or CpCehaloalkoxy. Specific examples of R2 include hydrogen, F, CI, Br, I, CF3, -O-methyl, -O-ethyl, -O-propyl, O-butyl, methyl, ethyl, propyl, and butyl (e.g. i-butyl). Preferably, R2 represents hydrogen, halogen, Ci-C4alkyl, Ci-C4haloalkyl, Cp C4alkoxy or Ci-C4haloalkoxy. More preferably, R2 represents hydrogen, halogen, Ci-C4alkyl, Cihaloalkyl or Ci-C2alkoxy. Again more preferably, R2 represents hydrogen, halogen, Ci-C4alkyl or CF3. Still more preferably, R2 represents hydrogen, F, CI, Br, i-butyl or CF3.

R3 represents hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy or CpCehaloalkoxy. Specific examples of R3 include hydrogen, F, CI, Br, I, CF3, -O-methyl, -O-ethyl, -O-propyl, -O-butyl, methyl, ethyl, propyl, and butyl (e.g. i-butyl). Preferably, R3 represents hydrogen, halogen, Ci-C4alkyl, Ci-C4haloalkyl, Cp C4alkoxy or Ci-C4haloalkoxy. More preferably, R3 represents hydrogen, halogen, Ci-C4alkyl, Cihaloalkyl or Ci-C2alkoxy. Again more preferably, R3 represents hydrogen, halogen, Ci-C4alkyl or CF3. Still more preferably, R3 represents hydrogen, F, CI, Br, i-butyl or CF3. Most preferably, R3 represents hydrogen. R4 represents hydrogen, halogen, CpCealkyl optionally substituted by 1 to 5 RlOa, C2-C6alkenyl optionally substituted by 1 to 5 RlOa, CrC6alkylene-R10b, C2-C6alkenylene-R10b, C(0)0R1 la, CHO,

C(0)N(R12)R13 or 0-R14. Specific examples of R4 include hydrogen, F, CI, Br, methyl, ethyl, propyl, butyl (e.g. i-butyl), O-methyl, O-ethyl, O-propyl, O-butyl, O-allyl, C(0)-NH2, C(=0)-NH-(CH2)3-0-CH3, CHO, CH=CH-C(=0)0-CH2-CH3, and 0-CH2-CH2-imidazole. Preferably, R4 represents hydrogen, halogen, Ci-C4alkyl, C2-C4alkenyl, CrC4alkylene-R10b, C2-C6alkenylene-R10b, C(0)ORl la, CHO, C(0)N(R12)R13 or 0-R14. More preferably, R4 represents hydrogen, halogen, Ci-C4alkyl, C2-C4alkenylene-R10b,

C(0)ORl la, CHO, C(0)N(R12)R13 or 0-R14. Even more preferably R4 represents hydrogen, halogen, Cr C4alkyl, C2-C4alkenylene-R10b, CHO, C(0)N(R12)R13 or 0-R14. Still more preferably, R4 represents hydrogen, halogen, CrC4alkyl, C2-C4alkenylene-R10b, C(0)N(R12)R13 or 0-R14.

RlOa represents independently at each occurrence halogen, hydroxyl, CpCealkoxy or d-Cehaloalkoxy. Preferably, RlOa represents independently at each occurrence halogen, hydroxyl or Ci-C4alkoxy.

RlOb represents C3-C8cycloalkyl, C(0)ORl la, CHO, C(0)N(R12)R13, N(R12)R13, Cycle-P or Cycle-Q. Preferably, RlOb represents C(0)0R1 la, CHO or C(0)N(R12)R13, more preferably RlOb represents C(0)ORl la.

Rl la represents hydrogen or CpCealkyl, preferably Rl la represents hydrogen or Ci-C4alkyl, even more preferably Rl 1 a represents Ci-C4alkyl.

Rl lb represents hydrogen or CpCealkyl, preferably Rl lb represents hydrogen or Ci-C4alkyl.

R12 represents hydrogen, Ci-C4alkyl, Ci-C4haloalkyl or Ci-C4alkoxy-Ci-C4alkyl. Preferably, R12 represents

Ci-C4alkyl or Ci-C4alkoxy-Ci-C4alkyl. More preferably, R12 represents Ci-C2alkyl or methoxy-Ci-C4alkyl.

R13 represents hydrogen, Ci-C4alkyl, Ci-C4haloalkyl or Ci-C4alkoxy-Ci-C4alkyl. Preferably, R13 represents hydrogen, Ci-C4alkyl or Ci-C4alkoxy-Ci-C4alkyl. More preferably, R13 represents hydrogen or Ci-C2alkyl.

Again more preferably, Rl 3 represents hydrogen or methyl.

R14 represents CpCealkyl, CpCehaloalkyl, C2-Cealkenyl, C2-C6haloalkenyl, CpCealkylene-Cycle-P or Cp C6alkylene-Cycle-Q. Preferably, R14 represents CpCealkyl, C2-Cealkenyl or CpCealkylene-Cycle-Q. More preferably, R14 represents C3-C6alkyl, C2-Cealkenyl or C2-C4alkylene-Cycle-Q.

Cycle-P represents independently at each occurrence a saturated or partially unsaturated C5-C6 carbocyclic ring optionally substituted by 1 to 3 R15, or a saturated or partially unsaturated 5- or 6-membered heterocyclic ring optionally substituted by 1 to 3 Rl 5 containing carbon atoms as ring members and one or two ring members independently selected from N(R1 lb) and O. Preferably, Cycle-P represents

independently at each occurrence cyclopentyl or cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl or morpholinyl, each optionally substituted by 1 to 3 R15, and wherein preferably R15 represents independently at each occurrence halogen, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy or Cp

C ihaloalkoxy; and wherein more preferably Rl 5 represents independently at each occurrence halogen, methyl, halomethyl, methoxy or halomethoxy.

Cycle-Q represents independently at each occurrence phenyl optionally substituted by 1 to 3 Rl 6 or a 5- to 6-membered heteroaryl ring containing one to four heteroatoms independently selected from O, S and N, optionally substituted by 1 to 3 R16. More preferably, Cycle-Q represents independently at each occurrence phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, tetrazolyl, furanyl or thiophenyl, each optionally substituted by 1 to 3 R16. Again even more preferably, Cycle-Q represents independently at each occurrence furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl. Still more preferably Cycle-Q represents

independently at each occurrence furanyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl.

R15 represents halogen, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy or Ci-C4haloalkoxy. Preferably, R15 represents halogen, methyl, halomethyl, methoxy or halomethoxy.

R16 represents halogen, Ci-C4alkyl, Ci-C4haloalkyl, Ci-C4alkoxy or Ci-C4haloalkoxy. Preferably, R16 represents halogen, methyl, halomethyl, methoxy or halomethoxy.

Considering R4 and its substituents as a whole, R4 preferably represents hydrogen, halogen, Ci-C4alkyl, C2- C4alkenyl, CrC4alkylene-R10b, C2-C6alkenylene-R10b, C(0)ORl l a, CHO, C(0)N(R12)R13 or 0-R14;

Rl Ob represents C(0)ORl l a, CHO or C(0)N(R12)R13; Rl 1 a represents hydrogen or CrC4alkyl; R12 represents hydrogen, Ci-C2alkyl or Ci-C4alkoxy-Ci-C4alkyl; R13 represents hydrogen or methyl; R14 represents CpCealkyl, C2-Cealkenyl or CpCealkylene-Cycle-Q, wherein Cycle-Q represents a 5- to 6-membered heteroaryl ring containing one to four heteroatoms independently selected from O, S and N, optionally substituted by 1 to 3 R16.

More preferably, R4 represents hydrogen, halogen, Ci-C4alkyl, C2-C4alkenyl, Ci-C4alkylene-R10b, C2-C6alkenylene-R10b, C(0)ORl l a, CHO, C(0)N(R12)R13 or 0-R14; Rl Ob represents C(0)ORl l a, CHO or C(0)N(R12)R13; Rl l a represents hydrogen or Ci-C4alkyl; R12 represents hydrogen, Ci-C2alkyl or Cp C4alkoxy-Ci-C4alkyl; R13 represents hydrogen or methyl; R14 represents CpCealkyl, C2-Cealkenyl or Cp C6alkylene-Cycle-Q, wherein Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl.

Even more preferably, R4 represents hydrogen, halogen, Ci-C4alkyl, C2-C4alkenylene-R10b,

C(0)N(R12)R13 or 0-R14; Rl Ob represents C(0)ORl la; Rl l a represents hydrogen or CrC4alkyl; R12 represents hydrogen, Ci-C2alkyl or Ci-C4alkoxy; R13 represents hydrogen or methyl; R14 represents Cp Cealkyl, C2-Cealkenyl or CpCealkylene-Cycle-Q, wherein Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl.

Again more preferably, R4 represents hydrogen, halogen, C2-C4alkenylene-R10b, C(0)N(R12)R13 or O-R14; R12 represents hydrogen, Ci-C2alkyl or Ci-C4alkoxy-Ci-C4alkyl; R13 represents hydrogen or methyl; R14 represents CpCealkyl, C2-Cealkenyl or CpCealkylene-Cycle-Q, wherein Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl.

Again more preferably, R4 represents hydrogen, CI, F, C2-C4alkenylene-R10b, C(0)N(R12)R13 or 0-R14; Rl Ob represents C(0)0R1 l a; Rl l a represents Ci-C4alkyl; R12 represents hydrogen, Ci-C2alkyl or Cp C4alkoxy-Ci-C4alkyl; R13 represents hydrogen or methyl; R14 represents Ci-Cealkyl, C2-C6alkenyl or Cp C6alkylene-Cycle-Q, wherein Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl.

Again more preferably, R4 represents hydrogen, CI, F, C2-C4alkenylene-R10b, C(0)N(R12)R13 or 0-R14; Rl Ob represents C(0)ORl l a; Rl l a represents Ci-C4alkyl; R12 represents hydrogen, Ci-C2alkyl or Cp C4alkoxy-Ci-C4alkyl; R13 represents hydrogen or methyl; R14 represents CpCealkyl, C2-C6alkenyl or Cp C6alkylene-Cycle-Q, wherein Cycle-Q represents imidazolyl or pyridinyl.

LI represents -CH=CH-(Z, E or ZIE), -CH2-0-, -(CH2)2-0-, -0-CH2-, -CH2-S-, -(CH2)2-S-, -S-CH2-, - C(CH3)2-, -(CH2)2- or -CH=CH-CH2-(Z, E or ZIE). Preferably LI represents -CH=CH-(Z, E or ZIE), -CH2-0-, -(CH2)2-0-, -0-CH2-, -CH2-S-, -(CH2)2-S-, -S-CH2-, -C(CH3)2- or -CH=CH-CH2-(Z, E or ZIE). More preferably, LI represents -CH=CH-(Z, E or ZIE), -CH2-0-, -0-CH2-, -CH2-S-, -S-CH2-, -C(CH3)2- or -CH=CH-CH2-(Z, E or ZIE). Again more preferably LI represents -CH=CH-(Z, E or ZIE), -CH2-0-, -0-CH2-, -CH2-S-, -S-CH2- or -C(CH3)2-. Again more preferably LI represents -CH=CH-(Z, E or ZIE), -CH2-0-, -O-CH2-, -CH2-S- or -S-CH2-. Again more preferably LI represents -CH=CH-(£), -CH2-0-, -0-CH2-, -CH2-S-or -S-CH2-. Still more preferably LI represents -CH=CH-(£), -CH2-0-, -0-CH2- or -CH2-S-. In general, when L2 represents -CH=CH-, the (E) configuration is preferred.

L2 represents CpC7alkylene, wherein one or more -CH2- moieties in the alkylene moiety are optionally replaced independently by -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties and wherein the terminal moiety of L2 is not -C(=0)-. Preferably, L2 represents CpC4alkylene, wherein one or more -CH2- moieties in the alkylene moiety are optionally replaced independently by -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties and wherein the terminal moiety of L2 is not -C(=0)-. More preferably, L2 represents CpC3alkylene, wherein one or more -CH2- moieties in the alkylene moiety are optionally replaced independently by -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties and wherein the terminal moiety of L2 is not -C(=0)-. Again more preferably, L2 represents -CH2-, -CH2-CH2-or -C(0)-CH2-. Again more preferred, L2 represents -CH2- or -CH2-CH2-.

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, Ring A represents pyrrolidine.

In one embodiment, Ring A represents piperidine.

In one embodiment, Ring A represents l ,3-oxazinan-2-one.

In one embodiment, R8 represents methyl and the respective nitrogen atom carries a positive charge.

In one embodiment, R8 is absent.

In one embodiment, X represents a bond.

In one embodiment, X represents -CH2-.

In one embodiment, R9a represents hydrogen.

In one embodiment, R9a represents methyl.

In one embodiment, R9b represents hydrogen.

In one embodiment, R9b represents methyl.

In one embodiment R9a and R9b represent hydrogen.

In one embodiment R9a and R9b represent methyl.

In one embodiment R9a represents methyl and R9b represents hydrogen.

In one embodiment ASC represents ASC-a.

In one embodiment ASC represents ASC-b.

In one embodiment ASC represents ASC-c.

In one embodiment ASC represents ASC-d.

In one embodiment Rl represents CI.

In one embodiment Rl represents Br.

In one embodiment Rl represents CF3.

In one embodiment Rl represents C2-C6alkyl.

In one embodiment Rl represents C palkyl.

In one embodiment Rl represents teri-butyl.

In one embodiment R2 represents hydrogen.

In one embodiment R2 represents CI.

In one embodiment R2 represents Br.

In one embodiment R3 represents hydrogen.

In one embodiment R2 and R3 represent hydrogen.

In one embodiment Rl and R2 are both not hydrogen.

In one embodiment Rl represents CI and R2 represents Br.

In one embodiment Rl represents ί-Bu and R2 represents hydrogen.

In one embodiment R4 is not hydrogen.

In one embodiment R4 represents H.

In one embodiment R4 represents CI.

In one embodiment R4 represents CF3.

In one embodiment R4 represents C2-C6alkyl.

In one embodiment R4 represents C palkyl.

In one embodiment R4 represents teri-butyl.

In one embodiment R4 represents 0-R14, wherein R14 represents C2-C6alkenyl. In one embodiment R4 represents 0-R14, wherein R14 is C2-C4alkenyl.

In one embodiment R4 represents 0-R14, wherein R14 represents allyl.

In one embodiment R4 represents 0-R14, wherein R14 represents C2-C6alkyl, wherein R14 preferably represents C4alkyl.

In one embodiment R4 represents 0-R14, wherein R14 represents iso-butyl.

In one embodiment R4 represents 0-R14, wherein R14 represents (CH2)2-imidazole.

In one embodiment R4 represents C2-C4alkenylene-R10b, wherein RlOb represents C(0)0R1 la, and wherein Rl 1 a represents C 1 -C4alkyl.

In one embodiment R4 represents CH=CH-C02-R1 la, wherein Rl la represents Ci-C4alkyl.

In one embodiment R4 represents CH=CH-C02-R1 la, wherein Rl la represents ethyl.

In one embodiment R4 represents £"-CH=CH-C02-Rl la, wherein Rl la represents Ci-C4alkyl.

In one embodiment R4 represents £"-CH=CH-C02-Rl la, wherein Rl la represents ethyl.

In one embodiment R4 represents C(0)0R11 a, wherein Rl 1 a represents ethyl.

In one embodiment R4 represents CHO.

In one embodiment R4 represents C(0)N(R12)R13, wherein R12 represents Ci-C2alkyl or Ci-C4alkoxy-Cr C4alkyl and wherein R13 represents hydrogen, Ci-C4alkyl or Ci-C4alkoxy-Ci-C4alkyl.

In one embodiment R4 is C(0)N(R12)R13, wherein R12 represents Ci-C2alkyl or Ci-C4alkoxy-Ci-C4alkyl and wherein R13 represents hydrogen or Ci-C2alkyl.

In one embodiment R4 represents C(0)N(R12)R13, wherein R12 represents Ci-C2alkyl or methoxy-Cr C4alkyl and wherein Rl 3 represents hydrogen or methyl.

In one embodiment R4 represents C(0)N(R12)R13, wherein R12 represents methoxy-Ci-C4alkyl and wherein Rl 3 represents hydrogen or methyl.

In one embodiment R4 represents C(0)NH(CH2)3OCH3.

In one embodiment R4 represents C(0)NH2.

In one embodiment at least one of Rl, R2 and R4 is not hydrogen.

In one embodiment R5 represents hydrogen.

In one embodiment R6 represents hydrogen.

In one embodiment R7 represents hydrogen.

In one embodiment R5, R6 and R7 represent hydrogen.

In one embodiment R4 is not hydrogen and R5, R6 and R7 represent hydrogen.

In one embodiment Rl is not hydrogen, R2 and R3 represent hydrogen, R4 is not hydrogen, and R5, R6 and R7 represent hydrogen.

In one embodiment Rl and R2 are not hydrogen, R3 represents hydrogen, R4 is not hydrogen, and R5, R6 and R7 represent hydrogen.

In one embodiment Rl and R2 are not hydrogen, and R3, R4, R5, R6 and R7 represent hydrogen.

In one embodiment Rl, R2 and R3 represent hydrogen, R4 is not hydrogen and R5, R6 and R7 represent hydrogen.

In one embodiment LI represents -CH=CH-.

In one embodiment LI represents -CH=CH-(£).

In one embodiment LI represents -CH2-0-.

In one embodiment LI represents -0-CH2-.

In one embodiment LI represents -CH2-S-.

In one embodiment LI represents -S-CH2-.

In one embodiment LI represents -C(CH3)2-.

In one embodiment LI represents -CH=CH-CH2-.

In one embodiment L2 represents -CH2-In one embodiment L2 represents -(CH2)2-.

In one embodiment L2 represents -C(0)-(CH2)-.

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 L2 is at the meta position on AR2 with respect to R4.

In one embodiment L2 is at the meta position on AR2 with respect to the position of LI, and LI is (E)-CH=CH-, -CH2-0-, -0-CH2-, -CH2-S-, -S-CH2-, -C(CH3)2- or -CH=CH-CH2-.

In one embodiment L2 is at the ortho 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 .

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 R5, R6 and R7 represent 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 and R7 represent hydrogen.

In one embodiment R3, R5, R6 and R7 are hydrogen, L2 and R4 are at the meta positions on AR2 with respect to the position of LI, and R4 is not hydrogen.

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, and R3, R5, R6 and R7 are hydrogen, R4 is not hydrogen, and L2 and R4 are at the meta positions on AR2 with respect to the position of LI .

In one embodiment Rl is not hydrogen and is at the para position on AR1 with respect to LI, and R2, R3, R5, R6 and R7 are hydrogen, R4 is not hydrogen, and L2 and R4 are at the meta positions on AR2 with respect to the position of LI .

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 and 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 and R7 represent hydrogen and L2 is at the para 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 and R7 represent hydrogen and L2 is at the meta position on AR2 with respect to the position of LI .

In one embodiment Rl, R2 and R3 represent hydrogen and L2 is at the meta position on AR2 with respect to the position of LI .

In a preferred embodiment, R4 represents hydrogen, halogen, Ci-C4alkyl, C2-C6alkenylene-R10b,

C(0)ORl l a, CHO, C(0)N(R12)R13 or 0-R14; R5, R6 and R7 represent hydrogen; Rl Ob represents C(0)ORl l a, CHO or C(0)N(R12)R13; Rl l a represents hydrogen or CrC4alkyl; R12 represents hydrogen, Ci-C2alkyl or Ci-C4alkoxy-Ci-C4alkyl; R13 represents hydrogen or methyl; R14 represents Ci-Cealkyl, C2-Cealkenyl or CpCealkylene-Cycle-Q; Cycle-Q represents a 5- to 6-membered heteroaryl ring containing one to four heteroatoms independently selected from O, S and N, optionally substituted by 1 to 3 R16.

In another preferred embodiment, Ring A represents a ring selected from azetidine, pyrrolidine, piperidine or l ,3-oxazinan-2-one; Rl and R2 represent independently hydrogen, halogen or Ci-C4alkyl; R3 represents hydrogen; R4 represents hydrogen, halogen, Ci-C4alkyl, C2-C4alkenyl, Ci-C4alkylene-R10b, C2-C4alkenylene-R10b, C(0)ORl l a, CHO, C(0)N(R12)R13 or 0-R14; R5, R6 and R7 represent hydrogen; R9a and R9b represent hydrogen; RlOb represents C(0)ORl l a; Rl l a represents hydrogen or Ci-C4alkyl; R12 represents Ci-C4alkyl or Ci-C4alkoxy-Ci-C4alkyl; R13 represents hydrogen; R14 represents Ci-Cealkyl, C2-Cealkenyl or CpCealkylene-Cycle-Q; Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl; LI represents -CH=CH-, -CH2-0-, -0-CH2-, -CH2-S- or -S-CH2; and L2 represents -CH2-, -CH2-CH2- or -C(0)-CH2-.

In another preferred embodiment, Ring A represents a ring selected from pyrrolidine, piperidine; Rl and R2 represent independently hydrogen, halogen or Ci-C4alkyl; R3 represents hydrogen; R4 represents 0-R14; R5, R6 and R7 represent hydrogen; R9a and R9b represent hydrogen; R12 represents Ci-C4alkyl or Cp C4alkoxy-Ci-C4alkyl; R13 represents hydrogen; R14 represents Ci-Cealkyl, C2-Cealkenyl or CpCealkylene-Cycle-Q; Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl; LI represents -CH=CH-, -CH2-0-, -0-CH2-, -CH2-S- or -S-CH2; and L2 represents -CH2-, -CH2-CH2- or -C(0)-CH2-.

In another preferred embodiment, Ring A represents a ring selected from pyrrolidine, piperidine; Rl and R2 represent independently hydrogen, halogen or Ci-C4alkyl; R3 represents hydrogen; R4 represents 0-R14; R5, R6 and R7 represent hydrogen; R9a and R9b represent hydrogen; R12 represents Ci-C4alkyl or Cp C4alkoxy-Ci-C4alkyl; R13 represents hydrogen; R14 represents CpCealkyl, C2-Cealkenyl or CpCealkylene-Cycle-Q; Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl; LI represents -CH=CH-, -CH2-0-, -0-CH2-, -CH2-S- or -S-CH2; and L2 represents -CH2-, -CH2-CH2- or -C(0)-CH2- and wherein L2 is at the meta position on AR2 with respect to the position of LI and L2 is at the meta position on AR2 with respect to R4.

In another preferred embodiment, Ring A represents a ring selected from azetidine, pyrrolidine, piperidine, l,3-oxazolidin-2-one and l,3-oxazinan-2-one and R8 represents methyl.

In another preferred embodiment, Ring A represents a ring selected from azetidine, pyrrolidine, piperidine and l,3-oxazinan-2-one and R8 represents methyl.

In another preferred embodiment, Ring A represents a ring selected from pyrrolidine, piperidine and 1,3-oxazinan-2-one and R8 represents methyl.

In another preferred embodiment, Ring A represents a ring selected from pyrrolidine and piperidine and R8 represents methyl.

In another preferred embodiment Ring A represents a ring selected from azetidine, pyrrolidine, piperidine or l,3-oxazinan-2-one, L2 represents -CH2-, -CH2-CH2- or -C(0)-CH2-, and wherein preferably L2 represents -CH2- or -CH2-CH2- and R9a and R9b represent independently hydrogen or methyl, and preferably R9a and R9b represent hydrogen.

In another preferred embodiment Ring A represents a ring selected from azetidine, pyrrolidine, piperidine or l,3-oxazinan-2-one, L2 represents -CH2-, -CH2-CH2- or -C(0)-CH2-, preferably-CH2- or -CH2-CH2-, LI represents -CH=CH-, -CH2-0-, -0-CH2-, -CH2-S- or -S-CH2- and R9a and R9b represent independently hydrogen or methyl, and preferably R9a and R9b represent hydrogenJn another preferred embodiment Ring A represents a ring selected from azetidine, pyrrolidine, piperidine or l,3-oxazinan-2-one, L2 represents -CH2-, -CH2-CH2- or -C(0)-CH2-, preferably-CH2- or -CH2-CH2-, LI represents -CH=CH-, -CH2-0-, -O-CH2-, -CH2-S- or -S-CH2-, X represents -CH2- and R9a and R9b represent independently hydrogen or methyl, and preferably R9a and R9b represent hydrogen.

In another preferred embodiment, Ring A represents a ring selected from pyrrolidine, piperidine or 1,3-oxazinan-2-one, wherein X is at the 2- or 3-position on the pyrrolidine ring, at the 4-position on the piperidine ring and at the 5-position on the l,3-oxazinan-2-one ring and R9a and R9b represent

independently hydrogen or methyl, and preferably R9a and R9b represent hydrogen.

In another preferred embodiment, Ring A represents a ring selected from pyrrolidine, piperidine or 1,3-oxazinan-2-one, wherein X is at the 2- or 3-position on the pyrrolidine ring, at the 4-position on the piperidine ring and at the 5-position on the l,3-oxazinan-2-one ring, L2 represents -CH2-, -CH2-CH2- or -C(0)-CH2-, preferably-CH2- or -CH2-CH2- and R9a and R9b represent independently hydrogen or methyl, and preferably R9a and R9b represent hydrogen.

In another preferred embodiment, Ring A represents a ring selected from pyrrolidine, piperidine or 1,3-oxazinan-2-one, wherein X is at the 2- or 3-position on the pyrrolidine ring, at the 4-position on the piperidine ring and at the 5-position on the l,3-oxazinan-2-one ring, L2 represents -CH2-, -CH2-CH2- or -C(0)-CH2-, preferably-CH2- or -CH2-CH2-, LI represents -CH=CH-, -CH2-0-, -0-CH2-, -CH2-S- or -S-CH2- and R9a and R9b represent independently hydrogen or methyl, and preferably R9a and R9b represent hydrogen.

In another preferred embodiment, Ring A represents a ring selected from pyrrolidine, piperidine or 1,3-oxazinan-2-one, wherein X is at the 2- or 3-position on the pyrrolidine ring, at the 4-position on the piperidine ring and at the 5-position on the l,3-oxazinan-2-one ring, L2 represents -CH2-, -CH2-CH2- or -C(0)-CH2-, preferably-CH2- or -CH2-CH2-, LI represents -CH=CH-, -CH2-0-, -0-CH2-, -CH2-S- or -S-CH2-, X is -CH2- and R9a and R9b represent independently hydrogen or methyl, and preferably R9a and R9b represent hydrogen.

In another preferred embodiment, Ring A represents a ring selected from pyrrolidine, piperidine or 1,3-oxazinan-2-one, wherein X is at the 2- or 3-position on the pyrrolidine ring, at the 4-position on the piperidine ring and at the 5-position on the l,3-oxazinan-2-one ring and R8 represents methyl.

In another preferred embodiment, Ring A represents a ring selected from pyrrolidine or piperidine, wherein X is at the 3-position on the pyrrolidine ring and at the 4-position on the piperidine ring and R8 represents methyl.

In another preferred embodiment, Rl and R2 represent independently hydrogen, halogen, Ci-C4alkyl, Cp C ihaloalkyl, Ci-C4alkoxy or Ci-C4haloalkoxy and R3 represents hydrogen.

In another preferred embodiment, Rl and R2 represent independently hydrogen, halogen, Ci-C4alkyl, Cihaloalkyl or Ci-C2alkoxy and R3 represents hydrogen.

In another further preferred embodiment, Rl and R2 represent independently hydrogen, halogen, Ci-C4alkyl or CF3 and R3 represents hydrogen.

In another preferred embodiment, Rl and R2 represent independently hydrogen, F, CI, Br, i-butyl or CF3 and R3 represents hydrogen.

In another preferred embodiment, Rl and R2 represent independently hydrogen, F, CI, Br, i-butyl or CF3 and R3 represents hydrogen, wherein at least one of Rl and R2 is not hydrogen and at least one or Rl and R2 is at the para position with respect to LI .

In another preferred embodiment, Rl and R2 represent independently F, CI, Br or CF3 and R3 represents hydrogen, wherein Rl and R2 are at the ortho and para position with respect to LI .

In another preferred embodiment, Rl and R2 represent independently CI, Br or i-butyl and R3 represents hydrogen.

In another preferred embodiment Rl and R2 represent independently CI or Br and R3 represents hydrogen.

In a further preferred embodiment the compound of formula I is a compound of formula 1-20


wherein Rl, R2, R4, L2 and ASC as defined for compounds of formula I.

a further preferred embodiment the compound of formula I is a compound of formula 1-21


wherein Rl, R2, R4, L2 and ASC as defined for compounds of formula I.

In a further preferred embodiment the compound of formula I is a compound of formula 1-22


wherein Rl, R2, R4, L2 and ASC as defined for compounds of formula I.

In a further preferred embodiment the compound of formula I is a compound of formula I


wherein Rl, R2, R4, L2 and ASC as defined for compounds of formula I.

In a further preferred embodiment the compound of formula I is a compound of formula 1-24


wherein Rl, R2, R4, L2 and ASC as defined for compounds of formula I.

In embodiment Al the compound of formula I is a compound of formula 1-20, 1-21 , 1-22, 1-23 or 1-24 wherein

ASC is


wherein

Ring A represents a ring selected from azetidine, pyrrolidine, piperidine, l ,3-oxazolidin-2-one or 1 ,3-oxazinan-2-one;

Rl , R2, represent independently hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, CpCealkoxy or Cp Cehaloalkoxy;

R4 represents hydrogen, halogen, Ci-C4alkyl, C2-C4alkenyl, Ci-C4alkylene-R10b, C2-C6alkenylene-R10b, C(0)ORl l a, CHO, C(0)N(R12)R13 or 0-R14;

R8 represents methyl or is absent, and when R8 is present the respective nitrogen atom carries a positive charge;

R9a and R9b represent independently hydrogen or methyl;

Rl Ob represents C3-C8cycloalkyl, C(0)ORl l a, CHO, C(0)N(R12)R13, N(R12)R13, Cycle-P or Cycle-Q; R14 represents Ci-Cealkyl, Ci-Cehaloalkyl, C2-Cealkenyl, C2-C6haloalkenyl, CpCealkylene-Cycle-P or Cp C6alkylene-Cycle-Q;

Cycle-P represents independently at each occurrence cyclopentyl or cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl or morpholinyl, each optionally substituted by 1 to 3 R15; Cycle-Q represents independently at each occurrence phenyl or a 5- to 6-membered heteroaryl ring containing one to four heteroatoms independently selected from O, S and N, optionally substituted by 1 to 3 R16;

L2 represents Ci-C7alkylene, wherein one or more -CH2- moieties in the alkylene moiety are optionally replaced independently by -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties and wherein the terminal moiety of L2 is not -C(=0)-.

In embodiment A2 the compound of the invention is a compound of formula 1-20, 1-21 , 1-22, 1-23 or 1-24, as defined in embodiment Al , wherein L2 represents Ci-C4alkylene, wherein one or more -CH2- moieties in the alkylene moiety are optionally replaced independently by -C(=0)-, wherein within L2 there are no adjacent -C(=0)- moieties and wherein the terminal moiety of L2 is not -C(=0)-.

In embodiment A3 the compound of the invention is a compound of formula 1-20, 1-21 , 122, 123 or 1-24, as defined in embodiment A2, wherein R14 represents CpCealkyl, C2-Cealkenyl or CpCealkylene-Cycle-Q.

In embodiment A4 the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24, as defined in embodiment A3, wherein L2 represents -CH2-, -CH2-CH2- or -C(0)-CH2-.

In embodiment A5 the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24, as defined in embodiment A4, wherein Ring A represents a ring selected from azetidine, pyrrolidine, piperidine or l,3-oxazinan-2-one.

In embodiment A6 the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24, as defined in embodiment A5, wherein Rl 0b represents C(0)0R11 a, CHO or C(0)N(R12)R13.

In embodiment A7 the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24 as defined in embodiment A6, wherein R12 represents Ci-C4alkyl or Ci-C4alkoxy-Ci-C4alkyl; and

R13 represents hydrogen or methyl.

In embodiment A8 the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24 as defined in embodiment A7, wherein Rl and R2 represent independently hydrogen, halogen or Ci-C4alkyl.

In embodiment A9 the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24 as defined in embodiment A8, wherein R4 represents hydrogen, halogen, Ci-C4alkyl, C2-C6alkenylene-R10b, C(0)ORl la, CHO, C(0)N(R12)R13 or 0-R14; and RlOb represents C(0)ORl la.

In embodiment A10 the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24 as defined in embodiment A9, wherein Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl.

In embodiment Al 1 the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24 as defined in embodiment A10, wherein R13 represents hydrogen.

In embodiment A12 the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24 as defined in embodiment Al 1, wherein X is at the 2- or 3-position on the pyrrolidine ring, at the 4-position on the piperidine ring or at the 5-position on the l,3-oxazinan-2-one ring.

In embodiment A13 the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24, wherein

ASC is ASC-a, ASC-b or ASC-c

Rl and R2 represent independently hydrogen, halogen or Ci-C4alkyl;

R4 represents hydrogen, halogen, CrC4alkyl, C2-C6alkenylene-R10b, C(0)ORl l a, CHO, C(0)N(R12)R13 or 0-R14;

R9a and R9b represent independently hydrogen or methyl;

Rl Ob represents C(0)ORl l a;

Rl l a represents hydrogen or Ci-C4alkyl;

R12 represents Ci-C4alkyl or Ci-C4alkoxy-Ci-C4alkyl;

R13 represents hydrogen;

R14 represents Ci-Cealkyl, C2-C6alkenyl or CpCealkylene-Cycle-Q;

Cycle-Q represents furanyl, thiophenyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl; and L2 represents -CH2-, -CH2-CH2- or -C(0)-CH2-.

In embodiment A14 the compound of the invention is a compound of formula 1-20, 1-21 , 122, 123 or 1-24 as defined in embodiment A13, wherein R8 is absent.

In embodiment A15 the compound of the invention is a compound of formula 1-20, 1-21 , 122, 123 or 1-24 as defined in embodiment A13, wherein R8 represents methyl.

In embodiment A16 the compound of the invention is a compound of formula 1-20, 1-21 , 122, 123 or 1-24 as defined in embodiment A13, wherein R8 is absent; and R9a and R9b represent hydrogen.

In embodiment A17 the compound of the invention is a compound of formula 1-20, 1-21 , 122, 123 or 1-24 as defined in embodiment A13, wherein R8 represents methyl; and R9a and R9b represent hydrogen.

In embodiment A18 the compound of the invention is a compound of formula 1-20, 1-21 , 122, 123 or 1-24 as defined in embodiment A13, wherein R8 is absent; R9a and R9b represent hydrogen; and

R4 represents hydrogen, halogen, CrC4alkyl, C2-C6alkenylene-R10b, CHO, C(0)N(R12)R13 or 0-R14.

In embodiment A19 the compound of the invention is a compound of formula 1-20, 1-21 , 122, 123 or 1-24 as defined in embodiment A13, wherein R8 represents methyl; R9a and R9b represent hydrogen; and

R4 represents hydrogen, halogen, CrC4alkyl, C2-C6alkenylene-R10b, CHO, C(0)N(R12)R13 or 0-R14.

In embodiment A20 the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24 as defined in embodiment A13, wherein R8 is absent; R9a and R9b represent hydrogen; and R4 represents hydrogen, halogen, CrC4alkyl, CH=CH-C(0)ORl la, CHO, C(0)N(R12)R13 or 0-R14.

In embodiment A21 the compound of the invention is a compound of formula 1-20, 1-21, 122, 123 or 1-24 as defined in embodiment A13, wherein R8 represents methyl; R9a and R9b represent hydrogen; and R4 represents hydrogen, halogen, CrC4alkyl, CH=CH-C(0)ORl la, CHO, C(0)N(R12)R13 or 0-R14.

In embodiment A22 the compound of the invention is a compound of formula 1-20, 1-21 or 122 as defined in embodiment A13, wherein ASC is ASC-a or ASC-b


R8 is absent; R9a and R9b represent hydrogen; Cycle-Q represents furanyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl; and L2 represents -CH2- or -CH2-CH2-.

In embodiment A23 the compound of the invention is a compound of formula 1-20, 1-21 or 122 as defined in embodiment A13, wherein ASC is ASC-a or ASC-b


R8 represents methyl and the respective nitrogen atom carries a positive charge; R9a and R9b represent hydrogen; Cycle-Q represents furanyl, pyrrolyl, pyrazolyl, imidazolyl or pyridinyl; L2 represents -CH2- or - CH2-CH:

A further embodiment A24 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 1-20.

A further embodiment A25 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 1-21

A further embodiment A26 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 1-22

A further embodiment A27 of compounds of the invention is represented by any one of the embodiments Al to A21, wherein the compound of formula I is a compound of formula 1-23.

A further embodiment A28 of compounds of the invention is represented by any one of the embodiments Al to A21, wherein the compound of formula I is a compound of formula 1-24.

A further embodiment A29 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 1-20 and ASC is ASC-a.

A further embodiment A30 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 120 and ASC is ASC-b.

A further embodiment A31 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 121 and ASC is ASC-a.

A further embodiment A32 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 121 and ASC is ASC-b.

A further embodiment A33 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 122 and ASC is ASC-a.

A further embodiment A34 of compounds of the invention is represented by any one of the embodiments Al to A23, wherein the compound of formula I is a compound of formula 122 and ASC is ASC-b.

Further embodiments of compounds of the invention are represented by embodiments B 1 to B9, wherein, in each case, Rl, R2, R3, R4, R5, R6, R7, RlOa, RlOb, Rl la, Rl lb, R12, R13, R14, R15, R16, R17a, R17b, Cycle-P, Cycle Q and LI are as defined for compounds of formula I.

Embodi¬

L2 ASC

ment

Bl CH2 N+(CH3)(Pyrrolidine)-CH2-NH2

B2 CH2 Pyrrolidine-CH2-NH2

B3 CH2 Piperidine- CH2-NH2

B4 CH2 5-(aminomethyl)-l,3-oxazinan-2-one

B5 CH2 Pyrrolidine-NH2

B6 (CH2)2 Pyrrolidine-CH2-NH2

B7 (CH2)2 N+(CH3)(Pyrrolidine)-CH2-NH2

B8 C(=0)-CH2 Pyrrolidine-CH2-NH2

B9 C(=0)-CH2 N+(CH3)(Pyrrolidine)-CH2-NH

Further embodiments of compounds of the invention are represented by embodiments B 1 to B9, wherein, in each case, Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as in any one of the embodiments Al to A34.

Further embodiments of compounds of the invention are represented by embodiments Bal-Ba9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment Al .

Further embodiments of compounds of the invention are represented by embodiments Bbl-Bb9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A2.

Further embodiments of compounds of the invention are represented by embodiments Bcl-Bc9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A3.

Further embodiments of compounds of the invention are represented by embodiments Bdl-Bd9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A4.

Further embodiments of compounds of the invention are represented by embodiments Bel-Be9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A5.

Further embodiments of compounds of the invention are represented by embodiments Bfl-Bf9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A6.

Further embodiments of compounds of the invention are represented by embodiments Bgl-Bg9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A7.

Further embodiments of compounds of the invention are represented by embodiments Bhl-Bh9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A8.

Further embodiments of compounds of the invention are represented by embodiments Bil -Bi9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A9.

Further embodiments of compounds of the invention are represented by embodiments Bj l -Bj9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A10.

Further embodiments of compounds of the invention are represented by embodiments Bkl-Bk9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment Al 1.

Further embodiments of compounds of the invention are represented by embodiments B11 -B19, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A12.

Further embodiments of compounds of the invention are represented by embodiments Bml-Bm9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A13.

Further embodiments of compounds of the invention are represented by embodiments Bnl-Bn9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A14.

Further embodiments of compounds of the invention are represented by embodiments Bol-Bo9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A15.

Further embodiments of compounds of the invention are represented by embodiments Bpl-Bp9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A16.

Further embodiments of compounds of the invention are represented by embodiments Bql-Bq9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A17.

Further embodiments of compounds of the invention are represented by embodiments Brl-Br9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A18.

Further embodiments of compounds of the invention are represented by embodiments Bsl-Bs9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A19.

Further embodiments of compounds of the invention are represented by embodiments Btl-Bt9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A20.

Further embodiments of compounds of the invention are represented by embodiments Bul-Bu9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A21.

Further embodiments of compounds of the invention are represented by embodiments Bvl-Bv9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A22.

Further embodiments of compounds of the invention are represented by embodiments Bwl-Bw9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A23.

Further embodiments of compounds of the invention are represented by embodiments Bxl-Bx9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A24.

Further embodiments of compounds of the invention are represented by embodiments Byl-By9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A25.

Further embodiments of compounds of the invention are represented by embodiments Bzl-Bz9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A26.

Further embodiments of compounds of the invention are represented by embodiments Baal-Baa9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A27.

Further embodiments of compounds of the invention are represented by embodiments Bbbl-Bbb9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A28.

Further embodiments of compounds of the invention are represented by embodiments Bccl -Bcc9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A29.

Further embodiments of compounds of the invention are represented by embodiments Bddl -Bdd9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A30.

Further embodiments of compounds of the invention are represented by embodiments Beel -Bee9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A31.

Further embodiments of compounds of the invention are represented by embodiments Bffl-Bff9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A32.

Further embodiments of compounds of the invention are represented by embodiments Bggl -Bgg9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A33.

Further embodiments of compounds of the invention are represented by embodiments Bhhl -Bhh9, which correspond to embodiments Bl to B9, but wherein Rl, R2, R4, RlOb, Rl la, Rl lb, R12, R13, R14, Cycle-P, and Cycle Q are as defined as for compounds of formula I in embodiment A34.

Further embodiments of compounds of the invention are represented by embodiments CI to CI 8, wherein, in each case, R3, R5, R6, R7, R8, R9a, R9b, R17a, R17b, L2 and ASC are as defined for compounds of formula I.


Further embodiments of compounds of the invention are represented by embodiments CI to CI 8, wherein, in each case, R3, R5, R6, R7, L2 and ASC are as defined as in any one of the embodiments Al to A34.

Further embodiments of compounds of the invention are represented by embodiments Cal-Cal 8, which correspond to embodiments CI to C18, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment Al .

Further embodiments of compounds of the invention are represented by embodiments Cbl-Cbl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A2.

Further embodiments of compounds of the invention are represented by embodiments Ccl-Ccl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A3.

Further embodiments of compounds of the invention are represented by embodiments Cdl-Cdl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A4.

Further embodiments of compounds of the invention are represented by embodiments Cel-Cel 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A5.

Further embodiments of compounds of the invention are represented by embodiments Cfl-Cfl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A6.

Further embodiments of compounds of the invention are represented by embodiments Cgl -Cgl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A7.

Further embodiments of compounds of the invention are represented by embodiments Chi -Chi 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A8.

Further embodiments of compounds of the invention are represented by embodiments Cil -Cil 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A9.

Further embodiments of compounds of the invention are represented by embodiments Cj l-Cjl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A10.

Further embodiments of compounds of the invention are represented by embodiments Ckl-Ckl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment Al 1.

Further embodiments of compounds of the invention are represented by embodiments C11-C118, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A12.

Further embodiments of compounds of the invention are represented by embodiments Cml-Cml 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A13.

Further embodiments of compounds of the invention are represented by embodiments Cnl-Cnl 8, which correspond to embodiments CI to C18, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A14.

Further embodiments of compounds of the invention are represented by embodiments C0I-C0I 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A15.

Further embodiments of compounds of the invention are represented by embodiments Cpl-Cpl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A16.

Further embodiments of compounds of the invention are represented by embodiments Cql-Cql 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A17.

Further embodiments of compounds of the invention are represented by embodiments Crl-Crl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A18.

Further embodiments of compounds of the invention are represented by embodiments Cs 1 -Cs 18, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A19.

Further embodiments of compounds of the invention are represented by embodiments Ctl-Ctl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A20.

Further embodiments of compounds of the invention are represented by embodiments Cul-Cul 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A21.

Further embodiments of compounds of the invention are represented by embodiments Cvl-Cvl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A22.

Further embodiments of compounds of the invention are represented by embodiments Cwl-Cwl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A23.

Further embodiments of compounds of the invention are represented by embodiments Cxi -Cxi 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A24.

Further embodiments of compounds of the invention are represented by embodiments Cyl-Cyl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A25.

Further embodiments of compounds of the invention are represented by embodiments Czl-Czl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A26.

Further embodiments of compounds of the invention are represented by embodiments Caal-Caal 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A27.

Further embodiments of compounds of the invention are represented by embodiments Cbbl-Cbbl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A28.

Further embodiments of compounds of the invention are represented by embodiments Cccl-Cccl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A29.

Further embodiments of compounds of the invention are represented by embodiments Cddl -Cddl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A30.

Further embodiments of compounds of the invention are represented by embodiments Ceel -Ceel 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A31.

Further embodiments of compounds of the invention are represented by embodiments Cffl-Cffl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A32.

Further embodiments of compounds of the invention are represented by embodiments Cggl -Cggl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A33.

Further embodiments of compounds of the invention are represented by embodiments Chhl -Chhl 8, which correspond to embodiments CI to CI 8, but wherein R3, R5, R6, R7, L2 and ASC are as defined as for compounds of formula I in embodiment A34.

Further embodiments of compounds of the invention are represented by embodiments Dl to D25, wherein, in each case, R3, R5, R6, and R7 are as defined for compounds of formula I.

Embodi¬

Rl R2 LI R4 L2 ASC

ment

Dl CI Br 0-CH2 H CH2 Piperidine-NH2

D2 CI Br 0-CH2 H CH2 Pyrrolidine-CH2-NH2

D3 CI Br 0-CH2 H CH2 Pyrrolidine-NH2

D4 CI Br CH2-0 O-Allyl CH2 Pyrrolidine-CH2-NH2

5-(aminomethyl)-l,3- D5 CI Br CH2-0 C(=0)-NH2 CH2

oxazinan-2-one

C(=0)-NH-(CH2)3-0- 5-(aminomethyl)-l,3- D6 CI Br CH2-0 CH2

CH3 oxazinan-2-one

5-(aminomethyl)-l,3- D7 CI Br CH2-0 CHO CH2

oxazinan-2-one

5-(aminomethyl)-l,3- D8 CI Br CH2-0 CH=CH-C02Et CH2

oxazinan-2-one

D9 CI CF3 CH2-0 H CH2 Pyrrolidine-CH2-NH2

D10 CI Br CH2-0 H C(=0)-CH2 Pyrrolidine-CH2-NH2

Dl l CI Br CH=CH H CH2 Pyrrolidine-CH2-NH2

D12 CI Br CH2-0 H C(=0)-CH2 Pyrrolidine-CH2-NH2

D13 CI Br CH2-0 H C(=0)-CH2 Pyrrolidine-CH2-NH2

D14 CI Br CH2-S H CH2 Pyrrolidine-CH2-NH2

D15 CI Br CH=CH CI CH2 Pyrrolidine-CH2-NH2

D16 CI Br CH=CH H (CH2)2 Pyrrolidine-CH2-NH2

5-(aminomethyl)-l,3- D17 iBu H CH=CH O-Allyl CH2

oxazinan-2-one

5-(aminomethyl)-l,3- D18 CI Br CH=CH O-Allyl CH2

oxazinan-2-one

5-(aminomethyl)-l,3- D19 CI Br CH=CH C(=0)-NH2 CH2

oxazinan-2-one

5-(aminomethyl)-l,3- D20 iBu H CH=CH C(=0)-NH2 CH2

oxazinan-2-one

N+(CH3)(Pyrrolidine)- D21 CI Br CH2-0 O-Allyl CH2

CH2-NH2

N+(CH3)(Pyrrolidine)- D22 CI Br CH2-0 O-zBu CH2

CH2-NH2

N+(CH3)(Pyrrolidine)- D23 CI Br CH2-0 0-CH2-CH2-Imidazole CH2

CH2-NH2

N+(CH3)(Pyrrolidine)- D24 CI Br CH=CH O-Allyl CH2

CH2-NH2

N+(CH3)(Pyrrolidine)- D25 CI Br CH=CH 0-CH2-CH2-Imidazole CH2

CH2-NH2

Further embodiments of compounds of the invention are represented by embodiments D11, D15, D16, D17, D18, D19, D20, D24 or D25, 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 D4, D5, D6, D7, D8, D9, D10, D12, D13, D21, D22 or D23, wherein, in each case, the compound of the invention is a compound of formula 1-21.

Further embodiments of compounds of the invention are represented by embodiments Dl, D2 or D3, wherein, in each case, the compound of the invention is a compound of formula 1-22.

Further embodiments of compounds of the invention are represented by embodiments D14, wherein the compound of the invention is a compound of formula 1-23.

Further embodiments of compounds of the invention are represented by embodiments Dl to D25, wherein, in each case, R3, R5, R6, and R7 are H.

Further embodiments of compounds of the invention are represented by embodiments D11, D15, D16, D17, D18, D19, D20, D24 or D25, 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 D11, D15, D16, D18, D19, D24 or D25, 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 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 D4, D5, D6, D7, D8, D9, D10, D12, D13, D21, D22 or D23, wherein, in each case, the compound of the invention is a compound of formula 1-21, and wherein Rl is at the para position on ARl with respect to LI .

Further embodiments of compounds of the invention are represented by embodiments D4, D5, D6, D7, D8, D9, D10, D12, D13, D21, D22 or D23, wherein, in each case, the compound of the invention is a compound of formula 1-21, and wherein Rl is at the para position on ARl with respect to LI, and wherein R2 is at the ortho position on ARl with respect to LI .

Further embodiments of compounds of the invention are represented by embodiments Dl, D2 or D3, wherein, in each case, the compound of the invention is a compound of formula 1-22, and wherein Rl is at the para position on ARl with respect to LI .

Further embodiments of compounds of the invention are represented by embodiments Dl, D2 or D3, wherein, in each case, the compound of the invention is a compound of formula 1-22, and wherein Rl is at the para position on ARl with respect to LI, and wherein R2 is at the ortho position on ARl with respect to LI .

Further embodiment of compounds of the invention are represented by embodiment D14, wherein the compound of the invention is a compound of formula 1-23, and wherein Rl is at the para position on ARl with respect to LI .

Further embodiment of compounds of the invention are represented by embodiment D14, wherein the compound of the invention is a compound of formula 1-23, and wherein Rl is at the para position on ARl with respect to LI, and wherein R2 is at the ortho position on ARl with respect to LI .

Further embodiments of compounds of the invention are represented by any one of the compounds 1 -25 of Table 1.

The methods of the invention relate to administering the compound of formula I in combination with the antimicrobial agent. Administering the compound of formula I in combination with an antimicrobial agent means, for example, that the compound of formula I and antimicrobial agent are administered

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, 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, 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, Cef uperazone, 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, ME1036, BAL30072, SYN 2416, Ceftiofur, Cefquinome, Cefovecin, Aztreonam, Tigemonam, Carumonam, Tebipenem, Tomopenem, RWJ-442831, RWJ-333441, BAL30072 or RWJ-333442.

Macro lides: Macro lides 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, PD 131628, PD 138312, PD 140248, Q-35, AM-1155, NM394, T-3761, rufloxacin, OPC-17116, DU-6859a (AAC 37: 1419), J J-Q2 or DV-7751a (AAC 37:2212).

Tetracyclines and glycylcyclines: 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.

Pleuromutilins: Pleuromutilins 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), (c) or (d) described below; followed, if necessary, by removing any protecting groups, forming a pharmaceutically acceptable salt, or forming a pharmaceutically acceptable solvate or hydrate.

Process (a):

This process variant can be used for the manufacture of compounds of formula I as defined above, wherein LI is -(CH2)m-0- and-(CH2)m-S-, in which formulae m is 1 or 2 within the limits defined by the claims.

In this process a compound of formula II- 1


is reacted with a compound of formula III


to generate a compound of formula IV- 1


in which formulae

AR1, AR2, Rl, R2, R3, R5, R6 and R7 are as in formula I,

m is lor 2,

Yl is -OH, a halogen atom or a leaving group like mesylate, tosylate, triflate,

Al is -O- or -S-,

PG1 is a hydrogen atom or a hydroxyl protecting group (such as allyl, benzyl, tetrahydropyranyl or silyl ethers),

A2 is -(CH2)0-Y2,

wherein o is 0, 1, 2 or 3,

Y2 is -OH, a halogen atom, a leaving group like mesylate, tosylate, triflate, -COOH, -CHO or -C(0)-CH2-X,

wherein X is a halogen atom,

A3 is R4, wherein R4 is as defined for compounds of formula I, or A3 is a halogen atom, -OH, -CHO or -COOH.

When A3 is a halogen atom, the compound of formula IV- 1 further reacted with a compound of formula V

R'4-X (V)

wherein X is -CH2-OH,

to generate a compound of formula VI- 1


wherein R4 is 0-R14, wherein 0-R14 is as defined for compounds of 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 0-R14, wherein 0-R14 is as defined for compounds of formula I.

When A3 is -CHO, the compound of formula IV- 1 can further react with a compound of formula V wherein X is a phosphonium salt or a phosphonate, to generate a compound of formula VI-1 wherein R4 is a C2-C6-alkenyl group.

When A3 is -COOH, the compound of formula IV- 1 can further react with a compound of formula V wherein X is -NHE or -NH2, E being an amino protecting group (such as allyloxycarbonyl,

benzyloxycarbonyl, 9-fluorenylmethylcarbonyl, tert-butoxycarbonyl or benzyl), to generate a compound of formula VI-1 wherein R4 is an amide group.

When Y2 is -OH, the compound of formula VI-1 can be converted to the corresponding halide, mesylate, tosylate, triflate compound, and further react with a compound of VII

ASC-H (VII)

to generate a compound of formula 1-1 wherein L2 is -(CH2)0-.

When Y2 is a halogen atom, a leaving group like mesylate, tosylate, triflate, -CHO, -C(0)-CH2-X or -COOH, compound of formula VI-I is reacted with a compound of formula VII

ASC-H (VII)

to generate a compound of formula 1-1 wherein L2 is -(CH2)0-, -(CH2)P-, -(CH2)0-C(0)-CH2- or -(CH2)0-C(O)-, respectively, wherein p is 1, 2, 3 or 4.

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- or -S-(CH2)n-, in which formulae n is 1 or 2 within the limits defined by the claims.

In this process a compound of formula VIII


is reacted with a compound of formula IX


to generate a compound of formula IV-2


in which formulae

ARl, AR2, Rl, R2, R3, R5, R6 and R7 are as defined for compounds of formula I,

n is 1 or 2,

Al is -O- or -S-,

PG1 is a hydrogen atom or a hydroxyl protecting group,

Y is a halogen atom, a hydroxyl group or a leaving group like mesylate, tosylate, triflate,

A2 and A3 have the same meaning as in formulae III and IV- 1.

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


(VI-2)

wherein R4 is as defined for compounds of 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


is reacted with a compound of formula X


to generate a compound of formula IV-3


in which formulae

ARl , AR2, Rl , R2, R3, R5, R6 and R7 are as defined for compounds of formula I,

Y is a phosphonium salt or a phosphonate,

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


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 -

Process (d):

This process variant can be used for the manufacture of compounds of formula I as defined above, that present a quaternary amine. These molecules can be obtained by reacting a methyl halide or the

corresponding mesylate, tosylate or triflate with any compound of formula I or VI for which a free secondary amine is present.

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 - or -(CH2)m-S -, with m being lor 2 (within the limits defined by the claims), can be obtained as summarized in Scheme 1.

R2_(. AR1 j_(CH2)m-Y1 + PG1 -A1


11-1 III IV-1

R'4-X (V)


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-l . The benzyl group is removed by hydrogenolysis over a noble metal catalyst (e.g. palladium or palladium hydroxide on activated carbon); the tetrahydropyranyl group is removed in presence of /jara-toluenesulfonic acid at pH 3, between 40 °C and 70 °C in a solvent such as methanol; the silyl ether groups are removed either using fluoride anion sources such as tetra-n-butylammonium fluoride in a solvent such as tetrahydrofuran or NN-dimethylformamide between 0 °C and 40 °C or in hydrofluoric acid in acetonitrile between 0 °C and 40 °C or using acidic conditions such as acetic acid in tetrahydrofuran-methanol or hydrochloric acid in methanol. 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- wherein LI is -(CH2)m-0 - 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 A1-PG1 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-dimethoxyethane 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 wherein LI is -(CH2)m-0 - consists of reacting compounds of formula III wherein Al -PG1 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 100 °C. Activation of the hydroxyl group of compounds of formula II- 1 wherein Yl is -OH as for example a mesylate, a tosylate or a triflate can be achieved by reacting the corresponding alcohol with methanesulfonyl chloride or methanesulfonic anhydride, / toluenesulfonyl chloride, trifluoromethanesulfonyl chloride or

trifluoromethanesulfonic anhydride, 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.

The same procedure can also be applied to generate compounds of formula IV-1 wherein LI is -(CH2)m-S -starting from compounds of formula II- 1 wherein Yl is a halogen atom or a leaving group and compounds of formula III wherein A1-PG1 is a thiol group.

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 0-R14, wherein 0-R14 is as defined for compounds of formula I. 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 -CH2-OH can lead to the generation of compounds of formula VI-1 wherein R4 is 0-R14, wherein 0-R14 is as defined for compounds of formula I.

Additionally, when A3 is a hydroxyl group, compounds of formula IV-1 can react with a compound of formula V for which X is a halogen atom or a leaving group, in presence of an inorganic base such as sodium hydride or the like in a solvent such as tetrahydrofuran or NN-dimethylformamide at a temperature ranging between -20 °C and 80 °C, to generate compounds of formula VI-1 wherein R4 is 0-R14, wherein 0-R14 is as defined for compounds of formula I.

When A3 is -CHO, compounds of formula IV- 1 can react with compounds of formula V for which X is a phosphonium salt or a phosphonate via a Wittig or Horner- Wadsworth-Emmons reaction, respectively, to generate compounds of formula VI- 1 for which R4 is a C2-C6-alkenyl group.

The Wittig reaction is the reaction of an aldehyde with a triphenyl phosphonium ylide to afford an alkene and triphenylphosphine oxide. The Wittig reagent is usually prepared from a phosphonium salt, which is, in turn, prepared by alkylation of triphenylphosphine with a benzyl halide. To form the Wittig reagent (benzyl ylide), the phosphonium salt is suspended in a solvent such as diethyl ether or tetrahydroiuran 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 tetrahydroiuran, 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.

When A3 is -COOH, compounds of formula IV- 1 can react with compounds of formula V for which X is -NH2 or -NHE, E being an amino protecting group, via a peptidic coupling reaction, to generate compounds of formula VI- 1 for which R4 is an amide group. The reaction takes place in the presence of an activating agent such as NN'-dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, with the optional addition of 1 -hydroxybenzotriazole. Other suitable coupling agents may be utilized such as, 0-(7-azabenzotriazol-l-yl)-N,NN',N'-tetramethyluronium hexafluorophosphate, 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline, carbonyldiimidazole or diethylphosphorylcyanide. 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 a compound of formula II- 1 in an aprotic solvent like dichloromethane, chloroform, acetonitrile, NN-dimethylformamide and tetrahydroiuran to generate a compound of formula 1-1. Optionally, a base like triethylamine, NN-diisopropylethylamine, pyridine, sodium hydroxide, sodium carbonate, potassium carbonate can be added to perform the coupling.

The amino protecting group E is introduced by reacting the corresponding free amine with allyl,

fluorenylmethyl or benzyl chloroformate or with di-teri-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.

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 compounds and react with compounds of formula VII via a substitution reaction as previously described above.

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 via a substitution reaction as previously described above, to generate compounds of formula 1-1 wherein L2 is -(CH2)o- or -(CH2)o-C(0)-CH2-, respectively.

When Y2 is -CHO, compounds of formula VI- 1 can react with compounds of formula VII via a reductive amination reaction, to generate compounds of formula 1-1 for which L2 is -(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 5 traces of acid (usually acetic acid). The intermediate imine is reduced subsequently or simultaneously with a suitable reducing agent (e.g. sodium borohydride, sodium cyanoborohydride, sodiumtriacetoxyborohydride; R.O. and M.K. Hutchins, Comprehensive Organic Synthesis, B.M. Trost, I. 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 10 60 °C. The reaction can also be carried out in one pot. It can also be performed in protic solvents such as methanol or water in presence of a picoline-borane complex (Tetrahedron, 2004, 60, 7899).

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 derivatives are further reduced into their corresponding alcohols. This reduction is performed with a reducing agent like boron or aluminium hydride reducing agent such as lithium aluminium hydride, lithium borohydride, sodium borohydride in a solvent such as tetrahydrofuran between -20 °C and 80 °C. 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 via a peptidic 30 coupling reaction as previously described above, to generate compounds of formula 1-1 wherein L2 is -

In Scheme 1 , the amino protecting groups can be removed at any convenient step of the process.

35 The compounds of formula I wherein LI is -0-(CH2)n- or -S-(CH2)n-, with n being 1 or 2 (within the limits defined by the claims), can be obtained as summarized in Scheme 2.


Scheme 2.

In Scheme 2, all the symbols have the same meanings as previously described in process (b).

Compounds of formula IV-2 wherein LI is -0-(CH2)n- or -S-(CH2)n- can be obtained via a substitution reaction between compounds of formula VIII for which -A1-PG1 is -OH or -SH, respectively, 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 wherein LI is -0-(CH2)n-, can be obtained from compounds of formula VIII wherein -A1-PG1 is -OH via a Mitsunobu coupling (as reviewed in O. Mitsunobu, Synthesis 1981, 1) with compounds of formula IX for which Y is a hydroxyl group, following procedures previously described above in Scheme 1.

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 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.


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, following procedures previously described above in Scheme 1.

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, Vl-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, Vl-3 and 1-4, respectively, for which LI is or -(CH2)m+2- via hydrogeno lysis 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 can be removed at any convenient step of the process.

Finally, some compounds of formula I present a quaternary amine. These compounds can be obtained by reacting a methyl halide or the corresponding mesylate, tosylate or triflate with any compounds of formula I or VI for which a free amine is present, in presence of a base such as sodium hydrogen carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, triethylamine, in a variety of organic solvents including methanol, acetonitrile, acetone, dichloromethane and NN-dimethylformamide, aqueous solvents and under biphasic conditions. Reactions are typically run from 0°C to 150°C.

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 μιη, 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 μL of 20 mM sample DMSO solution

Flow: 1.6 mL/min

Gradient: Time (min) % Mobile Phase B

0 5

8 95

10 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:

CDC13: Deuterated chloroform

CD3OD: Deuterated methanol

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 spectoscopy

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.





Preparation of Example 1 : l-[[3-[(2-bromo-4-chloro-phenoxy)methyllphenyllmethyllpiperidin-4-amine:

Preparation of 3-[(2-bromo-4-chloro-phenoxy)methyl]benzonitrile:

Potassium carbonate (20.0 g, 144.6 mmol, 3.0 eq) is added at room temperature to a stirred solution of 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] in NN-dimethylformamide (100 mL). After 16 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3 x 200 mL) and water (200 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 3-[(2-bromo-4-chloro-phenoxy)methyl]benzonitrile as a white solid (12.1 g, 78% yield) that is directly engaged in the next step without further purification.

'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:

Diisobutylalumimum hydride (1M solution in n-hexane, 18.6 mL, 18.6 mmol, 1.5 eq) is added dropwise at 0°C to a stirred solution of 3-[(2-bromo-4-chloro-phenoxy)methyl]benzonitrile (4.0 g, 12.4 mmol, 1.0 eq) in dichloromethane (40 mL). After 2 hours stirring at 0°C, the reaction mixture is poured in a 6N hydrochloric acid aqueous solution (40 mL). The phases are separated and the aqueous phase is extracted with ethyl acetate (3 x 50 mL). The combined organic layers are washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel; petroleum ethenethyl acetate, 10: 1, v/v) to afford 3-[(2-bromo-4-chloro-phenoxy)methyl]benzaldehyde as a white solid (3.3 g, 82% yield).

'H-NMR (400 MHz, CDCI3) 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 ferf-butyl N-[l-[3-[(2-bromo-4-chloro-phenoxy)methyl]phenyl]methyl]-4-piperidyl]carbamate:

tert-Butyl N-(4-piperidyl)carbamate [73874-95-0] (492 mg, 2.46 mmol, 2.0 eq) is added at room temperature to a stirred solution of 3-[(2-bromo-4-chloro-phenoxy)methyl]benzaldehyde (400 mg, 1.23 mmol, 1.0 eq) in dichloromethane (15 mL), followed by one drop of acetic acid. After 30 minutes stirring at room

temperature, sodium cyanoborohydride (154 mg, 2.46 mmol, 2.0 eq) is added. After 16 hours stirring at room temperature, the reaction mixture is concentrated to afford tert-butyl N-[l-[3-[(2-bromo-4-chloro-phenoxy)methyl]phenyl]methyl]-4-piperidyl]carbamate (624 mg, 99%> yield) that is directly engaged in the next step without further purification.

MS m/z (+ESI): 509.2, 511.2 [M+H]+.

Preparation of l-[[3-[(2-bromo-4-chloro-phenoxy)methyl]phenyl]methyl]piperidin-4-amine:

A solution of tert-butyl N-[l-[3-[(2-bromo-4-chloro-phenoxy)methyl]phenyl]methyl]-4-piperidyl]carbamate (600 mg, 1.17 mmol, 1.0 eq) in a 2N hydrochloric acid solution in ethyl acetate (20 niL) is stirred at room temperature for 2 hours. Then the reaction mixture is concentrated to give a residue that is purified by preparative HPLC to afford l-[[3-[(2-bromo-4-chloro-phenoxy)methyl]phenyl]methyl]piperidin-4-amine as a white solid (150 mg, 30% yield).

Preparation of Example 5: 3-[[5-(aminomethyl)-2-oxo-l,3-oxazinan-3-yllmethyll-5-[(2-bromo-4-chloro-phenvDmethoxylbenzamide:

Preparation of ferf -butyl 3 - 1"[ [3 - |"(2-bromo-4-chloro-phenyl)methoxyl -5-carbamoyl-phenyllmethyll -tert-butoxycarbonyl-amino"|methyll azetidine- 1 -carboxylate :

Pyridine (8 μΐ^, 0.094 mmol, 0.6 eq) is added at room temperature to a stirred solution of 3-[(2-bromo-4-chloro-phenyl)methoxy]-5-[[tert-butoxycarbonyl-[(l-tert-butoxycarbonylazetidin-3-yl)methyl]amino]methyl]benzoic acid (100 mg, 0.15 mmol, 1.0 eq), ammonium bicarbonate (20 mg, 0.25 mmol, 1.6 eq) and di-tert-butyl dicarbonate (58 mg, 0.26 mmol, 1.7 eq) in acetonitrile (2 mL). After 15 hours stirring at room temperature, the reaction mixture is concentrated to give a residue that is purified by column chromatography (silica gel; petroleum ether:ethyl acetate, 2:1, v/v) to afford tert-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-carbamoyl-phenyl]methyl]-tert-butoxycarbonyl-amino]methyl]azetidine-l-carboxylate as a colorless semi-solid (74 mg, 74% yield).

'H-NMR (400 MHz, DMSO-i/6 + D20) δ ppm: 7.98 (s, 1H), 7.85 (s, 1H), 7.59 (d, J= 8.4 Hz, 1H), 7.50 (dd, J= 2.0 Hz, 8.0 Hz, 1H), 7.46 (s, 1H), 7.38 (s, 2H), 6.94 (s, 1H), 5.15 (s, 2H), 4.38 (s, 2H), 3.75 (m, 2H), 3.50 (m, 2H), 3.35 (m, 2H), 2.70 (m, 1H), 1.30-1.50 (m, 18H).

MS m/z (+ESI): 638.2, 640.2 [M+H]+.

Preparation of 3-rr5-(aminomethyl)-2-oxo-l,3-oxazinan-3-yllmethyll-5-r(2-bromo-4-chloro-phenyDmethoxylbenzamide:

The titled compound is prepared as a white solid (28 mg, 12%> yield) following Scheme 1 and in analogy to Example 7 using tert-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-carbamoyl-phenyl]methyl]-tert-butoxycarbonyl-amino]methyl] azetidine- 1 -carboxylate (235 mg, 0.37 mmol) as starting material.

Preparation of Example 6: 3-[[5-(aminomethyl)-2-oxo-l,3-oxazinan-3-yllmethyll-5-[(2-bromo-4-chloro-phenyl)methoxyl-Ar-(3-methoxypropyl)benzamide:

Preparation of ferf -butyl 3 - 1"[ [3 - |"(2-bromo-4-chloro-phenyl)methoxyl -5-methoxycarbonyl-phenyllmethyl-fer?-butoxycarbonyl-aminolmethyll azetidine- 1 -carboxylate :

The titled compound is prepared as a white foam following Scheme 1 and in analogy to Example 7 using methyl 3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(hydroxymethyl)benzoate, 4-methylbenzenesulfonyl chloride, teri-butyl 3-(aminomethyl)azetidine-l-carboxylate [325775-44-8] and di-teri-butyl dicarbonate as starting materials.

'H-NMR (400 MHz, CDC13) δ ppm: 7.63 (s, 1H), 7.33-7.56 (m, 4H), 7.02 (s, 1H), 5.12 (s, 2H), 4.45 (s, 2H), 3.93 (s, 3H), 3.88 (m, 2H), 3.60 (m, 2H), 3.45 (m, 2H), 2.75 (m, 1H), 1.38-1.55 (m, 18H).

Preparation of 3 - [(2-bromo-4-chloro-phenyl)methoxy] -5- [[ferf-butoxycarbonyl- [( 1 -tert-butoxycarbonylazetidin-3 -yl)methyl] amino]methyl]benzoic acid:

Sodium hydroxide (31 mg, 0.78 mmol, 10.0 eq) is added at room temperature to a stirred solution of tert-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-methoxycarbonyl-phenyl]methyl-teri-butoxycarbonyl-amino]methyl]azetidine-l-carboxylate (50 mg, 0.08 mmol, 1.0 eq) in methanol (3 mL) and water (0.5 mL). After 5 hours stirring at 40°C, solvent is evaporated and the residue is extracted with ethyl acetate (3 x 10 mL) and saturated ammonium chloride aqueous solution (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; ethyl acetate) to afford 3-[(2-bromo-4-chloro-phenyl)methoxy]-5-[[teri-butoxycarbonyl-[(l-teri-butoxycarbonylazetidin-3-yl)methyl]amino]methyl]benzoic acid as a colorless semi-solid (38 mg, 78% yield).

'H-NMR (400 MHz, CDC13) δ ppm: 7.56-7.64 (m, 3H), 7.50 (d, J= 8.0 Hz, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.06 (s, 1H), 5.13 (s, 2H), 4.44 (m, 2H), 3.92 (m, 2H), 3.61 (m, 2H), 3.45 (m, 2H), 2.60-2.80 (m, 1H), 1.38-1.55 (m, 18H).

Preparation of ferf-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(3-methoxypropylcarbamoyl)phenyl]methyl-fer?-butoxycarbonyl-amino]methyl]azetidine-l-carboxylate: 0-(7-azabenzotriazol-l-yl)-N,NN',N'-tetramethyluronium hexafluorophosphate (357 mg, 0.94 mmol, 1.5 eq) is added at room temperature to a stirred solution of 3-[(2-bromo-4-chloro-phenyl)methoxy]-5-[[teri-butoxycarbonyl-[(l -teri-butoxycarbonylazetidin-3-yl)methyl]amino]methyl]benzoic acid (400 mg, 0.62 mmol, 1.0 eq), N,N-diisopropylethylamine (217 \L, 1.25 mmol, 2.0 eq) and 3-methoxypropan-l-amine [5332-73-0] (50 mg, 0.47 mmol, 1.5 eq) in NN-dimethylformamide (12 mL). After 3 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3 x 20 mL) and water (20 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, 2:1, v/v) to afford teri-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(3-methoxypropylcarbamoyl)phenyl]methyl-teri-butoxycarbonyl-amino]methyl]azetidine-l-carboxylate as a white solid (340 mg, 77% yield).

'H-NMR (400 MHz, CDC13) δ ppm: 7.62 (s, 1H), 7.48 (d, J= 8.0 Hz, 1H), 7.35 (d, J= 8.0 Hz, 1H), 7.31 (s, 1H), 7.20 (s, 1H), 7.00 (s, 1H), 6.94 (s, 1H), 5.13 (s, 2H,), 4.45 (s, 2H), 3.92 (m, 2H), 3.60 (m, 6H), 3.45 (m, 5H), 2.78 (m, 1H), 1.90 (m, 2H), 1.42 (s, 18H).

Preparation of 3- [[5-(aminomethyl)-2-oxo- 1 ,3 -oxazinan-3 -yl"|methyll -5- [(2-bromo-4-chloro-phenyl)methoxy] -N-(3-methoxypropyl)benzamide:

The titled compound is prepared as a white solid (30 mg, 12% yield) following Scheme 1 and in analogy to Example 7 using tert-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(3-methoxypropylcarbamoyl)phenyl]methyl-tert-butoxycarbonyl-amino]methyl]azetidine-l-carboxylate (330 mg, 0.46 mmol) as starting material.

Preparation of Example 7: 3-[[5-(aminomethyl)-2-oxo-l,3-oxazinan-3-yllmethyll-5-[(2-bromo-4-chloro-phenvDmethoxyl benzaldehyde :

Preparation of dimethyl 5-r(2-bromo-4-chloro-phenyl methoxylbenzene-l,3-dicarboxylate:

The titled compound is prepared as a white solid following Scheme 1 and in analogy to Example 1 using 2-bromo-l-(bromomethyl)-4-chloro-benzene [33924-45-7] and dimethyl 5-hydroxybenzene-l,3-dicarboxylate [13036-02-7] as starting materials.

'H-NMR (400 MHz, CDCI3) δ ppm: 8.33 (s, 1H), 7.84 (s, 2H), 7.63 (s, 1H), 7.50 (d, J= 8.0 Hz, 1H), 7.35 (d, J= 8.0 Hz, 1H), 5.17 (s, 2H), 3.96 (s, 6H).

Preparation of [3-[(2-bromo-4-chloro-phenyl methoxy]-5-(hydroxymethyl phenyl]methanol:

Lithium borohydride (1.26 g, 58.02 mmol, 5.0 eq) is added at room temperature to a stirred solution of dimethyl 5-[(2-bromo-4-chloro-phenyl)methoxy]benzene-l,3-dicarboxylate (4.8 g, 11.6 mmol, 1.0 eq) in tetrahydrofuran (100 mL). After 18 hours stirring at room temperature, the reaction mixture is quenched with a saturated sodium sulfate aqueous solution, filtered and concentrated to give a residue that is purified by column chromatography (silica gel; ethyl acetate) to afford [3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(hydroxymethyl)phenyl]methanol (500 mg, 12% yield) and methyl 3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(hydroxymethyl)benzoate (3.7 g, 83%> yield).

[3 - [(2-bromo-4-chloro-phenyl)methoxy] -5 -(hydroxymethyl)phenyl]methanol:

'H-NMR (400 MHz, CD3OD) δ ppm: 7.70 (s, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.42 (d, J= 8.0 Hz, 1H), 6.97 (s, 1H), 6.94 (s, 2H), 5.15 (s, 2H), 4.60 (s, 4H).

methyl 3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(hydroxymethyl)benzoate:

'H-NMR (400 MHz, CDCI3) δ ppm: 7.69 (s, 1H), 7.64 (s, 1H), 7.58 (s, 1H), 7.52 (d, J= 8.0 Hz, 1H), 7.36 (d, J= 8.0 Hz, 1H), 7.24 (s, 1H), 5.15 (s, 2H), 4.76 (s, 2H), 3.94 (s, 3H).

Preparation of [3-r(2-bromo-4-chloro-phenyl methoxyl-5-(hydroxymethyl phenyllmethyl methanesulfonate: Methanesulfonyl chloride (44 L, 0.56 mmol, 1.0 eq) [124-63-0] is added at 0°C to a stirred solution of [3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(hydroxymethyl)phenyl]methanol (200 mg, 0.56 mmol, 1.0 eq) and triethylamine (96 \L, 0.56 mmol, 1.0 eq) in dichloromethane (10 mL). After 1 hour stirring at 0°C, the reaction mixture is quenched with water, filtered and concentrated to give a residue that is purified by column chromatography (silica gel; petroleum ether: ethyl acetate, 2:1, v/v) to afford [3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(hydroxymethyl)phenyl]methyl methanesulfonate as a colorless oil (150 mg, 71% yield). 'H-NMR (400 MHz, CDC13) δ ppm: 7.62 (s, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.34 (d, J= 8.4 Hz, 1H), 7.05 (s, 1H), 7.03 (s, 1H), 6.94 (s, 1H), 5.22 (s, 2H), 5.11 (s, 2H), 4.70 (s, 2H), 2.98 (s, 3H).

Preparation of ferf-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(hydroxymethyl)phenyllmethylaminolmethyllazetidine-l-carboxylate:

tert-Butyl 3-(aminomethyl)azetidine-l -carboxylate [325775-44-8] (620 mg, 3.30 mmol, 1.2 eq) is added at room temperature to a stirred solution of [3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(hydroxymethyl)phenyl] methyl methanesulfonate (1.2 g, 2.75 mmol, 1.0 eq) in acetonitrile (20 mL). After 4 hours stirring at 60°C, the reaction mixture is concentrated to give a residue that is purified by column chromatography (silica gel; dichloromethane:methanol, 10: 1, v/v) to afford tert-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(hydroxymethyl)phenyl]methylamino]methyl]azetidine-l-carboxylate as a white foam (700 mg, 48% yield).

'H-NMR (400 MHz, CDC13) δ ppm: 7.60 (s, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.33 (d, J= 8.0 Hz, 1H), 7.25 (s, 1H), 6.98 (s, 1H), 6.90 (s, 1H), 5.15 (s, 2H), 4.65 (s, 2H), 3.95-4.20 (m, 4H), 3.68 (m, 2H), 3.10 (m, 2H), 2.95 (m, 1H), 1.43 (s, 9H).

MS m/z (+ESI): 525.2, 527.1 [M+H]+.

Preparation of ferf -butyl 3 - [[ [3 - [(2-bromo-4-chloro-phenyl)methoxy] -5-(hydroxymethyl)phenyl]methyl-fer/-butoxycarbonyl-amino]methyl] azetidine- 1 -carboxylate :

Triethylamine (637 L, 4.56 mmol, 1.5 eq) is added at room temperature to a stirred solution of tert-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(hydroxymethyl)phenyl]methylamino]methyl]azetidine-l-carboxylate (1.6 g, 3.04 mmol, 1.0 eq) in dichloromethane (60 mL), followed by di-tert-butyl dicarbonate (797 mg, 3.65 mmol, 1.2 eq). After 2 hours stirring at room temperature, the reaction mixture is concentrated to give a residue that is purified by column chromatography (silica gel; petroleum ether: ethyl acetate, 5:3, v/v) to afford tert-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(hydroxymethyl)phenyl]methyl-tert-butoxycarbonyl-amino]methyl] azetidine- 1 -carboxylate as a white foam (1.17 g, 61%> yield).

'H-NMR (400 MHz, CDCI3) δ ppm: 7.62 (s, 1H), 7.49 (d, J= 8.0 Hz, 1H), 7.33 (d, J= 8.0 Hz, 1H), 6.92 (s, 1H), 6.83 (s, 1H), 6.74 (s, 1H), 5.08 (s, 2H), 4.68 (s, 2H), 4.42 (s, 2H), 3.90 (m, 2H), 3.53 (m, 2H), 3.43 (m, 2H), 2.74 (m, 1H), 1.40-1.55 (m, 18H).

MS m/z (+ESI): 625.4, 627.4 [M+H]+.

Preparation of ferf-butyl 3-rrr3-r(2-bromo-4-chloro-phenyl methoxyl-5-formyl-phenyllmethyl-fer?-butoxycarbonyl-aminolmethyllazetidine-l-carboxylate:

Dess Martin periodinane solution (0.75 mL, 0.74 mmol, 1.5 eq) is added at 0°C to a stirred solution of tert-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-(hydroxymethyl)phenyl]methyl-tert-butoxycarbonyl-amino]methyl]azetidine-l-carboxylate (310 mg, 0.49 mmol, 1.0 eq) in dichloromethane (20 mL). After 1 hour stirring at 0°C, the reaction mixture is quenched with a saturated sodium thiosulfate aqueous solution (20 mL). The organic layer is washed with water (20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel; petroleum ether:ethyl acetate, 2:1, v/v) to afford tert-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-formyl-phenyl]methyl-tert-butoxycarbonyl-amino]methyl]azetidine-l-carboxylate as a white foam (260 mg, 84% yield).

'H-NMR (400 MHz, CDC13) δ ppm: 9.98 (s, 1H), 7.65 (s, 1H), 7.49 (d, J= 8.0 Hz, 1H), 7.37 (m, 3H), 7.10 (s, 1H), 5.15 (s, 2H), 4.50 (s, 2H), 3.90 (m, 2H), 3.62 (m, 2H), 3,48 (m, 2H), 2.76 (m, 1H), 1.40-1.55 (m, 18H).

Preparation of 3-rr5-(aminomethyl)-2-oxo-L3-oxazinan-3-yllmethyll-5-r(2-bromo-4-chloro-phenyDmethoxylbenzaldehyde:

Trifluoroacetic acid (2 mL, 26.12 mmol, 81.6 eq) is added at room temperature to a stirred solution of tert-butyl 3 - [[ [3 - [(2-bromo-4-chloro-phenyl)methoxy] -5-formyl-phenyl]methyl-tert-butoxycarbonyl-amino]methyl]azetidine-l-carboxylate (200 mg, 0.32 mmol, 1.0 eq) in dichloromethane (2 mL). After 2 hours stirring at room temperature, the reaction mixture is concentrated and the residue is purified by preparative HPLC to afford 3-[[5-(aminomethyl)-2-oxo-l,3-oxazinan-3-yl]methyl]-5-[(2-bromo-4-chloro-phenyl)methoxy]benzaldehyde as a white solid (12 mg, 8% yield).

Preparation of Example 8: Ethyl (^-S- -ffS-CaminomethvD-l-oxo-l^-o azinan-S-yllmethyll-S-Kl-bromo-4-chloro-phenyl)methoxyl phenyll prop-2-enoate :

Preparation of ferf-butyl 3-rrr3-r(2-bromo-4-chloro-phenyl)methoxyl-5-r(£')-3-ethoxy-3-oxo-prop-l-enyllphenyllmethyl-fer?-butoxycarbonyl-aminolmethyllazetidine-l-carboxylate:

A solution of tert-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-formyl-phenyl]methyl-tert-butoxycarbonyl-amino]methyl]azetidine-l-carboxylate (50 mg, 0.08 mmol, 1.0 eq) in acetonitrile (2 mL) is added at 0°C to a stirred mixture of ethyl 2-diethoxyphosphorylacetate (27 mg, 0.12 mmol, 1.5 eq), lithium chloride (17 mg, 0.40 mmol, 5.0 eq) and N,N-diisopropylethylamine (28 iL, 0.16 mmol, 2.0 eq) in acetonitrile (3 mL). After 15 hours stirring at 5-10°C, the reaction mixture is concentrated to give a residue that is purified by column chromatography (silica gel; petroleum ether:ethyl acetate, 4: 1, v/v) to afford tert-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-[(£')-3-ethoxy-3-oxo-prop-l-enyl]phenyl]methyl-tert-butoxycarbonyl-amino]methyl]azetidine-l-carboxylate as a colorless semi-solid (22 mg, 39% yield).

'H-NMR (400 MHz, CDC13) δ ppm: 7.63 (m, 2H), 7.48 (d, J= 8.4Hz, 1H), 7.36 (dd, J= 1.6 Hz, 8.4 Hz, 1H), 7.03 (s, 1H), 6.97 (s, 1H), 6.84 (s, 1H), 6.40 (d, J= 16.0 Hz, 1H), 5.09 (s, 2H), 4.43 (m, 2H), 4.29 (q, J= 7.2 Hz, 2H), 3.90 (m, 2H), 3.59 (m, 2H), 3.45 (m, 2H), 2.68 (m, 1H), 1.47 (m, 18H), 1.34 (t, J= 7.2 Hz, 3H).

Preparation of ethyl (E)- - [3 - [[5-(aminomethyl)-2-oxo- 1 ,3 -oxazinan-3 -yl]methyl] -5- |"(2-bromo-4-chloro-phenyl)methoxylphenyllprop-2-enoate:

The titled compound is prepared as a white solid (28 mg, 12% yield) following Scheme 1 and in analogy to Example 7 using teri-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-[(£')-3-ethoxy-3-oxo-prop-l-enyl]phenyl]methyl-teri-butoxycarbonyl-amino]methyl]azetidine-l-carboxylate (310 mg, 0.45 mmol) as starting material.

Preparation of Example 12: 2-[3-(aminomethyl)pyrrolidin-l-yll-l-[3-[(2-bromo-4-chloro-phenvDmethoxylphenyllethanone:

Preparation of 1 -[3-r(2-bromo-4-chloro-phenyl)methoxylphenyllethanone:

The titled compound is prepared as a white solid (1.0 g, 56%> yield) following Scheme 1 and in analogy to Example 1 using 2-bromo-l-(bromomethyl)-4-chloro-benzene [33924-45-7] (1.5 g, 5.27 mmol, 1.0 eq) and l-(3-hydroxyphenyl)ethanone [121-71 -1] (0.72 g, 5.27 mmol, 1.0 eq) as starting materials.

'H-NMR (400 MHz, DMSO-i/6) δ ppm: 7.82 (s, 1H), 7.44-7.62 (m, 5H), 7.42 (dd, J= 1.6 Hz, 8.0 Hz, 1H), 5.17 (s, 2H), 2.60 (s, 3H).

MS m/z (+ESI): 338.9, 340.9 [M+H]+.

Preparation of 2-bromo-l -[3-[(2-bromo-4-chloro-phenyl)methoxy]phenyl]ethanone:

Copper(II) bromide (1.05 g, 4.7 mmol, 2.0 eq) is added at room temperature to a stirred solution of l-[3-[(2-bromo-4-chloro-phenyl)methoxy]phenyl]ethanone (800 mg, 2.35 mmol, 1.0 eq) in chloroform (10 mL) and ethyl acetate (10 mL). After 3 hours stirring at 90°C, ethyl acetate (100 mL) is added and the resulting mixture is filtered and concentrated to give a residue that is purified by column chromatography (silica gel; petroleum ethenethyl acetate, 20:1, v/v) to afford 2-bromo-l-[3-[(2-bromo-4-chloro-phenyl)methoxy]phenyl]ethanone as a white solid (400 mg, 41%> yield).

'H-NMR (400 MHz, DMSO-i/6) δ ppm: 7.84 (s, 1H), 7.45-7.65 (m, 5H), 7.33 (d, J= 8.0 Hz, 1H), 5.18 (s, 2H), 4.94 (s, 2H).

Preparation of 2- [3 -(aminomethyl)pyrroridin- 1 -yl] - 1 - [3 - [(2-bromo-4-chloro-phenyl)methoxy]phenyl]ethanone:

feri-Butyl N-(pyrrolidin-3-ylmethyl)carbamate (280 mg, 1.42 mmol, 2.0 eq) [149366-79-0] is added at room temperature to a stirred solution of 2-bromo-l-[3-[(2-bromo-4-chloro-phenyl)methoxy]phenyl]ethanone (300 mg, 0.72 mmol, 1.0 eq) in acetonitrile (20 mL), followed by NN-diisopropylethylamine (0.24 mL, 1.42 mmol, 3.0 eq). After 30 minutes stirring at room temperature, a 2.5N hydrochloric acid solution in ethyl acetate (10 mL) is added and after 1 hour stirring the reaction mixture is concentrated to give a residue that is purified by preparative HPLC to afford 2-[3-(aminomethyl)pyrrolidin-l -yl]-l-[3-[(2-bromo-4-chloro-phenyl)methoxy]phenyl]ethanone as a white solid (300 mg, 63% yield).

Preparation of Example 14: [l-[[3-[(2-bromo-4-chloro-phenyl)methylsulfanyllphenyllmethyllpyrrolidin-3-yllmethanamine:

Preparation of 3 - [(2-bromo-4-chloro-phenyl)methylsulfanyl]phenyl]methanol:

The titled compound is prepared as a light yellow oil following Scheme 1 and in analogy to Examples 1 and 7 using 2-bromo-l -(bromomethyl)-4-chloro-benzene [33924-45-7] and methyl 3-sulfanylbenzoate [32886-42-1] as starting materials.

'H-NMR (400 MHz, DMSO-i/6) δ ppm: 7.76 (s, 1H), 7.38 (s, 2H), 7.15-7.30 (m, 4H), 5.22 (t, J= 5.6 Hz, 1H), 4.46 (d, J= 6.0 Hz, 2H), 4.27 (s, 2H).

MS m/z (+ESI): 342.9, 344.9 [M+H]+.

Preparation of 3-[(2-bromo-4-chloro-phenyl)methylsulfanyl]benzaldehyde:

Manganese dioxide (2.38 g, 27.4 mmol, 10.0 eq) is added at room temperature to a stirred solution of 3-[(2-bromo-4-chloro-phenyl)methylsulfanyl]phenyl]methanol (940 mg, 2.74 mmol, 1.0 eq) in dichloromethane (20 mL). After 16 hours stirring at room temperature, manganese dioxide is removed by filtration and the solution is evaporated to afford 3-[(2-bromo-4-chloro-phenyl)methylsulfanyl]benzaldehyde as a light yellow oil (640 mg, 69% yield) that is directly engaged in the next step without further purification.

'H-NMR (400 MHz, DMSO-i/6) δ ppm: 9.98 (s, 1H), 7.87 (s, 1H), 7.75 (m, 2H), 7.68 (m, 1H), 7.55 (m, 1H), 7.40 (m, 2H), 4.37 (s, 2H).

Preparation of ferf-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methylsulfanyl]phenyl]methylamino]methyl]pyrrolidine-l-carboxylate:

teri-Butyl 3-(aminomethyl)pyrrolidine-l-carboxylate [149366-79-0] (97 mg, 0.49 mmol, 1.1 eq) is added at room temperature to a stirred solution of 3-[(2-bromo-4-chloro-phenyl)methylsulfanyl]benzaldehyde (150 mg, 0.44 mmol, 1.0 eq) in 1 ,2-dichloroethane (5 mL), followed by one drop of acetic acid. After 30 minutes stirring at room temperature, sodium triacetoxyborohydride (179 mg, 0.88 mmol, 2.0 eq) is added. After 16

hours stirring at room temperature, the reaction mixture is quenched with a saturated sodium hydrogen carbonate aqueous solution (20 mL) and extracted with ethyl acetate (3 x 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; dichloromethane:methanol, 15: 1, v/v) to afford teri-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methylsulfanyl]phenyl]methylamino]methyl]pyrrolidine-l -carboxylate as a colorless oil (177mg, 77% yield).

'H-NMR (400 MHz, DMSO-i/6 + D20) δ ppm: 7.70 (s, 1H), 7.10-7.35 (m, 6H), 4.22 (s, 2H), 3.63 (s, 2H), 3.35 (m, 1H), 3.25 (m, 1H), 3.13 (m, 1H), 2.85 (m, 1H), 2.40 (m, 2H), 2.23 (m, 1H), 1.88 (m, 1H), 1.45 (m, 1H), 1.35 (s, 9H).

MS m/z (+ESI): 525.1, 527.1 [M+H]+.

Preparation of [l-[[3-r(2-bromo-4-chloro-phenyl)methylsulfanyllphenyllmethyllpyrrolidin-3-yllmethanamine:

The titled compound is prepared as a white solid (110 mg, 80% yield) following Scheme 1 and in analogy to Example 7 using teri-butyl 3-[[[3-[(2-bromo-4-chloro-phenyl)methylsulfanyl]phenyl]methylamino]methyl]pyrrolidine-l-carboxylate (170 mg, 0.32 mmol) as starting material.

Preparation of Example 15: [l-[[3-[(.£')-2-(2-bromo-4-chloro-phenyl)vinyll-5-chloro-phenyll methyllpyrrolidin-3-yll methanamine :

Preparation of 3-r(£')-2-(2-bromo-4-chloro-phenyl)vinyll-5-chloro-benzoic acid:

The titled compound is prepared as a white solid (400 mg, 76%> yield) following Scheme 3 and in analogy to Example 16 using methyl 3-chloro-5-formyl-benzoate [879542-48-0] (280 mg, 1.41 mmol, 1.0 eq) and 2-bromo-4-chloro-l -(diethoxyphosphorylmethyl)benzene (480 mg, 1.41 mmol, 1.0 eq) as starting materials. 'H-NMR (400 MHz, DMSO-i/6) δ ppm: 13.48 (br, 1H), 8.09 (s, 1H), 7.81-7.97 (m, 4H), 7.37-7.55 (m, 3H).

Preparation of methyl 3-r(£')-2-(2-bromo-4-chloro-phenyl)vinyll-5-chloro-benzoate:

Potassium carbonate (220 mg, 1.61 mmol, 1.5 eq) is added at room temperature to a stirred solution of 3-[(£')-2-(2-bromo-4-chloro-phenyl)vinyl]-5-chloro-benzoic acid (400 mg, 1.07 mmol, 1.0 eq) in NN-dimethylformamide (5 mL), followed by iodomethane (100 μΕ, 1.61 mmol, 1.5 eq). After 3 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3 x 10 mL) and water (10 mL). The combined organic layers are washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford methyl 3-[(£')-2-(2-bromo-4-chloro-phenyl)vinyl]-5-chloro-benzoate as a white solid (501 mg, 99%> yield) that is directly engaged in the next step without further purification.

'H-NMR (400 MHz, DMSO-i/6) δ ppm: 8.09 (s, 1H), 8.01 (s, 1H), 7.85 (m, 3H), 7.53 (m, 1H), 7.47 (d, J = 16.4 Hz, 1H), 7.40 (d, J= 16.4 Hz, 1H), 3.91 (s, 3H) .

Preparation of [l-[[3-[(jn-2-(2-bromo-4-chloro-phenyl)vinyl]-5-c^^

yllmethanamine:

The titled compound is prepared as a white solid following Scheme 3 and in analogy to Examples 1, 7 and 14 using methyl 3-[(£')-2-(2-bromo-4-chloro-phenyl)vinyl]-5-chloro-benzoate and tert-butyl 3-(aminomethyl)azetidine-l-carboxylate [149366-79-0] as starting materials.

Preparation of Example 16: [l-fl- -K^-l-Cl-bromo^-chloro-phenvDvinyllphenyllethyllpyrrolidin-S-yllmethanamine:

Preparation of 2-bromo-4-chloro- 1 -(diethoxyphosphoryrmethyl)benzene:

Triethyl phosphite (30.3 niL, 175.82 mmol, 5.0 eq) is added at room temperature to a stirred solution of 2-bromo-l-(bromomethyl)-4-chloro-benzene [33924-45-7] (10.0 g, 35.16 mmol, 1.0 eq) in toluene (100 mL). 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-[(£')-2-(2-bromo-4-chloro-phenyl)vinyl]benzonitrile:

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 [24964-64-5] (1.24 g, 6.45 mmol, 1.0 eq). After 16 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3 x 20 mL) and water (20 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 3-[(£')-2-(2-bromo-4-chloro-phenyl)vinyl]benzaldehyde:

The titled compound is prepared as a yellow solid (330 mg, 82% yield) following Scheme 3 and in analogy to Example 1 using 3-[(£')-2-(2-bromo-4-chloro-phenyl)vinyl]benzonitrile (400 mg, 1.26 mmol, 1.0 eq) as starting material.

'H-NMR (400 MHz, DMSO-i/6) δ ppm: 10.07 (s, 1H), 8.15 (s, 1H), 7.80-8.00 (m, 4H), 7.65 (dd, J= 7.6 Hz, 8.4 Hz, 1H), 7.53 (dd, J= 2.0 Hz, 8.4 Hz, 1H), 7.44-7.52 (m, 2H).

Preparation of 2-[3-r(£')-2-(2-bromo-4-chloro-phenyl)vinyllphenyllacetaldehyde:

Lithium diisopropylamide (2M solution in tetrahydrofuran, 2.40 mL, 4.80 mmol, 3.0 eq) is added at 0°C to as stirred suspension of (methoxymethyl)triphenylphosphonium chloride (800 mg, 2.33 mmol, 1.5 eq) in tetrahydrofuran (20 mL). After 1 hour stirring at room temperature, 3-[(£)-2-(2-bromo-4-chloro-phenyl)vinyl]benzaldehyde (500 mg, 1.55 mmol, 1.0 eq) is added at room temperature to the reaction mixture. After 1 hour stirring at room temperature, a saturated ammonium chloride aqueous solution (20 mL) is added to quench the reaction. The resulting mixture is extracted with ethyl acetate (3 x 20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a yellow oil that is dissolved in tetrahydrofuran (5 mL) and concentrated hydrochloric acid aqueous solution (2.0 mL). After 1 hour stirring at room temperature, the reaction mixture is extracted with ethyl acetate (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; petroleum ether:ethyl acetate, 20: 1 to 10: 1, v/v) to afford 2-[3-[(£)-2-(2-bromo-4-chloro-phenyl)vinyl]phenyl]acetaldehyde as a yellow oil (180 mg, 37% yield).

'H-NMR (400 MHz, DMSO-i/6) δ ppm: 9.75 (s, 1H), 7.78 (m, 2H), 7.48 (m, 3H), 7.30-7.43 (m, 2H), 7.25 (m, 2H), 3.83 (s, 2H).

Preparation of [ 1 - [2- [3 - [(£')-2-(2-bromo-4-chloro-phenyl)vinyllphenyll ethyl"|pyrrolidin-3 -yllmethanamine: The titled compound is prepared as a white solid following Scheme 3 and in analogy to Example 1 using 2-[3-[(£')-2-(2-bromo-4-chloro-phenyl)vinyl]phenyl]acetaldehyde and tert-butyl N-(pyrrolidin-3-ylmethyl)carbamate [149366-79-0] as starting materials.

Preparation of Example 18: S-f -allyloxy-S-K^-l-Cl-bromo^-chloro-phenvDvinyllphenyllmethyll-S-(aminomethyl)-l,3-oxazinan-2-one:

Preparation of dimethyl 5-allyloxybenzene-L3-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 [13036-02-7] (1.0 g, 4.66 mmol, 1.0 eq) and allyl bromide [106-95-6] (620 mg, 5.13 mmol, 1.1 eq) as starting materials.

'H-NMR (400 MHz, CDC13) δ ppm: 8.30 (s, 1H), 7.79 (s, 2H), 6.07 (m, 1H), 5.46 (m, 1H), 5.35 (m, 1H), 4.65 (m, 2H), 3.96 (s, 6H).

MS m/z (+ESI): 251.1 [M+H]+.

Preparation of methyl 3-allyloxy-5-(hydroxymethyl)benzoate:

Lithium aluminium hydride (360 mg, 9.5 mmol, 0.85 eq) is added at 0°C to a stirred solution of dimethyl 5-allyloxybenzene-l,3-dicarboxylate (2.80 g, 11.2 mmol, 1.0 eq) in tetrahydrofuran (40 mL). After 2 hours stirring at 0°C, the reaction mixture is quenched with brine (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford methyl 3-allyloxy-5-(hydroxymethyl)benzoate as a colorless oil (1.0 g, 40% yield) that is directly engaged in the next step without further purification.

'H-NMR (400 MHz, DMSO-i/6) δ ppm: 7.52 (s, 1H), 7.30 (s, 1H), 7.15 (s, 1H), 6.02 (m, 1H), 5.23-5.40 (m, 3H), 4.60 (m, 2H), 4.50 (d, J= 5.6 Hz, 2H), 3.82 (s, 3H).

MS m/z (+ESI): 223.1 [M+H]+.

Preparation of ferf-butyl 3-rrr3-allyloxy-5-(hydroxymethyl)phenyllmethyl-fer?-butoxycarbonyl-aminolmethyl"|azetidine-l-carboxylate:

The titled compound is prepared as a white solid following Scheme 3 and in analogy to Example 7 using methyl 3-allyloxy-5-(hydroxymethyl)benzoate, methanesulfonyl chloride [124-63-0], tert-butyl 3-(aminomethyl)azetidine-l-carboxylate [325775-44-8] and di-tert-butyl dicarbonate as starting materials. 'H-NMR (400 MHz, DMSO-i/6) δ ppm: 6.80 (s, 1H), 6.75 (s, 1H), 6.62 (s, 1H), 6.02 (m, 1H), 5.23-5.40 (m, 2H), 5.18 (t, J= 5.6 Hz, 1H), 4.54 (m, 2H), 4.44 (d, J= 5.6 Hz, 2H), 4.32 (s, 2H), 3.75 (m, 2H), 3.55 (m, 4H), 2.69 (m, 1H), 1.36-1.45 (m, 18H).

MS m/z (+ESI): 463.3 [M+H]+.

Preparation of ferf-butyl 3-[[(3-allyloxy-5-formyl-phenyl)methyl-fer?-butoxycarbonyl-amino]methyl]azetidine-l-carboxylate:

2-Iodobenzoic acid (1.10 g, 3.93 mmol, 2.6 eq) is added at room temperature to a stirred solution of tert-butyl 3-[[[3-allyloxy-5-(hydroxymethyl)phenyl]methyl-tert-butoxycarbonyl-amino]methyl]azetidine-l-carboxylate (700 mg, 1.51 mmol, 1.0 eq) in ethyl acetate (20 mL). After 3 hours stirring at 60°C, solvent is evaporated and the residue is purified by column chromatography (silica gel; petroleum ether: ethyl acetate, 4: 1, v/v) to afford tert-butyl 3-[[(3-allyloxy-5-formyl-phenyl)methyl-tert-butoxycarbonyl-amino]methyl]azetidine-l -carboxylate as a colorless oil (430 mg, 62% yield).

'H-NMR (400 MHz, DMSO-i/6) δ ppm: 9.95 (s, 1H), 7.37 (s, 1H), 7.34 (s, 1H), 7.11 (s, 1H), 6.05 (m, 1H), 5.40 (m, 2H), 4.66 (m, 2H), 4.43 (s, 2H), 3.75 (m, 2H), 3.55 (m, 4H), 2.72 (m, 1H), 1.35-1.45 (m, 18H). MS m/z (+ESI): 461.2 [M+H]+.

Preparation of 3-rr3-allyloxy-5-r(£ -2-(2-bromo-4-chloro-phenyl vinyllphenyllmethyll-5-(aminomethyl -l,3-oxazinan-2-one:

The titled compound is prepared as a white solid following Scheme 3 and in analogy to Examples 1 and 7 using teri-butyl 3 - [[(3 -allyloxy-5 -formyl-phenyl)methyl-teri-butoxycarbonyl-amino]methyl] azetidine- 1 -carboxylate and 2-bromo-4-chloro-l -(diethoxyphosphorylmethyl)benzene as starting materials.

Preparation of Example 19: S-ffS-CaminomethyD-l-oxo-l^-oxazinan-S-yllmethyll-S-K^-l-Cl-bromo-4-chloro-phenyl)vinyllbenzamide:

Preparation of ferf-butyl 3-rrfer?-butoxycarbonyl-rr3-(hydroxymethyl -5-methoxycarbonyl-phenyl]methyllamino]methyll azetidine- 1 -carboxylate:

The titled compound is prepared as a white solid following Scheme 3 and in analogy to Examples 1 and 7 using dimethyl 5-formylbenzene-l,3-dicarboxylate [164073-80-7] and teri-butyl N-(pyrrolidin-3-ylmethyl)carbamate [325775-44-8] as starting materials.

'H-NMR (400 MHz, DMSO-i/6) δ ppm: 7.82 (s, 1H), 7.70 (s, 1H), 7.44 (s, 1H), 5.36 (t, J= 5.6 Hz, 1H), 4.55 (d, J= 5.6 Hz, 2H), 4.43 (s, 2H), 3.85 (s, 3H), 3.75 (m, 2H), 3.40-3.55 (m, 4H), 2.70 (m, 1H), 1.35-1.45 (m, 18H).

MS m/z (+ESI): 465.3 [M+H]+.

Preparation of ferf-butyl 3-[[fer?-butoxycarbonyl-[(3-formyl-5-methoxycarbonyl-phenyl methyl]amino]methyl] azetidine- 1 -carboxylate:

Pyridinium chlorochromate (1.3 g, 5.8 mmol, 1.5 eq) is added at room temperature to a stirred solution of teri-butyl 3-[[teri-butoxycarbonyl-[[3-(hydroxymethyl)-5-methoxycarbonyl-phenyl]methyl]amino]methyl] azetidine- 1 -carboxylate (1.8 g, 3.87 mmol, 1.0 eq) in dichloromethane (50 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, 2:1, v/v) to afford teri-butyl 3-[[teri-butoxycarbonyl-[(3-formyl-5-methoxycarbonyl-phenyl)methyl]amino]methyl] azetidine- 1 -carboxylate as a white solid (1.7 g, 95% yield).

'H-NMR (400 MHz, DMSO-i/6) δ ppm: 10.10 (s, 1H), 8.38 (s, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 4.54 (s, 2H), 3.91 (s, 3H), 3.75 (m, 2H), 3.45-3.60 (m, 4H), 2.71 (m, 1H), 1.35-1.45 (m, 18H).

MS m/z (+ESI): 463.3 [M+H]+.

Preparation of 3-[[5-(aminomethyl)-2-oxo-l,3-oxazinan-3-yl]methyl]-5-[(£')-2-(2-bromo-4-chloro-phenyl)vinyl]benzamide:

The titled compound is prepared as a yellow solid following Scheme 3 and in analogy to Examples 5, 6, 7 and 16 using teri-butyl 3-[[teri-butoxycarbonyl-[(3-formyl-5-methoxycarbonyl-phenyl)methyl] amino]methyl] azetidine- 1 -carboxylate and 2-bromo-4-chloro- 1 -(diethoxyphosphorylmethyl)benzene as starting materials.

Preparation of Example 22: [l-[[3-[(2-bromo-4-chloro-phenyl)methoxyl-5-isobutoxy-phenyllmethyll-1 -methyl-pyrrolidin-1 -ium-3 -yll methanamine :

Preparation of ferf-butyl N-[[l-[[3-r(2-bromo-4-chloro-phenyl methoxyl-5-isobutoxy-phenyllmethyllpyrrolidin-3-yllmethyllcarbamate:

The titled compound is prepared as a white solid following Scheme 1 and in analogy to Example 1 using 2-bromo-l-(bromomethyl)-4-chloro-benzene [33924-45-7], 3,5-dihydroxybenzaldehyde [26153-38-8], 1-bromo-2-methyl-propane [78-77-3] and teri-butyl N-(pyrrolidin-3-ylmethyl)carbamate [149366-79-0] as starting materials.

'H-NMR (400 MHz, DMSO-i/6) δ ppm: 7.82 (d, J= 1.6 Hz, 1H), 7.59 (d, J= 8.4 Hz, 1H), 7.52 (dd, J= 2.0 Hz, 8.4 Hz, 1H), 6.85 (s, 1H), 6.52 (s, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 5.08 (s, 2H), 3.71 (m, 2H), 3.46 (s, 2H), 2.88 (m, 2H), 2.40-2.50 (m, 4H), 2.20 (m, 2H), 1.98 (m, 1H), 1.80 (m, 1H), 1.36 (s, 9H), 0.97 (d, J = 6.8 Hz, 6H).

MS m/z (+ESI): 581.1, 583.1 [M+H]+.

Preparation of ferf -butyl N- [[ 1 - [[3 - [(2-bromo-4-chloro-phenyl methoxy] -5-isobutoxy-phenyl]methyl] - 1 -methyl-pyrrolidin-1 -ium-3-yl]methyl]carbamate:

Potassium carbonate (126 mg, 0.91 mmol, 2.0 eq) is added at room temperature to a stirred solution of tert-butyl N- [[ 1 - [[3 - [(2-bromo-4-chloro-phenyl)methoxy] -5 -isobutoxy-phenyl]methyl]pyrrolidin-3 -yl]methyl]carbamate (265 mg, 0.46 mmol, 1.0 eq) in NN-dimethylformamide (10 mL), followed by iodomethane (57 μΕ, 0.91 mmol, 2.0 eq). After 3 hours stirring at room temperature, solvent is evaporated and the residue is extracted with ethyl acetate (3 x 10 mL) and water (10 mL). The combined organic layers are washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to afford teri-butyl N-[[ 1 - [[3 - [(2-bromo-4-chloro-phenyl)methoxy] -5 -isobutoxy-phenyl]methyl] - 1 -methyl-pyrrolidin- 1 -ium-3 -yl]methyl]carbamate as a light yellow semi-solid (306 mg, 99% yield) that is directly engaged in the next step without further purification.

MS m/z (+ESI): 595.1, 597.1 [M+H]+.

Preparation of [ 1 - [[3 - [(2-bromo-4-chloro-phenyl)methoxy] -5 -isobutoxy-phenyl]methyl] - 1 -methyl-pyrrolidin-l-ium-3-yl]methanamine:

The titled compound is prepared as a light yellow semi-solid (123 mg, 47% yield) following Scheme 1 and in analogy to Example 7 using teri-butyl N-[[l-[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-isobutoxy- phenyl]methyl]-l-methyl-pyrrolidin-l-ium-3-yl]methyl]carbamate (300 mg, 0.50 mmol, 1.0 eq) as starting material.

5

Preparation of Example 23: [l-[[3-[(2-bromo-4-chloro-phenyl)methoxyl-5-[2-(iH-imidazol-4- yl)ethoxylphenyllmethyll-l-methyl-pyrrolidin-l-ium-3-yllmethanamine:

Preparation of 3-r(2-bromo-4-chloro-phenyl)methoxyl-5-hydroxy-benzaldehyde:

10 The titled compound is prepared as a white solid (1.12 g, 25% yield) following Scheme 1 and in analogy to

Example 1 using 2-bromo-l-(bromomethyl)-4-chloro-benzene [33924-45-7] (4.08 g, 14.3 mmol, 1.1 eq) and

3,5-dihydroxybenzaldehyde [26153-38-8] (1.80g, 13.0 mmol, 1.0 eq), as starting materials.

'H-NMR (400 MHz, DMSO-i/6) δ ppm: 10.06 (s, 1H), 9.87 (s, 1H), 7.85 (d, J= 2.0 Hz, 1H), 7.62 (m, 1H),

7.53 (m, 1H), 7.01 (s, 1H), 6.93 (s, 1H), 6.72 (s, 1H), 5.14 (s, 2H).

15 MS m/z (+ESI): 339.0, 340.9 [M+H]+.

Preparation of ferf-butyl 4-[2-[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-formyl-phenoxy]ethyl]imidazole-l- carboxylate:

A solution of 3-[(2-bromo-4-chloro-phenyl)methoxy]-5-hydroxy-benzaldehyde (500 mg, 1.46 mmol, 1.0 eq), 20 teri-butyl 4-(2-hydroxyethyl)imidazole-l-carboxylate (342 mg, 1.60 mmol, 1.1 eq), tributylphosphine (444 mg, 2.20 mmol, 1.5 eq) and azodicarboxylic acid dipiperidine (554 mg, 2.20 mmol, 1.5 eq) in toluene (60 mL) is stirred at 110°C for 16 hours. Then solvent is evaporated and the residue is purified by column chromatography (silica gel; petroleum ether:ethyl acetate, 3:2, v/v) to afford teri-butyl 4-[2-[3-[(2-bromo-4- chloro-phenyl)methoxy]-5-formyl-phenoxy]ethyl]imidazole-l-carboxylate as a light yellow oil (362 mg, 25 46% yield).

'H-NMR (400 MHz, CDC13) δ ppm: 9.90 (s, 1H), 8.07 (s, 1H), 7.61 (s, 1H), 7.47 (d, J= 8.4 Hz, 1H), 7.33 (dd, J= 2.0 Hz, 8.4 Hz, 1H), 7.25 (d, J= 2.0 Hz, 1H), 7.07 (s, 2H), 6.81 (s, 1H), 5.10 (s, 2H), 4.30 (t, J= 6.4 Hz, 2H), 3.08 (t, J= 6.4 Hz, 2H), 1.62 (s, 9H).

MS m/z (+ESI): 534.9, 537.0 [M+H]+.

30

Preparation of [l-[[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-[2-(7H-imidazol-4-yl)ethoxy]phenyl]methyl]- l-methyl-pyrrolidin-l-ium-3-yl]methanamine:

The titled compound is prepared as a light yellow semi-solid following Scheme 1 and in analogy to Examples 1, 7 and 22 using teri-butyl 4-[2-[3-[(2-bromo-4-chloro-phenyl)methoxy]-5-formyl-phenoxy]ethyl]imidazole-35 1 -carboxylate and iodomethane as starting materials.

Biological Examples

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 μΕ 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 or linezolid 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:

1-25 of Table 1.

The following compounds reduce growth of E. coli ATCC25922 to no more than 50% growth of the uninhibited control in the antibacterial activity assay with minocycline when the compound is present at 50 μΜ:

1, 2, 3, 4, 8, 9, 11, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 of Table 1.

The following compounds reduce growth of E. coli ATCC25922 to no more than 10% growth of the uninhibited control in the antibacterial activity assay with minocycline when the compound is present at 50 μΜ:

1, 2, 3, 4, 8, 9, 11, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 of Table 1.

The following compounds reduce growth of P. aeruginosa PAOl to no more than 50%> growth of the uninhibited control in the antibacterial activity assay with minocycline when the compound is present at 50 μΜ:

1, 2, 3, 4, 8, 9, 11, 14, 15, 16, 19, 20, 21, 22, 23, 24, 25 of Table 1.

The following compounds reduce growth of P. aeruginosa PAOl to no more than 10%> growth of the uninhibited control in the antibacterial activity assay with minocycline when the compound is present at 50 μΜ:

1, 2, 3, 4, 8, 9, 11, 14, 15, 16, 19, 21, 22, 23, 24, 25 of Table 1.

The following compounds reduce growth of E. coli ATCC25922 to no more than 50%> growth of the uninhibited control in the antibacterial activity assay with minocycline when the compound is present at 25 μΜ:

1, 2, 3, 4, 8, 9, 11, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25 of Table 1.

The following compounds reduce growth of E. coli ATCC25922 to no more than 10%> growth of the uninhibited control in the antibacterial activity assay with minocycline when the compound is present at 25 μΜ:

1, 2, 3, 4, 8, 9, 11, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25 of Table 1.

The following compounds reduce growth of P. aeruginosa PAOl to no more than 50%> growth of the uninhibited control in the antibacterial activity assay with minocycline when the compound is present at 25 μΜ:

1, 2, 3, 4, 8, 11, 15, 16, 21, 22, 23, 24, 25 of Table 1.

The following compounds reduce growth of P. aeruginosa PAOl to no more than 10%> growth of the uninhibited control in the antibacterial activity assay with minocycline when the compound is present at 25 μΜ:

1, 2, 4, 8, 15, 16, 21, 22, 23, 24, 25 of Table 1.

The following compounds reduce growth of E. coli ATCC25922 to no more than 50% growth of the uninhibited control in the antibacterial activity assay with linezolid when the compound is present at 50 μΜ:

1, 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 of Table 1.

The following compounds reduce growth of E. coli ATCC25922 to no more than 10%> growth of the uninhibited control in the antibacterial activity assay with linezolid when the compound is present at 50 μΜ: 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25of 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:

2, 11, 15, 19, 21, 22, 23, 24, 25 of Table 1.

The following compounds reduce growth of P. aeruginosa PAOl to no more than 10%> growth of the uninhibited control in the antibacterial activity assay with linezolid when the compound is present at 50 μΜ: 2, 11, 15, 19, 21, 22, 24, 25 of Table 1.

The following compounds reduce growth of E. coli ATCC25922 to no more than 50%> growth of the uninhibited control in the antibacterial activity assay with linezolid when the compound is present at 25 μΜ: 1, 2, 3, 4, 8, 9, 11, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25 of Table 1.

The following compounds reduce growth of E. coli ATCC25922 to no more than 10%> growth of the uninhibited control in the antibacterial activity assay with linezolid when the compound is present at 25 μΜ: 1, 2, 3, 4, 8, 9, 11, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25 of Table 1.

The following compounds reduce growth of P. aeruginosa PAOl to no more than 50%> growth of the uninhibited control in the antibacterial activity assay with linezolid when the compound is present at 25 μΜ: 15, 16, 22, 24, 25 of Table 1.

The following compounds reduce growth of P. aeruginosa PAOl to no more than 10%> growth of the uninhibited control in the antibacterial activity assay with linezolid when the compound is present at 25 μΜ: 15, 16, 22, 24, 25 of Table 1.