Patent Description:
Hospital-acquired bacterial pneumonia is the most frequent nosocomial infection. It is classified into two categories: HAP, which develops in hospitalized patients after <NUM> of admission, and does not require artificial ventilation at the time of diagnosis, and VAP, which occurs in patients who have received mechanical ventilation for at least <NUM>. Both types have a high mortality rate (><NUM>%) in spite of adequate antibiotic therapy and require considerable health resources. aureus is among the most common pathogens associated with hospital acquired pneumonia worldwide. Treatment of these infections has become more challenging because of the global emergence of S. aureus strains resistant to commonly used antibiotics. In developed countries such as the USA, MRSA strains are a major problem in hospitals with up to one half of staphylococcal pneumonia isolates classified as MRSA, resulting in mortality as high as <NUM>%.

The Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) recommended vancomycin or linezolid in patients with hospital- and ventilation-acquired pneumonia (HAPNAP) when empiric coverage of MRSA is indicated. Vancomycin poorly penetrates into the lung parenchyma, and high serum levels are often required to achieve adequate lung levels for bacterial killing. Unfortunately, increasing serum vancomycin levels comes with the risk of nephrotoxicity. Furthermore, the increasing prevalence of S. aureus strains with elevated vancomycin MIC (<NUM>-<NUM>µg/mL) is associated with significantly treatment failure. Linezolid is not bactericidal against S. aureus and is not suitable for all patients due to drug interactions and hematologic effects.

The limited effectiveness of available standard-of-care treatments poses increasing public health risks. Thus, an improvement of current treatment regimens is critically needed for patients with HAP/VAP caused by S. An improvement cannot be achieved by bacterial killing with antibiotics alone, but require pre-emptive or adjunctive therapies that prevent or ameliorate the disease pathology on the host side. A highly promising approach, validated by preclinical and clinical data, is to block S. aureus' key virulence factor Hla and hence interfere with the capacity of S. aureus to colonize the lungs, thereby halting pathogenesis until the host immune response or antibiotics kill the bacteria.

It has therefore been an object of the present invention to provide novel inhibitors of virulence factor Hla.

The present invention provides compounds of formula (I):
<CHM>
wherein.

The present invention moreover provides compounds of formula (I):
<CHM>
wherein.

Preferably, R<NUM> is hydrogen or fluorine; especially preferably, R<NUM> is hydrogen.

Further preferably, R<NUM> is F, Cl, Br, a methyl group, an ethyl group, an iso-propyl group, a NO<NUM> group, a -CF<NUM> group, a methoxy group, a -O-CF<NUM> group, a cyclopropyl group, a CN group, a CD<NUM> group, a -CHF<NUM> group, a -CH<NUM>F group, a -CH<NUM>OH group, a -NHMe group, an -O-cyclopropyl group, an -O-CH<NUM>CF<NUM> group, an ethoxy group, an - NHCH<NUM>CH<NUM>OH group, or a -NMe<NUM> group.

Moreover preferably, R<NUM> is F, Cl, Br, a methyl group, an ethyl group, an iso-propyl group, a NO<NUM> group, a -CF<NUM> group, a methoxy group, a -O-CF<NUM> group, a cyclopropyl group, a CN group, a CD<NUM> group, a -CHF<NUM> group, a -CH<NUM>F group, a -CH<NUM>OH group or a -NMe<NUM> group.

More preferably, R<NUM> is F, Cl, Br, a methyl group, an ethyl group, iso-propyl group, a methoxy group, a trifluoromethoxy group, a nitro group, a cyclopropyl group or a dimethylamino group.

Especially preferably, R<NUM> is a methyl group.

Further preferably, R<NUM> is an optionally substituted phenyl group; an optionally substituted naphthyl group; an optionally substituted heteroaryl group containing <NUM> or <NUM> rings and <NUM> to <NUM> ring atoms selected from O, S, N and C; an optionally substituted cycloalkyl aryl group comprising a phenyl group and a cycloalkyl group containing <NUM> or <NUM> ring atoms; an optionally substituted heterocycloalkyl aryl group comprising a phenyl group and a heterocycloalkyl group containing <NUM> or <NUM> ring atoms selected from O, S, N and C; an optionally substituted cycloalkyl heteroaryl group comprising a heteroaryl group comprising <NUM> or <NUM> ring atoms selected from O, S, N and C and a cycloalkyl group containing <NUM> or <NUM> ring atoms; or an optionally substituted heterocycloalkyl heteroaryl group comprising a heteroaryl group comprising <NUM> or <NUM> ring atoms selected from O, S, N and C and a heterocycloalkyl group containing <NUM> or <NUM> ring atoms selected from O, S, N and C.

Moreover preferably, R<NUM> is an optionally substituted phenyl group; an optionally substituted naphthyl group; an optionally substituted heteroaryl group containing <NUM> or <NUM> rings and <NUM> to <NUM> ring atoms selected from O, S, N and C or an optionally substituted cycloalkyl aryl group comprising a phenyl group and a cycloalkyl group containing <NUM> or <NUM> ring atoms.

Further preferably, R<NUM> is an optionally substituted phenyl group; an optionally substituted naphthyl group; or an optionally substituted heteroaryl group containing <NUM> or <NUM> rings and <NUM> to <NUM> ring atoms selected from O, S, N and C.

Moreover preferably, R<NUM> is an optionally substituted phenyl group; or an optionally substituted heteroaryl group containing <NUM> or <NUM> ring atoms selected from O, S, N and C.

Further preferably, R<NUM> has the following formula:
<CHM>
wherein.

Preferably, only one of M<NUM>, M<NUM>, M<NUM> and M<NUM> is N.

Moreover preferably, R<NUM> is hydrogen or methyl; especially preferably, R<NUM> is hydrogen.

Moreover preferably, R<NUM> is an optionally substituted phenyl group.

Moreover preferably, R<NUM> is hydrogen or methyl; especially hydrogen.

Further preferably, R5a is hydrogen, Cl, Br, -CN, methyl, methoxy, -CF<NUM>, -OCF<NUM>, -NMe<NUM>, -C=CH, or -SO<NUM>Me.

Moreover preferably, R5a is hydrogen, Cl, Br, methyl or methoxy.

Further preferably, R<NUM> is F, Cl, Br, CN, a C<NUM>-<NUM> alkyl group, a C<NUM>-<NUM> alkenyl group, a C<NUM>-<NUM> alkynyl group, a C<NUM>-<NUM> heteroalkyl group, an optionally substituted C<NUM>-<NUM> cycloalkyl group, an optionally substituted heterocycloalkyl group containing one or two rings and from <NUM> to <NUM> ring atoms selected from O, S, C and N, an optionally substituted phenyl group, an optionally substituted -CH<NUM>-phenyl group, an optionally substituted heteroaryl group containing <NUM> or <NUM> to <NUM> ring atoms selected from O, S, N and C or an optionally substituted heterocycloalkyl aryl group comprising a phenyl group and a heterocycloalkyl group containing <NUM>, <NUM> or <NUM> ring atoms selected from O, S, N and C; preferably, R<NUM> is an optionally substituted phenyl group or an optionally substituted heteroaryl group containing <NUM> or <NUM> ring atoms selected from O, S, N and C.

Moreover preferably, R<NUM> is CN, a C<NUM>-<NUM> alkenyl group, a C<NUM>-<NUM> alkynyl group, a C<NUM>-<NUM> heteroalkyl group, an optionally substituted C<NUM>-<NUM> cycloalkyl group, an optionally substituted heterocycloalkyl group containing one or two rings and from <NUM> to <NUM> ring atoms selected from O, S, C and N, an optionally substituted phenyl group, an optionally substituted -CH<NUM>-phenyl group, an optionally substituted heteroaryl group containing <NUM> or <NUM> to <NUM> ring atoms selected from O, S, N and C or an optionally substituted heterocycloalkyl aryl group comprising a phenyl group and a heterocycloalkyl group containing <NUM>, <NUM> or <NUM> ring atoms selected from O, S, N and C; preferably, R<NUM> is an optionally substituted phenyl group or an optionally substituted heteroaryl group containing <NUM> or <NUM> ring atoms selected from O, S, N and C.

Further preferably, R<NUM> is an optionally substituted C<NUM>-<NUM> cycloalkyl group, an optionally substituted heterocycloalkyl group containing one or two rings and from <NUM> to <NUM> ring atoms selected from O, S, C and N, an optionally substituted phenyl group, an optionally substituted -CH<NUM>-phenyl group, an optionally substituted heteroaryl group containing <NUM> or <NUM> to <NUM> ring atoms selected from O, S, N and C or an optionally substituted heterocycloalkyl aryl group comprising a phenyl group and a heterocycloalkyl group containing <NUM>, <NUM> or <NUM> ring atoms selected from O, S, N and C; preferably, R<NUM> is an optionally substituted phenyl group or an optionally substituted heteroaryl group containing <NUM> or <NUM> ring atoms selected from O, S, N and C.

Moreover preferably, R<NUM> is F, Cl, Br, CN, a C<NUM>-<NUM> alkyl group, a C<NUM>-<NUM> alkenyl group, a C<NUM>-<NUM> alkynyl group, a C<NUM>-<NUM> heteroalkyl group, an optionally substituted C<NUM>-<NUM> cycloalkyl group, an optionally substituted heterocycloalkyl group containing one or two rings and from <NUM> to <NUM> ring atoms selected from O, S, C and N, an optionally substituted phenyl group, an optionally substituted heteroaryl group containing <NUM> or <NUM> ring atoms selected from O, S, N and C or an optionally substituted heterocycloalkyl aryl group comprising a phenyl group and a heterocycloalkyl group containing <NUM> or <NUM> ring atoms selected from O, S, N and C.

Further preferably, R<NUM> is a group of formula OR6a, wherein R6a is an optionally substituted C<NUM>-<NUM> cycloalkyl group, an optionally substituted heterocycloalkyl group containing one or two rings and from <NUM> to <NUM> ring atoms selected from O, S, C and N, an optionally substituted phenyl group, an optionally substituted heteroaryl group containing <NUM> or <NUM> ring atoms selected from O, S, N and C or an optionally substituted heterocycloalkyl aryl group comprising a phenyl group and a heterocycloalkyl group containing <NUM> or <NUM> ring atoms selected from O, S, N and C.

Moreover preferably, R<NUM> is a group of formula NHR6a, wherein R6a is an optionally substituted C<NUM>-<NUM> cycloalkyl group, an optionally substituted heterocycloalkyl group containing one or two rings and from <NUM> to <NUM> ring atoms selected from O, S, C and N, an optionally substituted phenyl group, an optionally substituted heteroaryl group containing <NUM> or <NUM> ring atoms selected from O, S, N and C or an optionally substituted heterocycloalkyl aryl group comprising a phenyl group and a heterocycloalkyl group containing <NUM> or <NUM> ring atoms selected from O, S, N and C.

Further preferably, R<NUM> and R<NUM> together are a group of formula -O-CH<NUM>-O-, -O-CF<NUM>-O- or -O-CH<NUM>-CH<NUM>-O-.

Moreover preferably, R<NUM> is OCF<NUM>.

Further preferably, R<NUM> is an optionally substituted phenyl group or an optionally substituted heteroaryl group containing <NUM> or <NUM> to <NUM> ring atoms selected from O, S, N and C or an optionally substituted heterocycloalkyl aryl group comprising a phenyl group and a heterocycloalkyl group containing <NUM> or <NUM> ring atoms selected from O, S, N and C.

Moreover preferably, R<NUM> is an optionally substituted phenyl group or an optionally substituted heteroaryl group containing <NUM> or <NUM> ring atoms selected from O, S, N and C.

According to a preferred embodiment, R<NUM> is unsubstituted or substituted by <NUM>, <NUM> or <NUM> substituents that are independently selected from halogen, CN, OH, NH<NUM>, =O, - P(=O)Me<NUM>, COOH, CONH<NUM>, a C<NUM>-<NUM> alkyl group, a C<NUM>-<NUM> alkenyl group, a C<NUM>-<NUM> alkynyl group, a C<NUM>-<NUM> heteroalkyl group, a C<NUM>-<NUM> cycloalkyl group, an -O-C<NUM>-<NUM> cycloalkyl group or a heterocycloalkyl group containing from <NUM> to <NUM> ring atoms selected from O, S, C and N; especially wherein R<NUM> is unsubstituted or substituted by <NUM>, <NUM> or <NUM> substituents that are independently selected from halogen, CN, COOH, CONH<NUM>, a C<NUM>-<NUM> alkyl group, a C<NUM>-<NUM> alkenyl group, a C<NUM>-<NUM> alkynyl group, a C<NUM>-<NUM> heteroalkyl group, a C<NUM>-<NUM> cycloalkyl group or a heterocycloalkyl group containing from <NUM> to <NUM> ring atoms selected from O, S, C and N.

Especially preferably, the optionally substituted phenyl group or the optionally substituted heteroaryl group containing <NUM> or <NUM> ring atoms selected from O, S, N and C at R<NUM> is unsubstituted or substituted by <NUM>, <NUM> or <NUM> substituents that are independently selected from halogen, CN, COOH, a C<NUM>-<NUM> alkyl group, a C<NUM>-<NUM> alkenyl group, a C<NUM>-<NUM> alkynyl group, a C<NUM>-<NUM> heteroalkyl group, a C<NUM>-<NUM> cycloalkyl group or a heterocycloalkyl group containing from <NUM> to <NUM> ring atoms selected from O, S, C and N.

The most preferred compounds of the present invention are the compounds disclosed in the examples, or a salt, solvate or a hydrate thereof.

It is further preferred to combine the preferred embodiments of the present invention in any desired manner.

According to one embodiment of the present invention, compounds of formula (I) as such, wherein R<NUM> is H, R<NUM> is Me, R4a is hydrogen and R<NUM> is selected from the following groups:
<CHM>
<CHM>
<CHM>
<CHM>
are excluded from the present invention. According to another embodiment, the use of these compounds in the prophylaxis, decolonization and treatment of a Staphylococcus aureus infection; especially for use in the prophylaxis and treatment of pneumonia caused by Staphylococcus aureus is encompassed by the present invention.

According to a further embodiment of the present invention, compound No. <NUM> disclosed in <NPL> is excluded from the present invention.

According to a further embodiment of the present invention, the following compound is excluded from the present invention:
<CHM>
wherein R is a group having the following structure:
<CHM>.

The expression alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from <NUM> to <NUM> carbon atoms, preferably from <NUM> to <NUM> carbon atoms, especially from <NUM> to <NUM> (e.g. <NUM>, <NUM>, <NUM> or <NUM>) carbon atoms, for example a methyl (Me, CH<NUM>), ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, <NUM>,<NUM>-dimethylbutyl or n-octyl group.

The expression C<NUM>-<NUM> alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from <NUM> to <NUM> carbon atoms. The expression C<NUM>-<NUM> alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from <NUM> to <NUM> carbon atoms. Examples are a methyl (Me), CF<NUM>, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl group.

The expressions alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups that contain from <NUM> to <NUM> carbon atoms, preferably from <NUM> to <NUM> carbon atoms, especially from <NUM> to <NUM> (e.g. <NUM>, <NUM> or <NUM>) carbon atoms, for example an ethenyl (vinyl), propenyl (allyl), iso-propenyl, butenyl, ethinyl, propinyl, butinyl, acetylenyl, propargyl, isoprenyl or hex-<NUM>-enyl group. Preferably, alkenyl groups have one or two (especially preferably one) double bond(s), and alkynyl groups have one or two (especially preferably one) triple bond(s).

Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl) such as, for example, a <NUM>,<NUM>,<NUM>-trichloroethyl, difluoromethyl, fluoromethyl or a trifluoromethyl group.

The expression heteroalkyl refers to an alkyl, alkenyl or alkynyl group as defined above in which one or more (preferably <NUM> to <NUM>; especially preferably <NUM>, <NUM>, <NUM> or <NUM>) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus, boron, selenium, silicon or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or by a SO or a SO<NUM> group. The expression heteroalkyl furthermore refers to a carboxylic acid or to a group derived from a carboxylic acid, such as, for example, acyl, acylalkyl, alkoxycarbonyl, acyloxy, acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy. Furthermore, the term heteroalkyl refers to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl).

Preferably, a heteroalkyl group contains from <NUM> to <NUM> carbon atoms and from <NUM> to <NUM> heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen). Especially preferably, a heteroalkyl group contains from <NUM> to <NUM> (e.g. <NUM>, <NUM>, <NUM> or <NUM>) carbon atoms and <NUM>, <NUM>, <NUM> or <NUM> (especially <NUM>, <NUM> or <NUM>) heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen). The term C<NUM>-C<NUM> heteroalkyl refers to a heteroalkyl group containing from <NUM> to <NUM> carbon atoms and <NUM>, <NUM>, <NUM> or <NUM> heteroatoms selected from O, S and/or N (especially O and/or N). The term C<NUM>-C<NUM> heteroalkyl refers to a heteroalkyl group containing from <NUM> to <NUM> carbon atoms and <NUM>, <NUM>, <NUM> or <NUM> heteroatoms selected from O, S and/or N (especially O and/or N). The term C<NUM>-C<NUM> heteroalkyl refers to a heteroalkyl group containing from <NUM> to <NUM> carbon atoms and <NUM>, <NUM> or <NUM> heteroatoms selected from O, S and/or N (especially O and/or N).

Further preferably, the expression heteroalkyl refers to an alkyl group as defined above (straight-chain or branched) in which one or more (preferably <NUM> to <NUM>; especially preferably <NUM>, <NUM>, <NUM> or <NUM>) carbon atoms have been replaced by an oxygen, sulfur or nitrogen atom or a CO group; this group preferably contains from <NUM> to <NUM> (e.g. <NUM>, <NUM>, <NUM> or <NUM>) carbon atoms and <NUM>, <NUM>, <NUM> or <NUM> (especially <NUM>, <NUM> or <NUM>) heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen); this group may preferably be substituted by one or more (preferably <NUM> to <NUM>; especially preferably <NUM>, <NUM>, <NUM> or <NUM>) fluorine, chlorine, bromine or iodine atoms or OH, =O, SH, =S, NH<NUM>, =NH, N<NUM>, CN or NO<NUM> groups.

Examples of heteroalkyl groups are groups of formulae: Ra-O-Ya-, Ra-S-Ya-, Ra-SO-Ya-, Ra-SO<NUM>-Ya-, Ra-N(Rb)-SO<NUM>-Ya-, Ra-SO<NUM>-N(Rb)-Ya-, Ra-N(Rb)-Ya-, Ra-CO-Ya-, Ra-C(=NRd)-Ya-, Ra-O-CO-Ya-, Ra-CO-O-Ya-, Ra-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-Ya-, Ra-N(Rp)-C(=NRd)-Ya-, Ra-O-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-O-Ya-, Ra-N(Rb)-CO-N(Rc)-Ya-, Ra-O-CO-O-Ya-, Ra-N(Rb)-C(=NRd)-N(Rc)-Ya-, Ra-CS-Ya-, Ra-O-CS-Ya-, Ra-CS-O-Ya-, Ra-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-Ya-, Ra-O-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-O-Ya-, Ra-N(Rb)-CS-N(Rc)-Ya-, Ra-O-CS-O-Ya-, Ra-S-CO-Ya-, Ra-CO-S-Ya-, Ra-S-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-S-Ya-, Ra-S-CO-O-Ya-, Ra-O-CO-S-Ya-, Ra-S-CO-S-Ya-, Ra-S-CS-Ya-, Ra-CS-S-Ya-, Ra-S-CS-N(Rb)-Ya-, Ra-N(Rb)-CS-S-Ya-, Ra-S-CS-O-Ya-, Ra-O-CS-S-Ya-, wherein Ra being a hydrogen atom, a C<NUM>-C<NUM> alkyl, a C<NUM>-C<NUM> alkenyl or a C<NUM>-C<NUM> alkynyl group; Rb being a hydrogen atom, a C<NUM>-C<NUM> alkyl, a C<NUM>-C<NUM> alkenyl or a C<NUM>-C<NUM> alkynyl group; Rc being a hydrogen atom, a C<NUM>-C<NUM> alkyl, a C<NUM>-C<NUM> alkenyl or a C<NUM>-C<NUM> alkynyl group; Rd being a hydrogen atom, a C<NUM>-C<NUM> alkyl, a C<NUM>-C<NUM> alkenyl or a C<NUM>-C<NUM> alkynyl group and Ya being a bond, a C<NUM>-C<NUM> alkylene, a C<NUM>-C<NUM> alkenylene or a C<NUM>-C<NUM> alkynylene group, wherein each heteroalkyl group contains at least one carbon atom. Further, one or more hydrogen atoms of the above groups may be replaced by fluorine or chlorine atoms.

Specific examples of heteroalkyl groups are methoxy, trifluoromethoxy, -OCD<NUM>, ethoxy, n-propyloxy, isopropyloxy, butoxy, tert-butyloxy, methoxymethyl, ethoxymethyl, -CH<NUM>CH<NUM>OH, -CH<NUM>OH, -SO<NUM>Me, -NHAc, -CONH<NUM>, methoxyethyl, <NUM>-methoxyethyl, <NUM>-ethoxyethyl, <NUM>-methoxyethyl or <NUM>-ethoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, isopropylethylamino, methylamino methyl, ethylamino methyl, diisopropylamino ethyl, methylthio, ethylthio, isopropylthio, enol ether, dimethylamino methyl, dimethylamino ethyl, acetyl, propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetylamino or propionylamino, carboxymethyl, carboxyethyl or carboxypropyl, N-ethyl-N-methylcarbamoyl or N-methylcarbamoyl. Further examples of heteroalkyl groups are nitrile (-CN), isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkylnitrile groups.

The expression cycloalkyl refers to a saturated or partially unsaturated (for example, a cycloalkenyl group) cyclic group that contains one or more rings (preferably <NUM> or <NUM>), and contains from <NUM> to <NUM> ring carbon atoms, preferably from <NUM> to <NUM> (especially <NUM>, <NUM>, <NUM>, <NUM> or <NUM>) ring carbon atoms. The expression cycloalkyl refers furthermore to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NH<NUM>, =NH, N<NUM> or NO<NUM> groups, thus, for example, cyclic ketones such as, for example, cyclohexanone, <NUM>-cyclohexenone or cyclopentanone. Further specific examples of cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclopentyl, spiro[<NUM>,<NUM>]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[<NUM>. <NUM>]nonyl, tetraline, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-<NUM>-enyl group.

The expression heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably <NUM>, <NUM> or <NUM>) ring carbon atoms have been replaced by an oxygen, nitrogen, silicon, boron, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or a SO group or a SO<NUM> group. A heterocycloalkyl group has preferably <NUM> or <NUM> ring(s) containing from <NUM> to <NUM> (especially <NUM>, <NUM>, <NUM>, <NUM> or <NUM>) ring atoms (preferably selected from C, O, N and S). The expression heterocycloalkyl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NH<NUM>, =NH, N<NUM> or NO<NUM> groups. Examples are a piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl (e.g. -N(CH<NUM>CH<NUM>)<NUM>O), urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or <NUM>-pyrazolinyl group and also lactames, lactones, cyclic imides and cyclic anhydrides.

The expression alkylcycloalkyl refers to groups that contain both cycloalkyl and also alkyl, alkenyl or alkynyl groups in accordance with the above definitions, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. An alkylcycloalkyl group preferably contains a cycloalkyl group that contains one or two rings having from <NUM> to <NUM> (especially <NUM>, <NUM>, <NUM>, <NUM> or <NUM>) ring carbon atoms, and one or two alkyl, alkenyl or alkynyl groups (especially alkyl groups) having <NUM> or <NUM> to <NUM> carbon atoms.

The expression heteroalkylcycloalkyl refers to alkylcycloalkyl groups as defined above in which one or more (preferably <NUM>, <NUM> or <NUM>) carbon atoms have been replaced by an oxygen, nitrogen, silicon, boron, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or a SO group or a SO<NUM> group. A heteroalkylcycloalkyl group preferably contains <NUM> or <NUM> rings having from <NUM> to <NUM> (especially <NUM>, <NUM>, <NUM>, <NUM> or <NUM>) ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups (especially alkyl or heteroalkyl groups) having from <NUM> or <NUM> to <NUM> carbon atoms. Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl, the cyclic groups being saturated or mono-, di- or tri-unsaturated.

The expression aryl refers to an aromatic group that contains one or more rings containing from <NUM> to <NUM> ring carbon atoms, preferably from <NUM> to <NUM> (especially <NUM>) ring carbon atoms. The expression aryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH<NUM>, N<NUM> or NO<NUM> groups. Examples are the phenyl, naphthyl, biphenyl, <NUM>-fluorophenyl, anilinyl, <NUM>-nitrophenyl or <NUM>-hydroxyphenyl group.

The expression heteroaryl refers to an aromatic group that contains one or more rings containing from <NUM> to <NUM> ring atoms, preferably from <NUM> to <NUM> (especially <NUM> or <NUM> or <NUM> or <NUM>) ring atoms, comprising one or more (preferably <NUM>, <NUM>, <NUM> or <NUM>) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N). The expression heteroaryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, N<NUM>, NH<NUM> or NO<NUM> groups. Examples are pyridyl (e.g. <NUM>-pyridyl), imidazolyl (e.g. <NUM>-imidazolyl), phenylpyrrolyl (e.g. <NUM>-phenylpyrrolyl), thiazolyl, isothiazolyl, <NUM>,<NUM>,<NUM>-triazolyl, <NUM>,<NUM>,<NUM>-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, <NUM>-hydroxypyridyl (<NUM>-pyridonyl), <NUM>,<NUM>-hydroxypyridyl (<NUM>,<NUM>-pyridonyl), oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, <NUM>,<NUM>'-bifuryl, pyrazolyl (e.g. <NUM>-pyrazolyl) and isoquinolinyl groups.

The expression aralkyl refers to groups containing both aryl and also alkyl, alkenyl, alkynyl and/or cycloalkyl groups in accordance with the above definitions, such as, for example, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylaryl-cycloalkyl and alkylarylcycloalkenyl groups. Specific examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, <NUM>-indene, tetraline, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indane. An aralkyl group preferably contains one or two aromatic ring systems (especially <NUM> or <NUM> rings), each containing from <NUM> to <NUM> carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups containing from <NUM> or <NUM> to <NUM> carbon atoms and/or a cycloalkyl group containing <NUM> or <NUM> ring carbon atoms.

The expression heteroaralkyl refers to groups containing both aryl and/or heteroaryl groups and also alkyl, alkenyl, alkynyl and/or heteroalkyl and/or cycloalkyl and/or heterocycloalkyl groups in accordance with the above definitions. A heteroaralkyl group preferably contains one or two aromatic ring systems (especially <NUM> or <NUM> rings), each containing from <NUM> or <NUM> to <NUM> or <NUM> ring atoms (preferably selected from C, N, O and S) and one or two alkyl, alkenyl and/or alkynyl groups containing <NUM> or <NUM> to <NUM> carbon atoms and/or one or two heteroalkyl groups containing <NUM> to <NUM> carbon atoms and <NUM>, <NUM> or <NUM> heteroatoms selected from O, S and N and/or one or two cycloalkyl groups each containing <NUM> or <NUM> ring carbon atoms and/or one or two heterocycloalkyl groups, each containing <NUM> or <NUM> ring atoms comprising <NUM>, <NUM>, <NUM> or <NUM> oxygen, sulfur or nitrogen atoms.

Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroaryl-heterocycloalkyl, heteroaryl heterocycloalkenyl, heteroarylalkylcycloalkyl, heteroaryl-alkylheterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroaryl heteroalkyl-cycloalkenyl and heteroarylheteroalkylheterocycloalkyl groups, the cyclic groups being saturated or mono-, di- or tri-unsaturated. Specific examples are a tetrahydroisoquinolinyl, benzoyl, phthalidyl, <NUM>- or <NUM>-ethylindolyl, <NUM>-methylpyridino, <NUM>-, <NUM>- or <NUM>-methoxyphenyl, <NUM>-ethoxyphenyl, <NUM>-, <NUM>- or <NUM>-carboxyphenylalkyl group.

As already stated above, the expressions cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NH<NUM>, =NH, N<NUM> or NO<NUM> groups.

The term halogen refers to F, Cl, Br or I.

The term "optionally substituted" refers to a group which is unsubstituted or substituted by one or more (especially by one, two or three; preferably by one or two; especially preferably by one) substituents. If a group comprises more than one substituent, these substituents are independently selected, i.e., they may be the same or different.

Examples for substituents are fluorine, chlorine, bromine and iodine and OH, SH, NH<NUM>, =O, -SO<NUM>H, -SO<NUM>NH<NUM>, -COOH, -COOMe, -COOEt, CH<NUM>OH, -COMe (Ac), -NHSO<NUM>Me, -SO<NUM>NMe<NUM>, -CH<NUM>NH<NUM>, -NHAc, -SO<NUM>Me, -CONH<NUM>, -CN, -NHCONH<NUM>, -NHC(NH)NH<NUM>, - NOHCH<NUM>, -N<NUM> and -NO<NUM> groups. Further examples of substituents are C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> alkenyl, C<NUM>-C<NUM> alkynyl, C<NUM>-C<NUM> heteroalkyl, C<NUM>-C<NUM> cycloalkyl, C<NUM>-C<NUM> heterocycloalkyl, C<NUM>-C<NUM> alkylcycloalkyl, C<NUM>-C<NUM> heteroalkylcycloalkyl, C<NUM>-C<NUM> aryl, C<NUM>-C<NUM> heteroaryl, C<NUM>-C<NUM> aralkyl and C<NUM>-C<NUM> heteroaralkyl groups; especially C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> alkenyl, C<NUM>-C<NUM> alkynyl, C<NUM>-C<NUM> heteroalkyl, C<NUM>-C<NUM> cycloalkyl, C<NUM>-C<NUM> heterocycloalkyl, C<NUM>-C<NUM> alkylcycloalkyl, C<NUM>-C<NUM> heteroalkylcycloalkyl, C<NUM>-C<NUM> aryl, C<NUM>-C<NUM> heteroaryl, C<NUM>-C<NUM> aralkyl and C<NUM>-C<NUM> heteroaralkyl groups, further preferably C<NUM>-C<NUM> alkyl and C<NUM>-C<NUM> heteroalkyl groups.

Preferred substituents are halogen atoms (e.g. F, Cl, Br) and groups of formula -OH, =O, -O-C<NUM>-<NUM> alkyl (e.g. -OMe, -OCD<NUM>, -OEt, -O-nPr, -O-iPr, -O-nBu, -O-iBu and -O-tBu), -NH<NUM>, -NHC<NUM>-<NUM> alkyl, -N(C<NUM>-<NUM> alkyl)<NUM>, -COOH, -COOMe, -COOEt, -CH<NUM>OH, -CH<NUM>NH<NUM>, - CH<NUM>CH<NUM>-O-CH<NUM>, -COMe, -NHSO<NUM>Me, -PO(CH<NUM>)<NUM>, -SO<NUM>NMe<NUM>, -SO<NUM>H, -SO<NUM>NH<NUM>, - CONH<NUM>, -CH<NUM>NH<NUM>, -CN, -C<NUM>-<NUM> alkyl (e.g. -Me, -Et, -nPr, -iPr, -nBu, -iBu, -tBu and -CF<NUM>), -SH, -S-CO-C<NUM>-<NUM> alkyl, -S-C<NUM>-<NUM> alkyl, -NHAc, -NO<NUM>, -C≡CH, -CH=C(CH<NUM>)<NUM>, - CH=CHCH<NUM>OCH<NUM>CH<NUM>, -NHCONH<NUM>, -SO<NUM>NMe<NUM>, -SO<NUM>Me, phenyl, cyclopropyl, -O-cyclopropyl, and heterocycloalkyl groups containing from <NUM> to <NUM> ring atoms selected from O, N and C (especially one nitrogen atom and from <NUM> to <NUM> ring atoms).

Further preferred substituents are F, Cl, Br, =O, a C<NUM>-<NUM> alkyl group (such as Me, Et, CF<NUM>, iPr, tBu), a O-C<NUM>-<NUM> alkyl group (such as OMe, OCD<NUM>, OCHF<NUM>, OCH<NUM>F, OiPr, OCF<NUM>), NH<NUM>, OH, a NHC<NUM>-<NUM> alkyl group, a N(C<NUM>-<NUM> alkyl)<NUM> group (such as NMe<NUM>), -CH<NUM>OH, - COOEt, -COOMe, -SO<NUM>Me, -CH<NUM>NH<NUM>, -CH<NUM>OH, -SO<NUM>NMe<NUM>, -NHCOCH<NUM>, -SCF<NUM>, - OCH<NUM>CH<NUM>NMe<NUM>, -CH<NUM>CH<NUM>OCH<NUM>, -NHCONMe<NUM>, -PO(CH<NUM>)<NUM>, -COMe, -CONH<NUM>, -COOH, -CN, -C≡CH, -CH=C(CH<NUM>)<NUM>, -CH=CHCH<NUM>OCH<NUM>CH<NUM>, a pyrrolidinyl group, a-N(CH<NUM>CH<NUM>)<NUM>O group, and an azetidinyl group.

When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl group contains more than one ring, these rings may be bonded to each other via a single or double bond or these rings may be annulated.

The rings of any cycloalkyl aryl group, heterocycloalkyl aryl group, cycloalkyl heteroaryl group and heterocycloalkyl heteroaryl group may be bonded to each other via a single or double bond or these rings may be annulated.

It should be appreciated that certain compounds of formula (I) may have tautomeric forms from which only one might be specifically mentioned or depicted in the following description, different geometrical isomers (which are usually denoted as cis/trans isomers or more generally as (E) and (Z) isomers) or different optical isomers as a result of one or more chiral carbon atoms (which are usually nomenclatured under the Cahn-Ingold-Prelog or R/S system). All these tautomeric forms, geometrical or optical isomers (as well as racemates and diastereomers) and polymorphous forms are included in the invention. Since the compounds of formula (I) may contain asymmetric C-atoms, they may be present either as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds. The present invention comprises both all pure enantiomers and all pure diastereomers, and also the mixtures thereof in any mixing ratio.

According to a further embodiment of the present invention, one or more hydrogen atoms of the compounds of the present invention may be replaced by deuterium. Deuterium modification improves the metabolic properties of a drug with little or no change in its intrinsic pharmacology. Deuterium substitution at specific molecular positions improves metabolic stability, reduces formation of toxic metabolites and/or increases the formation of desired active metabolites. Accordingly, the present invention also encompasses the partially and fully deuterated compounds of formula (I). The term hydrogen also encompasses deuterium.

The therapeutic use of compounds according to formula (I), their salts (especially their pharmacologically acceptable salts), solvates and hydrates, respectively, as well as formulations and pharmaceutical compositions also lie within the scope of the present invention.

The present invention further provides pharmaceutical compositions comprising one or more compounds described herein or a salt (especially a pharmaceutically acceptable salt), solvate or hydrate thereof, optionally in combination with one or more carrier substances and/or one or more adjuvants.

The present invention further provides a compound or a pharmaceutical composition as described herein for use in the prophylaxis, decolonization and treatment of a Staphylococcus aureus infection; especially for use in the prophylaxis and treatment of pneumonia caused by Staphylococcus aureus.

The present invention moreover provides a compound or a pharmaceutical composition as described herein for the preparation of a medicament, especially for use in the prophylaxis, decolonization and treatment of a Staphylococcus aureus infection; especially for use in the prophylaxis and treatment of pneumonia caused by Staphylococcus aureus.

Examples of pharmacologically acceptable salts of sufficiently basic compounds are salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic, fumaric, maleic and salicylic acid. Further, a sufficiently acidic compound may form alkali or earth alkali metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(<NUM>-hydroxyethyl)amine, lysine or arginine salts; all of which are also further examples of salts of the compounds described herein.

The compounds described herein may be solvated, especially hydrated. The hydratization/hydration may occur during the process of production or as a consequence of the hygroscopic nature of the initially water-free compounds. The solvates and/or hydrates may e.g. be present in solid or liquid form.

In general, the compounds and pharmaceutical compositions described herein will be administered by using the known and acceptable modes known in the art.

For oral administration such therapeutically useful agents can be administered by one of the following routes: oral, e.g. as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatine capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g. as an injectable solution or suspension, rectal as suppositories, by inhalation or insufflation, e.g. as a powder formulation, as microcrystals or as a spray (e.g. liquid aerosol), transdermal, for example via an transdermal delivery system (TDS) such as a plaster containing the active ingredient or intranasal. For the production of such tablets, pills, semisolids, coated tablets, dragees and hard, e.g. gelatine, capsules the therapeutically useful product may be mixed with pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like. For the production of soft capsules one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat, and polyols. For the production of liquid solutions, emulsions or suspensions or syrups one may use as excipients e.g. water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal or synthetic oils. Especially preferred are lipids and more preferred are phospholipids (preferred of natural origin; especially preferred with a particle size between <NUM> to <NUM>) preferred in phosphate buffered saline (pH = <NUM> to <NUM>, preferred <NUM>). For suppositories one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat and polyols. For aerosol formulations one may use compressed gases suitable for this purpose, as are e.g. oxygen, nitrogen and carbon dioxide. The pharmaceutically useful agents may also contain additives for conservation, stabilization, e.g. UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants.

In general, in the case of oral or parenteral administration to adult humans weighing approximately <NUM>, a daily dosage of about <NUM> to about <NUM>,<NUM>, preferably from about <NUM> to about <NUM>,<NUM>, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion or subcutaneous injection.

Abbreviations and Acronyms used in the description of the chemistry and in the Examples that follow are:.

In general, the compounds of formula (I) used of the invention might be prepared by standard techniques known in the art, by known processes analogous thereto, and/or by the processes described herein, using starting materials which are either commercially available or producible according to conventional chemical methods. The particular processes to be utilised in the preparation of the compounds of formula (I) of this invention depends upon the specific compound desired. Such factors as the type of substitution at various locations of the molecule and the commercial availability of the starting materials play a role in the path to be followed and in the chosen reaction conditions for the preparation of the specific compounds of formula (I) of this invention. Those factors are readily recognised by one of ordinary skill in the art.

The following preparative methods are presented to aid the reader in the synthesis of the compounds of the present invention.

HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a Waters Acquity Ultra Performance Liquid Chromatography (UPLC) equipped with a SQ <NUM> Mass detector spectrometer.

a final hold at <NUM>% B of <NUM>. Total run time: <NUM>.

The gradient described could be altered in function of the physico-chemical properties of the compound analysed and is in no way restrictive.

Preparative HPLC was performed using a Waters System consisting of a Waters <NUM> Sample Manager, a Waters <NUM> Binary Gradient Module, a Waters SFO (System Fluidics Organizer), a Waters <NUM> Mass Detector, and a Waters <NUM> UV/Visible Detector.

Alternatively, preparative HPLC was performed using a Waters System consisting of <NUM> Autosampler and waters <NUM> PDA detector supported by Empower Software. LC-MS - electrospray mass spectra (UPLC ES-MS) were obtained using a Waters Acquity Ultra Performance Liquid Chromatography (UPLC) equipped with a SQ detector-<NUM> supported by Masslynx Software.

Alternatively, preparative HPLC was performed using an Agilent System consisting of an Agilent Infinity <NUM> Autosampler, an Agilent Infinity <NUM> Binary Gradient Module, an Agilent <NUM> Quadrupole Mass Detector and an Agilent Infinity <NUM> DAD VL UV/Visible Detector.

General Gradient: elution from X% to Y% B over <NUM> with an initial hold of <NUM> and a final increase to <NUM>% B over <NUM> and hold at <NUM>% B of <NUM> followed by a <NUM> gradient back to the initial composition. Total run time: <NUM>. X = Y - <NUM>% where Y = concentration of elution for the above described LC-MS method.

The gradient described could be altered in function of the physico-chemical properties of the compound analyzed and is in no way restrictive.

High resolution masses were obtained using Maxis II TM HD mass spectrometer (Bruker).

Proton (<NUM>H) nuclear magnetic resonance (NMR) spectra were measured with an Oxford Varian <NUM>/<NUM> (<NUM>) spectrometer or a Bruker Avance II (<NUM>) spectrometer, or with a Bruker Avance III (<NUM>) spectrometer with residual protonated solvent (CHCl3 δ <NUM>; MeOH δ <NUM>; DMSO δ <NUM>) as standard. The NMR data of the synthesized examples are in agreement with their corresponding structural assignments.

The majority of the compounds of the invention were synthesised according to general scheme <NUM> described above, where M1 is a chlorosulfonylation reaction of a commercially available <NUM>-substituted quinoxaline-<NUM>,<NUM>(<NUM>,<NUM>)-dione to give a sulfonyl chloride of formula A. The sulfonamide formation is the coupling step M2 between sulfonyl chloride A and a commercially available aniline derivative to give compounds of formula B. When substituent R<NUM> is an amine, the non-commercially available anilines E were synthesised from a fluoro- or chloro-nitrobenzene derivative as described in general scheme <NUM>. When substituent R<NUM> is a halogen, a further Suzuki coupling could be performed to yield biaryls of formula C, where R<NUM> is an aryl or hereroaryl group, identified by -Ar in general scheme <NUM>. Similarly, a Buchwald reaction could be performed to obtain tertiary anilines, as an alternative to what highlighted in general scheme <NUM>. It should be apparent to a person skilled in the art that the sequence of the synthetic steps is dependent on starting materials availability and functional group compatibility and could vary from compound to compound. In particular, steps M2 and M3 could easily be reversed to obtain in a first instance a biarylaniline or a para-substituted dianiline intermediate, which could then be reacted with sulphonyl chlorides A to obtain the final compounds of formula C. Similar conditions as for described methods M2 and M3 can be applied.

The following specific examples are presented to illustrate the invention, but they should not be construed as limiting the scope of the invention in any way. In the tables listing the intermediates, the compounds might have characterization such as (M+H)+ mass spectrometry data, HPLC purity and / or NMR. When the route to final compounds C encompasses different reactions steps as those described in General Scheme <NUM>, the synthetic procedure is also exemplified below.

Chlorosulfonic acid (<NUM>µl, <NUM> mmol) was added to <NUM>,<NUM>-dihydro-<NUM>-methylquinoxaline-<NUM>,<NUM>-dione (<NUM>, <NUM> mmol) and stirred at <NUM> for <NUM>. The solution was cooled down to r. and poured onto ice. The suspension was filtered and then washed with ice-H<NUM>O. The product was dried over night to yield the desired product 1A (<NUM>, <NUM>%) as a yellow solid.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

MS (ES) C<NUM>H<NUM>ClN<NUM>O<NUM>S requires: <NUM>, found: <NUM> (M+H)+, <NUM>%.

The following sulphonyl chloride intermediates were synthesised in a similar manner as described in Method M1:.

The following sulphonyl chlorides intermediates were synthesised with different methods:.

A stirred mixture of conc. HNO<NUM> (<NUM>, <NUM>%) and conc. H<NUM>SO<NUM> (<NUM>, <NUM>%) was cooled in ice bath below <NUM>. <NUM>,<NUM>-dioxo-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydroquinoxaline-<NUM>-sulfonyl chloride (<NUM>, <NUM> mmol) was carefully added keeping the temperature below <NUM>. The reaction mixture was stirred for <NUM> at <NUM> - <NUM> and then for <NUM> at r. The reaction mixture was poured onto ice and extracted with EtOAc. The combined organic phases were washed with H<NUM>O, sat. NaHCO<NUM> solution and again H<NUM>O, dried over Na<NUM>SO<NUM>, filtered, and concentrated in vacuo to yield the desired product 9A (<NUM>, <NUM>%), which was used in the following step without further purification.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

<NUM>-fluoro-<NUM>-methyl-benzene-<NUM>,<NUM>-diamine (<NUM>, <NUM> mmol) was added to an oven-dried microwave vial, followed by diethyl oxalate (<NUM>) and the mixture was heated to <NUM> for <NUM>. The reaction was allowed to cool down to r. , diluted with of Et<NUM>O, the obtained solids were filtered, washed with Et<NUM>O and dried on air to afford the desired product (D) (<NUM>, <NUM>%) as a brown solid.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

MS (ES) C<NUM>H<NUM>FN<NUM>O<NUM> requires: <NUM>, found: <NUM> (M+H)+, <NUM>%.

Intermediate 10D (<NUM>, <NUM> mmol) was added to an oven-dried microwave vial followed by chlorosulfonic acid (<NUM>), and the mixture was heated to <NUM> for <NUM>. Thionyl chloride (<NUM>, <NUM> mmol) was then added to the reaction mixture and further stirred at <NUM> for <NUM>. The reaction mixture was poured onto to an ice-H<NUM>O and the precipitated solids were collected by filtration, washed with H<NUM>O and then dried on air to give the corresponding product as a mixture of isomers: ~<NUM>% of desired compound (10A) (minor isomer) and ~<NUM>% of the undesired product (11A) (major isomer). The mixture was used in the following step without attempt at separating the regioisomers.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

MS (ES) C<NUM>H<NUM>FN<NUM>O<NUM>S requires: <NUM>, found: <NUM> (M+H)+, ~<NUM>% (derivatization was used for LC/MS measurement to avoid hydrolysis. The compound was converted into dimethyl sulfonamide (M+H+=<NUM>)).

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). MS (ES) C11H12FN3O4S requires: <NUM>, found: <NUM> (M+H)+, ~<NUM>% (derivatization was used for LC/MS measurement to avoid hydrolysis. The compound was converted into dimethyl sulfonamide (M+H+=<NUM>)).

Deuterated building block 12D was synthesised according to scheme <NUM>:
<CHM>.

A mixture of <NUM>,<NUM>-dimethoxy-<NUM>-methylquinoxaline (<NUM>, <NUM> mmol), NBS (<NUM>, <NUM> mmol) and benzoyl peroxide (<NUM>, <NUM>% H<NUM>O) in absolute CHCl<NUM> without stabilizer (<NUM>) was heated under reflux for <NUM>. The reaction was allowed to cool down to r. and the solvents were reduced in vacuo. The residue was purified by column chromatography on silica gel using a gradient of EtOAc in pet-ether to yield the desired product (E') (<NUM>, <NUM>%) as a white solid.

MS (ES) C<NUM>H<NUM>BrN<NUM>O<NUM> requires: <NUM>/<NUM>, found: <NUM>/<NUM> (M+H)+, <NUM>%.

A mixture of <NUM>-(bromomethyl)-<NUM>,<NUM>-dimethoxyquinoxaline (E') (<NUM>, <NUM> mmol) and PPh<NUM> (<NUM>, <NUM> mmol) in toluene (<NUM>) was heated at reflux for <NUM> The reaction was allowed to cool down to r. and the solid was collected by filtration, washed with toluene and dried under vacuum at <NUM> to yield the desired compound (F') (<NUM>, <NUM>%) as a white solid.

<NUM>H NMR (<NUM>, DMSO-ds): <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (dt, J = <NUM>, <NUM>, <NUM>), <NUM> (d, JP-H = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). Purity: <NUM>%.

To a solution of ((<NUM>,<NUM>-dimethoxyquinoxalin-<NUM>-yl)methyl)triphenylphosphonium bromide (F') (<NUM>, <NUM> mmol) in THF (<NUM>) was added a solution of NaOD in D<NUM>O (<NUM>, <NUM> w/w %). The reaction mixture was stirred at <NUM> for <NUM>. EtOAc and H2O were added to the reaction mixture. The organic layer was separated, dried over Na<NUM>SO<NUM> and reduced in vacuo. The residue was purified by column chromatography in pet-ether to yield the desired product (G') (<NUM>, <NUM>%) as a white solid.

MS (ES) C<NUM>H<NUM>D<NUM>N<NUM>O<NUM> requires: <NUM>, found: <NUM> (M+H)+, <NUM>%.

<NUM> HCl (<NUM>) was added to a solution of <NUM>,<NUM>-dimethoxy-<NUM>-(methyl-d<NUM>)quinoxaline (G') in dioxane, and the reaction was heated at <NUM> for <NUM>. The mixture was allowed to cool down to r. and dioxane was reduced in vacuo. The resulting precipitate was filtered, washed with water and dried in vacuo to yield the desired product 12D (<NUM>, <NUM>%) as a white solid.

To a mixture of sulfonyl chloride 1A (<NUM>, <NUM> mmol) in dry pyridine (<NUM>) <NUM>-bromo-<NUM>-chloroanilin (<NUM>, <NUM> mmol) was added and stirred at r. After <NUM> the mixture was diluted with a <NUM> aq. HCl solution and extracted with DCM. The combined organic phases were dried on MgSO<NUM>, filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel using a gradient of EtOAc in cHex to yield the desired product (<NUM> - 1B) (<NUM>, <NUM>%) as a light brown solid.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>).

MS (ES) C<NUM>H<NUM>BrClN<NUM>O<NUM>S requires: <NUM>, found: <NUM> (M+H)+, <NUM>%.

Sulfonyl chloride 1A (<NUM>, <NUM> mmol) and <NUM>-(trifluoromethoxy)pyridin-<NUM>-amine (<NUM>, <NUM> mmol) were dissolved in dry THF (<NUM>). NaH (<NUM>% in mineral oil, <NUM>, <NUM> mmol) was added at once and the mixture was and stirred at r. The mixture was diluted with a sat. NH<NUM>Cl aq. solution, extracted with EtOAc and washed with H<NUM>O. The combined organic phases were dried on MgSO<NUM>, filtered and evaporated in vacuo. The crude product was purified by preparative HPLC using a gradient of MeCN in H<NUM>O with <NUM>% TFA to yield the desired product (<NUM>) (<NUM>, <NUM>%) as a white powder.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

MS (ES) C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>S requires: <NUM>, found: <NUM> (M+H)+, <NUM>%.

Intermediate 1B (<NUM>, <NUM> mmol), <NUM>-fluorophenylboronic acid (<NUM>, <NUM> mmol), K<NUM>CO<NUM> (<NUM>; <NUM> mmol) and Pd(PPh<NUM>)<NUM> (<NUM>, <NUM> mmol) were suspended in DME/H<NUM>O (<NUM>:<NUM>, <NUM>) and heated at <NUM> for <NUM> in a microwave. After cooling to r. , the mixture was filtered and evaporated in vacuo. The crude product was purified by reverse phase flash chromatography on C18 using a gradient of MeCN in H<NUM>O to yield the desired product (<NUM> - 1C) (<NUM>, <NUM>%) as a white solid.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

MS (ES) C<NUM>H<NUM>ClFN<NUM>O<NUM>S requires: <NUM>, found: <NUM>-H+, <NUM>%.

<NUM>-Nitro-<NUM>-(trifluoromethyl)aniline (<NUM>, <NUM> mmol) was added to chlorosulfonic acid (<NUM>) at r. The reaction mixture was stirred for <NUM> at <NUM>, upon which it was allowed to cool down to r. and was poured onto ice. layer was extracted with EtOAc. The combined organic phases were washed with H<NUM>O, dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo to yield the crude product (1E), which was used in the following step without further purification.

<NUM>-(trifluoromethoxy)aniline (<NUM>, <NUM> mmol) was reacted with crude sulfonyl chloride D according to method M2 to yield the desired product (1F) (<NUM>, <NUM>% over <NUM> steps).

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (br. s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

MS (ES) C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>S requires: <NUM>, found: <NUM> (M+H)+.

To a solution of intermediate 1F (<NUM>, <NUM> mmol) in EtOH (<NUM>) was added SnCl<NUM>*<NUM><NUM>O (<NUM>, <NUM> mmol) and conc. HCl (<NUM>). The reaction mixture was stirred for <NUM> at <NUM> and cooled to r. pH-value was adjusted to <NUM>-<NUM> using <NUM>% aq. The mixture was extracted with EtOAc, and the combined organic phases were dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo to yield the desired product <NUM> (<NUM>, ~<NUM>%), which was used in the following step without further purification.

To a suspension of the crude dianiline <NUM> (<NUM>, ca. 57mmol) in HCl (<NUM> N, <NUM>) was added oxalic acid (<NUM>, <NUM> mmol) and HCl (<NUM> N, <NUM>). The mixture was stirred at <NUM> <NUM>C for <NUM>, upon which it was allowed to cool down to r. The mixture was extracted with EtOAc, and the combined organic phases were dried over Na<NUM>SO<NUM>, filtered, and concentrated in vacuo. The residue was purified by two subsequent column chromatographies: the first column on silica gel using a gradient of MeOH in DCM, the second on reverse phase C18 silica using a gradient of MeCN in H<NUM>O to yield the desired product (<NUM>) (<NUM>, <NUM>% over <NUM> steps).

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br. s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM> Hz, <NUM>).

HRMS (ESI) calcd. for C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>S (M+H)+ <NUM>, found <NUM>.

<NUM>-Bromo-<NUM>-fluoroaniline (<NUM>, <NUM> mmol) was carefully added to conc. H<NUM>SO<NUM> (<NUM>), and the mixture was stirred at <NUM> for <NUM>. The reaction mixture was cooled to - <NUM> - -<NUM> (ice/NaCl bath) and KNO<NUM> (<NUM>, <NUM> mmol) was added in batches. The reaction mixture was stirred at <NUM> for <NUM>, poured into ice-H<NUM>O and extracted with EtOAc. The combined organic phases were washed with aq. NaHCO<NUM> and H<NUM>O, dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using a gradient of EtOAc in petroleum ether to yield the desired product (H) (<NUM>, <NUM>%).

MS (ES) C<NUM>H<NUM>BrFN<NUM>O<NUM> requires: <NUM>/<NUM>, found: <NUM>/<NUM> (M+H)+.

A mixture of bromo derivative H (<NUM>, <NUM> mmol), cyclopropyl boronic acid (<NUM>, <NUM> mmol), Pd(OAc)<NUM> (<NUM>, <NUM> mmol, <NUM> %), tricyclohexylphosphine (<NUM>, <NUM> mmol) and K<NUM>PO<NUM> (<NUM>, <NUM> mmol) was evacuated and backfilled with Ar three times, then H<NUM>O (<NUM>) and toluene (<NUM>) were added. The mixture was further degassed with Ar and stirred at <NUM> for <NUM> under Ar atmosphere, upon which it was allowed to cool down to r. EtOAc was added, and the organic layer was washed with brine, dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc in petroleum ether to yield the desired product (J) (<NUM>, <NUM>%).

<NUM>H NMR (<NUM>, DMSO-d<NUM>): <NUM> (d, JH-F = <NUM>, <NUM>), <NUM> (d, JH-F = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

<NUM>F NMR (<NUM>, DMSO-d<NUM>) δ -<NUM>.

In a first flask, intermediate J (<NUM>, <NUM> mmol) was dissolved in conc. HCl (<NUM>), and the resulting solution was cooled to -<NUM>, using an ice/NaCl bath. A solution of sodium nitrite (<NUM>, <NUM> mmol) in distilled H<NUM>O (<NUM>) was added in portions with stirring, while maintaining the temperature below <NUM>. The mixture was then kept at this temperature. In a second flask, SOCl<NUM> (<NUM>, <NUM>, <NUM> mmol) was added dropwise to distilled H<NUM>O (<NUM>), which had been pre-cooled to -<NUM> using an ice/NaCl bath. The resulting solution was allowed to warm to r. , CuCl (<NUM>, <NUM> mmol) was added, and the reaction mixture was re-cooled to -<NUM>. With continued cooling and stirring, the contents of the first flask were added in small portions to the contents of the second flask, and the mixture was stirred for <NUM> at -<NUM>. The mixture was then extracted with EtOAc, and the combined organic phases were dried over Na<NUM>SO<NUM>, filtered, and concentrated in vacuo, to yield the desired product (K) (<NUM>, <NUM>%), which was used in the following step without further purification or characterization.

<NUM>-(trifluoromethoxy)aniline (<NUM>, <NUM> mmol) was reacted with crude sulfonyl chloride J (<NUM>, <NUM> mmol) according to method M2 to yield the desired product (L) (<NUM>, <NUM>%).

<NUM>H NMR (<NUM>, DMSO-ds): <NUM> - <NUM> (br. s, <NUM>), <NUM> (d, JH-F = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, JH-F = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

NH<NUM> (<NUM>) was added to the solution of fluoro derivative L (<NUM>, <NUM> mmol) in EtOH (<NUM>) at r. The mixture was stirred at r. The solvent was removed under reduced pressure and the mixture was extracted with EtOAc, dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a gradient of EtOAc in pet-ether to yield the desired product (2F) (<NUM>, <NUM>%).

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

<NUM>F NMR (<NUM>, DMSO-d<NUM>): -<NUM>.

To a solution of nitro derivative 2F (<NUM>, <NUM> mmol) in dioxane (<NUM>) at <NUM> was added a suspension of SnCl<NUM>*<NUM><NUM>O (<NUM>, <NUM> mmol) in conc. HCl (<NUM>). The mixture was stirred for <NUM> at r. , neutralized with <NUM>% NaOH and extracted with EtOAc. The combined organic phases were dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo to yield the desired product (<NUM>) (<NUM>, <NUM>% excess wt), which was used in the following step without further purification.

The crude product dianiline <NUM> (<NUM>, ca. <NUM> mmol) was dissolved in diethyl oxalate (<NUM>). The mixture was heated to <NUM> and stirred for <NUM>. The reaction mixture was allowed to cool to r. and separated by two subsequent column chromatographies: the first column on silica gel using a gradient of MeOH in DCM, the second on reverse phase C18 silica using a gradient of MeCN in H<NUM>O to yield the desired product (<NUM>) (<NUM>, <NUM>%).

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

Morpholine (<NUM>µL, <NUM> mmol) and <NUM>-chloro-<NUM>-fluoro-<NUM>-nitrobenzene (<NUM>, <NUM> mmol) were dissolved in DMSO (<NUM>), and K<NUM>CO<NUM> (<NUM>, <NUM> mmol) was added. The mixture was shaken at <NUM> for <NUM>, followed by cooling down to r. The mixture was diluted with H<NUM>O and extracted with EtOAc. The combined organic phases were dried on MgSO<NUM>, filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel using a gradient of EtOAc in cHex to yield the desired product (1N) (<NUM>, <NUM>%) as a yellow solid.

MS (ES) C<NUM>H<NUM>ClN<NUM>O<NUM> requires: <NUM>, found: <NUM> (M+H)+, <NUM>%.

Nitro-derivative 1N (<NUM>, <NUM> mmol) was dissolved in EtOH (<NUM>), and Fe (<NUM>, <NUM> mmol) was added, followed by a <NUM> HCl solution (<NUM>). The mixture was stirred at <NUM> for <NUM>, and allowed to cool down to r. The mixture was diluted with EtOAc and washed with a sat. NaHCO<NUM> solution. The aqueous phase was extracted once more with EtOAc, and the combined organic phases were dried on MgSO<NUM>, filtered over celite and evaporated in vacuo to yield the desired product (1Q) (<NUM>, <NUM>%) as a brown powder.

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (ddd, J = <NUM>, <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>).

MS (ES) C<NUM>H<NUM>ClN<NUM>O requires: <NUM>, found: <NUM> (M+H)+, <NUM>%.

The following anilines intermediates were synthesised in a similar manner as described in Method M4 and M5:.

<NUM>-fluoro-<NUM>-nitroaniline (<NUM>, <NUM> mmol) was added portionwise to chlorosulfonic acid (<NUM>). After stirring for <NUM> at <NUM> the solution was cooled down to <NUM> and poured onto ice-H<NUM>O. The mixture was extracted with EtOAc. The combined organic phases were dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo to yield the desired product (3E) (<NUM>, <NUM>%) as a brown oil.

<NUM>H-NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (d, <NUM>JH-F = <NUM>, <NUM>), <NUM> (d, <NUM>JH-F = <NUM>, <NUM>).

Dry pyridine (<NUM>, <NUM> mmol) was added to a solution of <NUM>-(trifluoromethoxy)-aniline (<NUM>, <NUM> mmol) in dry DCM (<NUM>) under Ar atmosphere. A solution of intermediate 3E (<NUM>, <NUM> mmol) in dry DCM (<NUM>) was added over a period of <NUM> at <NUM> using a metal cannula. The reaction mixture was allowed to warm to r. and stirred for <NUM>. The solvents were reduced in vacuo and H<NUM>O was added to the residue and the mixture was extracted with EtOAc. The combined organic phases were dried over Na<NUM>SO<NUM>, filtered and concentrated in vacuo. The crude was purified by flash chromatography on silica gel using a gradient of acetone in DCM, followed by recrystallization using a mixture of acetone and DCM to yield the desired product (3F) (<NUM>, <NUM> %) as yellow needles.

<NUM>H-NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (d, <NUM>JH-F = <NUM>, <NUM>), <NUM> (br. s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (d, <NUM>JH-F = <NUM>, <NUM>).

MS (ES) C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>S requires: <NUM>, found <NUM> (M+H)+.

Intermediate 3F (<NUM>, <NUM> mmol) was dissolved in dry DMF (<NUM>) and added to previously in vacuo flame dried K<NUM>CO<NUM> (<NUM>, <NUM> mmol) under Ar atmosphere. <NUM>-lodoethanol (<NUM>, <NUM> mmol) was added and the reaction mixture was stirred for at <NUM> for <NUM>. The solvents were reduced in vacuo. After addition of H<NUM>O the pH of the mixture was adjusted to <NUM> with <NUM> HCl. The precipitated solid was dissolved in EtOAc, and the mixture was washed with a half-saturated NaCl solution. The organic phase was dried, filtered, and reduced in vacuo to yield the alkylated intermediate. The latter was dissolved in dry DMF (<NUM>) and Cs<NUM>CO<NUM> (<NUM>, <NUM> mmol) was added.

The reaction mixture was stirred at <NUM> for <NUM>, upon which the solvent was reduced in vacuo. H<NUM>O was added and the pH of the mixture was adjusted to <NUM> with <NUM> HCl. The precipitated solid was dissolved in EtOAc and the organic phase washed with half-saturated NaCl solution. The organic phase was dried over Na<NUM>SO<NUM>, filtered, and the solvent reduced in vacuo. The crude was purified by flash chromatography on silica gel using a gradient of EtOAc in petroleum ether to yield the desired product (R) (<NUM>, <NUM> %) as a yellow solid.

<NUM>H-NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (br. s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>).

Intermediate R (<NUM>, <NUM> mmol) was dissolved in dioxane (<NUM>) and conc. NH<NUM> solution (<NUM>) was added. Na<NUM>S<NUM>O<NUM> (<NUM>, <NUM> mmol) was dissolved in H<NUM>O (<NUM>) and added dropwise to the reaction solution. After stirring for <NUM> at r. , the organic solvents were reduced in vacuo and H<NUM>O was added. The pH of the aq. phase was adjusted to <NUM> with <NUM> HCl and the latter was extracted with EtOAc. The combined organic phases were dried over Na<NUM>SO<NUM>, filtered, and reduced in vacuo to yield the desired product (S) (<NUM>, <NUM>%) as a beige solid.

<NUM>H-NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (br. s, <NUM>), <NUM> (br. s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>).

MS (ESI) C<NUM>H<NUM>F<NUM>N<NUM>O<NUM>S requires: <NUM>, found <NUM> (M+H)+.

A mixture of dianiline S (<NUM>, <NUM> mmol) and dimethyl oxalate (<NUM>, <NUM> mmol) was stirred at <NUM> for <NUM>, upon which the it was allowed to cool down to r. and dissolved in MeOH. The solvents were reduced in vacuo and the residue was purified by preparative HPLC using a gradient of MeCN in H<NUM>O to yield the desired product (<NUM>) (<NUM>, <NUM> %) as a white solid.

<NUM>H-NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br. s, <NUM>), <NUM> (br. s, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (mc, <NUM>).

Dimethylamine derivative <NUM> was also synthesized from intermediate 3F using the procedure described below.

Intermediate 3F (<NUM>, <NUM> mmol) was dissolved in dry DMF (<NUM>) and DIPEA (<NUM>µL, <NUM> mmol) was added, followed by a <NUM> N,N-dimethylamine solution in THF (<NUM>µL, <NUM> mmol). The solution was stirred at <NUM> for <NUM> and the solvent was removed in vacuo. The residue was dissolved in EtOAc and washed with H<NUM>O. The organic layer was dried over Na<NUM>SO<NUM>, filtered, and reduced in vacuo. The residue was purified by flash chromatography on silica gel using a gradient of EtOAc in petroleum ether to yield the desired product 4F (<NUM>, <NUM> %) as a yellow solid.

<NUM>H-NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (br. s, <NUM>), <NUM> (mc, <NUM>), <NUM> (mc, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

Intermediate 4F (<NUM>, <NUM> mmol) was dissolved in <NUM> <NUM>,<NUM>-dioxane and conc. NH<NUM> solution (<NUM>, ca. <NUM>%) was added. Na<NUM>S<NUM>O<NUM> (<NUM>, <NUM> mmol) was dissolved in deionized H<NUM>O (<NUM>) and added dropwise to the starting material. The mixture was stirred for <NUM> at r. , upon which the organic solvents were reduced in vacuo. The pH value was adjusted to <NUM> with <NUM> HCl. The precipitated solid was extracted with EtOAc, and the combined organic layers were dried over Na<NUM>SO<NUM>, filtered and reduced in vacuo to yield the desired product <NUM> (<NUM>, <NUM>%) as a pale pink solid, which was used in the following step without further purification.

<NUM>H-NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br. s, <NUM>), <NUM> (mc, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

The following dianilines intermediates were synthesised in a similar manner as described for intermediate <NUM>. Reaction conditions and bases employed were dependent on functional group compatibility and operator, and could vary from compound to compound, as should be apparent to a person skilled in the art.

Dianiline <NUM> (<NUM>, <NUM> mmol) and <NUM>,<NUM>'-oxalyldiimidazole (<NUM>, <NUM> mmol), were dissolved in dry THF (<NUM>) under Ar atmosphere. After stirring for <NUM> at <NUM>, additional <NUM>,<NUM>'-oxalyldiimidazole (<NUM>, <NUM>µmol) was added to the reaction. The solution was stirred for <NUM> at <NUM>, upon which the volatiles were removed in vacuo and the residue purified by reverse phase chromatography on C18 using a gradient of MeCN in H<NUM>O, to yield the desired product <NUM> (<NUM>, <NUM> %) as a white solid.

<NUM>H-NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

An exemplified hydrogenation procedure to obtain compound <NUM> from compound <NUM> is described below. A similar procedure was employed to reduce compound <NUM> to <NUM> and compound <NUM> to compound <NUM>.

To a stirred solution of <NUM> (<NUM>, <NUM> mmol) in MeOH was added <NUM>% Pt-C (<NUM>) and the mixture was stirred at RT for <NUM> under H<NUM> balloon atmosphere. The suspension was filtered through a celite pad and the pad was washed with MeOH. The filtrate was concentrated under reduced pressure and the crude product was purified by prep HPLC by using NH<NUM>HCO<NUM> in H<NUM>O: acetonitrile as an eluent. The compound containing fractions were concentrated and dried to yield the desired product <NUM> (<NUM>, <NUM>%) as an off-white solid.

<NUM>H NMR (<NUM>, DMSO) δ: <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J =<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

MS (ESI) C<NUM>H<NUM>BrN<NUM>O<NUM>S requires: <NUM>, found <NUM> (M-H)-.

Occasionally, Boc-protected boronic acids or boronic esters were employed in the Suzuki coupling described in M3. An exemplified Boc-deprotection procedure to obtain final compound <NUM> is described below. A similar procedure was employed to yield compounds <NUM> and <NUM>.

To a stirred solution of tert-butyl (<NUM>'-chloro-<NUM>'-((<NUM>-methyl-<NUM>,<NUM>-dioxo-<NUM>,<NUM>,<NUM>,<NUM>-tetrahydroquinoxaline)-<NUM>-sulfonamido)-[<NUM>,<NUM>'-biphenyl]-<NUM>-yl)carbamate (<NUM>, <NUM> mmol) in DCM (<NUM>) was added <NUM> HCl in <NUM>, <NUM>-dioxane (<NUM>) at <NUM>. The reaction was stirred at RT for <NUM>. The mixture was concentrated in vacuo and the residue was washed with Et<NUM>O (<NUM>), pentane (<NUM>). The solvents were removed in vacuo to yield the desired product <NUM> (<NUM>, <NUM>%) as an off-white solid, HCl salt.

<NUM>H NMR (<NUM>, DMSO) δ: <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

MS (ESI) C<NUM>H<NUM>ClN<NUM>O<NUM>S requires: <NUM>, found <NUM> (M-H)-.

To obtain the anilines required for the synthesis of compounds <NUM> and <NUM>, <NUM>-Bromo-<NUM>'-fluoro-[<NUM>,<NUM>'-biphenyl]-<NUM>-amine obtained from standard method M3 was Boc-protected, following which a Buchwald reaction was performed. Boc-deprotection yielded the required aniline.

To a stirred solution of <NUM>-bromo-<NUM>'-fluoro-[<NUM>,<NUM>'-biphenyl]-<NUM>-amine (<NUM>, <NUM> mmol) in THF (<NUM>) at RT were added DIPEA (<NUM>) and Boc<NUM>O (<NUM>, <NUM> mmol). The reaction was stirred for <NUM> at <NUM>. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel using a gradient of EtOAc in petroleum, followed by by prep-HPLC using a gradient of <NUM>% HCOOH in H<NUM>O in MeOH to yield the desired product <NUM> (<NUM>, <NUM>%) as a brown solid.

MS (ESI) C<NUM>H<NUM>BrFNO<NUM> requires: <NUM>, found <NUM> [M-tBu+H]+.

To a degassed solution of intermediate <NUM> (<NUM>, <NUM> mmol), morpholine (<NUM>, <NUM> mmol) and t-BuONa (<NUM>, <NUM> mmol) in toluene (<NUM>) were added Pd<NUM>(dba)<NUM> (<NUM>, <NUM> mmol) and Xantphos (<NUM>, <NUM> mmol) at rt. The reaction was stirred for <NUM> at <NUM>, upon which the mixture was cooled to rt, quenched with water and extracted with EtOAc. The combined organic layer was dried over anhydrous Na<NUM>SO<NUM>, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel, using a gradient of EtOAc in pet-ether as an eluent to afford the desired compound 1T (<NUM>, <NUM>%) as a brown solid.

MS (ESI) C<NUM>H<NUM>FN<NUM>O<NUM> requires: <NUM>, found <NUM> [M+H]+.

4N HCl in <NUM>, <NUM>-dioxane (<NUM>) were added to a stirred solution of intermediate 1T (<NUM>, <NUM> mmol) in DCM (<NUM>) at <NUM>, and the reaction was stirred for <NUM> at rt. The mixture was concentrated in vacuo and the residue was washed with Et<NUM>O and dried to yield the desired product 1U (<NUM>, excess weight). The crude compound was used in the following step without further purification.

MS (ESI) C<NUM>H<NUM>FN<NUM>O requires: <NUM>, found <NUM> [M+H]+.

When the final compound contained one or more acetylene groups, silyl-group protections and deprotections were introduced to improve conversion and facilitate isolation of the intermediates. All or parts of the below-described route, leading to compound <NUM> were employed. It should be apparent to a person skilled in the art that the sequence of the synthetic steps, as well as reaction conditions and the protecting groups employed, are dependent on starting materials availability, functional group compatibility and operator, and could vary from compound to compound.

To a degassed solution of <NUM>-iodoaniline (<NUM>, <NUM> mmol) and (triisopropylsilyl)-acetylene (<NUM>, <NUM> mmol) in DMF (<NUM>) at r. were added Et<NUM>NH (<NUM>, <NUM> mmol), Cul (<NUM>, <NUM>) and Pd(PPh<NUM>)<NUM>Cl<NUM> (<NUM>, <NUM> mmol). The resulting reaction mixture was degassed with Ar for <NUM> and stirred for <NUM> at <NUM> in microwave. The reaction was allowed to cool to rt, and quenched with H<NUM>O, and extracted with Et<NUM>O. The combined organic layers were dried over anhydrous Na<NUM>SO<NUM>, filtered and reduced in vacuo. The residue was purified by column chromatography on silica gel using a gradient of EtOAc in pet-ether to yield the desired product (1V) (<NUM>, <NUM>%) as a brown gum.

MS (ESI) C<NUM>H<NUM>NSi requires: <NUM>, found <NUM> [M+H]+.

NIS (<NUM>, <NUM> mmol) was added to a stirred solution of intermediate 1V (<NUM>, <NUM> mmol) in DMSO (<NUM>) and the reaction was stirred at r. under Ar atmosphere for <NUM>. The mixture was poured into cold water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na<NUM>SO<NUM>, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a gradient of EtOAc in pet-ether to yield the desired product 1W (<NUM>, <NUM>%) as a brown gum.

MS (ESI) C<NUM>H<NUM>INSi requires: <NUM>, found <NUM> [M+H]+.

Compound 1W (<NUM>, <NUM> mmol) and (<NUM>-((trimethylsilyl)ethynyl)phenyl)boronic acid (<NUM>, <NUM> mmol) were dissolved in dioxane:H<NUM>O (<NUM>:<NUM>, <NUM>) and degassed Na<NUM>CO<NUM> (<NUM>, <NUM> mmol) and Pd(PPh<NUM>)<NUM> (<NUM>, <NUM> mmol) were added at rt. The reaction was degassed with Ar for <NUM> and stirred at <NUM> for <NUM> in the microwave. The mixture was allowed to coolto rt, quenched with H<NUM>O, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na<NUM>SO<NUM>, filtered and reduced in vacuo. The residue was purified by column chromatography on silica gel using a gradient of EtOAc in pet-ether to yield the desired product 1X (<NUM>, <NUM>%) as a pale yellow gum.

MS (ESI) C<NUM>H<NUM>NSi<NUM> requires: <NUM>, found <NUM> [M+H]+.

To a stirred solution of compound 1X (<NUM>, <NUM> mmol) in pyridine (<NUM>) at <NUM> was added intermediate 1A (<NUM>, <NUM> mmol) and the reaction was stirred at r. The mixture was quenched with cold water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na<NUM>SO<NUM>, filtered and reduced in vacuo. The crude product was purified by prep-HPLC using a gradient of NH<NUM>HCO<NUM> in H<NUM>O in ACN to yield the desired product 1Y (<NUM>, <NUM>%) as an off-white solid.

MS (ESI) C<NUM>H<NUM>N<NUM>O<NUM>SSi<NUM> requires: <NUM>, not seen.

TBAF (<NUM> in THF, <NUM>, <NUM> mmol) was added to a stirred solution of compound 1X (<NUM>, <NUM> mmol) in THF (<NUM>) at <NUM>. The reaction for <NUM> at rt. The mixture was quenched with cold water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na<NUM>SO<NUM>, filtered and reduced in vacuo. The residue was purified by prep-HPLC using a gradient of NH<NUM>HCO<NUM> in H<NUM>O in ACN to yield the desired product <NUM> (<NUM>, <NUM>%) as an off-white solid.

MS (ESI) C<NUM>H<NUM>N<NUM>O<NUM>S requires: <NUM>, found <NUM> [M-H]+.

A similar deprotection step was also necessary when the boronic acid building block contained a TBS-protected phenol, as is the case for compound <NUM>.

Further compounds exemplifying the invention are described in Table <NUM>.

When not otherwise specified, it should be assumed that M1, M2, sometimes followed by M3 were used to yield the target compounds. This is highlighted in the 'Synthetic Sequence' column. Occasionally, as specified in the table, a further deprotection or hydrolysis step was required to obtain the final product, as would be recognized by a person skilled in the art. It should also be apparent to a person skilled in the art that reaction conditions such as temperature, dilution, reaction time or work-up procedures, including pH adjustment, are dependent on reaction partners and functional group compatibility and could vary from compound to compound. For commercially available compounds, the CAS number is given.

The assay is based on the Fluo-<NUM> NW Calcium Assay Kit (#F36205) from Thermo Scientific. Here the effect of hemolysin alpha from staphylococcus aureus was monitored by loading non adherent U397 cells with the Ca<NUM>+-sensitive dye Fluo-<NUM> hemolysin alpha addition leads to the formation of Ca<NUM>+ permissive pores in the membrane of the U397 cells which results in a dose dependent increase of fluorescence.

Briefly, the protocol described here was applied for screening and activity determination in a low-volume <NUM>-well microtiter plate with cell culture treated surface. For high-throughput application in the <NUM>-well microtiter plate format, volumes of the reagent mixes were adjusted, maintaining the volumetric ratio.

The LDH-Glo-Cytotoxicity Assay is a bioluminescent plate-based assay to quantify the release of cellular Lactate Dehydogenase (LDH) into the assay medium upon plasma membrane damage by hemolysin treatment of the cells. LDH in the supernatant reduces an added substrate to generate luciferin which is converted into a bioluminescent signal by the Ultra Glo Luciferase (Promega).

A549-Cells (DSMZ, #ACC107), that are used for the assay, are maintained in RPMI <NUM> cell culture medium + glutamine (PAN Biotech GmbH, Aidenbach, Germany; #P04-<NUM>; P04-<NUM>) supplemented with <NUM>% fetal calf serum (Capricorn, #FBS-11A) and are grown at <NUM>, <NUM>% CO<NUM>.

For the LDH assay compounds or DMSO are prediluted at different concentrations in <NUM>µl cell culture medium RPMI <NUM> + <NUM>% FCS + <NUM> HEPES in black µclear <NUM>-well-plates (Greiner BioOne). Shortly afterwards <NUM>µl of <NUM> S. aureus Alpha hemolysin (IBT BIOSERVICES, #<NUM>-<NUM>) was added to get a final assay concentration of <NUM>. After adding <NUM>µl of A549 cells (<NUM> cells/well diluted in assay medium) the assay plates (total assay volume: <NUM>µl) were incubated for <NUM> at <NUM> / <NUM>% CO<NUM> in humidified chambers in order to allow hemolysis.

As a positive internal control, we use the hemolysin antibody (IBT Bioservices, #<NUM>-<NUM>) at a concentration range from <NUM> - <NUM>µg / ml and determine the IC<NUM> concentration. The standard IC<NUM> concentration for the antibody is approximately <NUM> ng / ml.

The determination of the LDH concentration was done after the <NUM> incubation time according to the instructions of the One Glo Luminescent assay Kit (Promega, cat no. Shortly, <NUM>µl of cell culture supernatant were incubated in a separated black µclear <NUM>-well plate at <NUM> for <NUM>, mixed with <NUM>µl of the LDH reagent using an orbital shaker (<NUM>, <NUM> rpm) and further incubated for <NUM> at <NUM>. The reaction was stopped by addition of <NUM>µl stop-reagent, provided with the assay kit. Shortly afterwards the fluorescent signal was measured by Victor X5 plate reader (Perkin Elmer) using the filters <NUM> (extinction) and <NUM> (emission). EC<NUM> values were calculated with the software Excel Fit (IDBS, Guildford, UK) from <NUM>-fold dilution series comprising at least <NUM> concentrations in duplicates.

Activities of compounds are listed in Table <NUM> together with compound number and IUPAC names. Biological activities are determined by two main assays with HIα-induced cell damage: hemolysin-α Ca2+-influx on U937 cells according to Example <NUM> and LDH-Glo Cytotoxicity Assay on A549 cells according to Example <NUM>, and were grouped according to the following scheme:.

Comparison of compounds of the present invention with compounds of formula (I) wherein R<NUM> is hydrogen:.

As can be taken from the above comparison, the presence of group R<NUM> significantly enhances the activity of the compounds of the present invention against S.

Claim 1:
A compound of formula (I):
<CHM>
wherein
R<NUM> is hydrogen, fluorine or a methyl group;
R<NUM> is halogen, OH, NO<NUM>, CN or NH<NUM>; or a C<NUM>-<NUM> alkyl group, a C<NUM>-<NUM> alkenyl group, a C<NUM>-<NUM> alkynyl group, a C<NUM>-<NUM> cycloalkyl group, an -O-C<NUM>-<NUM> cycloalkyl group, a C<NUM>-<NUM> alkylcycloalkyl group, or a C<NUM>-<NUM> heteroalkyl group;
R<NUM> is an optionally substituted phenyl group; an optionally substituted naphthyl group; an optionally substituted heteroaryl group containing <NUM> or <NUM> rings and <NUM> to <NUM> ring atoms selected from O, S, N and C; an optionally substituted cycloalkyl aryl group comprising a phenyl group and a cycloalkyl group containing <NUM> or <NUM> ring atoms; an optionally substituted heterocycloalkyl aryl group comprising a phenyl group and a heterocycloalkyl group containing <NUM> or <NUM> ring atoms selected from O, S, B, N and C; an optionally substituted cycloalkyl heteroaryl group comprising a heteroaryl group comprising <NUM> or <NUM> ring atoms selected from O, S, N and C and a cycloalkyl group containing <NUM> or <NUM> ring atoms; or an optionally substituted heterocycloalkyl heteroaryl group comprising a heteroaryl group comprising <NUM> or <NUM> ring atoms selected from O, S, N and C and a heterocycloalkyl group containing <NUM> or <NUM> ring atoms selected from O, S, N and C; or an optionally substituted cycloalkyl group containing <NUM> or <NUM> rings and <NUM> to <NUM> ring atoms; and
R4a is hydrogen; or
R<NUM> and R4a together are a group of formula -O-(CH<NUM>)n-, wherein n is <NUM>, <NUM> or <NUM>, wherein the oxygen is bound to the phenyl ring;
or a solvate, a hydrate or a salt thereof;
wherein the following compounds are excluded:
<NUM>. compounds of formula (I) wherein R<NUM> is H, R<NUM> is Me, R4a is hydrogen and R<NUM> is selected from the following groups:
<CHM>
<CHM>
<CHM>
<CHM>
and
<NUM>. the compound of the following formula:
<CHM>
wherein R is a group having the following structure:
<CHM>