Glycinamide derivatives for use in the treatment of salmonellosis

Abstract

The present invention relates to compounds of formula (la) that block invasion-associated pathogenicity of Salmonella Typhimurium by inhibiting the activity of the transcription factor HilD. These compounds are useful in the treatment or prophylaxis of Salmonella infections (salmonellosis).

Description

[0001] GLYCINAMIDE DERIVATIVES FOR USE IN THE TREATMENT OF SALMONELLOSIS

[0002] The present invention relates to compounds that block invasion-associated pathogenicity of Salmonella Typhimurium by inhibiting the activity of the transcription factor HilD.

[0003] Salmonella Typhimurium is an enteric pathogen causing inflammatory diarrhea which can develop into invasive non-typhoidal Salmonella (iNTS) infection once the bacteria invade the intestinal epithelium (Fabrega A, Vila J. 2013 "Salmonella enterica Serovar Typhimurium Skills to Succeed in the Host: Virulence and Regulation" Clin Microbiol Rev 26:308-341). Salmonella Typhimurium has a broad host range. It is therefore relevant to both human and animal health (Galan JE. 2021 "Salmonella Typhimurium and inflammation: a pathogen-centric affair" Nature Reviews Microbiology 1-10). Salmonellosis is the second most commonly reported gastrointestinal infection and an important cause of foodborne outbreaks in Europe (European Centre for Disease Prevention and Control. Salmonellosis. In: ECDC. Annual epidemiological report for 2017. Stockholm: ECDC; 2020). While iNTS case fatality rate remains low in developed countries, it reaches 20-25% in endemic regions like sub-Saharan Africa (Feasey NA, Dougan G, Kingsley RA, Heyderman RS, Gordon MA. 2012 "Invasive non-typhoidal salmonella disease: an emerging and neglected tropical disease in Africa" Lancet 379:2489-2499). Additionally, fluoroquinolone-resistant Salmonellae have been categorized as high-priority pathogens by the WHO owing to their potential future risk for human health even in countries with advanced healthcare systems.

[0004] Ingested Salmonella that reach the intestine are able to cause gastroenteritis by eliciting a local inflammation and by invading epithelial cells (Haraga A, Ohlson MB, Miller SI. 2008 "Salmonellae interplay with host cells" Nat Rev Microbiol 6:53-66). Attachment to target cells is mediated by adhesins encoded in Salmonella pathogenicity island 4 (SPI-4), while invasion relies on injection of effector proteins into the target cells by use of the type III secretion system-1 (T3SS-1) (Wagner S, Grin I, Malmsheimer S, Singh N, Torres-Vargas CE, Westerhausen S. 2018 "Bacterial type III secretion systems: a complex device for the delivery of bacterial effector proteins into eukaryotic host cells" FEMS Microbiol Lett 365). Once intracellular, a second T3SS (T3SS-2) is expressed and activated to inject effector proteins that facilitate intracellular survival and replication. Occasionally, Salmonella breach the epithelial barrier and enter the lamina propria, where they may be ingested by macrophages. Supported again by the action of T3SS-2, Salmonella are not killed inside macrophages but exploit them as shuttles through the bloodstream and eventually elicit systemic infections (Galan, 2021).

[0005] The infection stage-dependent sequential activation of the different secretion systems implies a fine-tuned regulation of the 5 pathogenicity islands of Salmonella (SPIs) to coordinate the adhesion and injection of virulence factors in response to environmental signals. To do so, Salmonella possesses virulence-associated two-component systems (TCS) responsible for environmental signals transduction that are directly or indirectly feeding into a feed-forward regulatory loop formed by the 3 AraC-like transcriptional regulators HilD, HilC, and RtsA. They positively regulate each other both at the transcriptional level and post-translational level by forming homodimers and heterodimers (https: / / doi.org / 10.1128 / JB.00012-20: Narm K-E, Kalafatis M, Slauch JM. 2020 "HilD, HilC, and RtsA Form Homodimers and Heterodimers to Regulate Expression of the Salmonella Pathogenicity Island I Type III Secretion System" J Bacteriol). HilD plays a central role in this regulation pathway. A ffz / D-deficient Salmonella strain is unable to activate its virulence genes encoded in SPIs and is therefore avirulent. HilC and RtsA play a minor role as signal amplifiers (Golubeva YA, Sadik AY, Ellermeier JR, Slauch JM. 2012 "Integrating global regulatory input into the Salmonella pathogenicity island 1 type III secretion system" Genetics 190:79-90). The HilD / HilC / RtsA regulatory loop coordinates the expression of the 5 SPIs, placing HilD at the centre of Salmonella pathogenicity regulation and therefore a drug target of high value for the development of antivirulence agents. There is currently an increasing number of antiinfectives drug development programs based on the antivirulence approach (Dickey SW, Cheung GYC, Otto M. 2017 "Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance" Nature Reviews Drug Discovery 16:457-471.), among them FDA-approved drugs targeting gram-positive bacteria. It has been the object of the present invention to provide novel inhibitors of transcription factor HilD.

[0006] The present invention provides compounds of formula (la): wherein

[0007] Ar is an optionally substituted arylene group; or an optionally substituted heteroarylene group;

[0008] X is CHR4; NH; O; or a bond;

[0009] R4is hydrogen; an alkyl group; or a heteroalkyl group;

[0010] Y is NR3; O; or S;

[0011] R1is an optionally substituted aryl group; or an optionally substituted heteroaryl group;

[0012] R2is a halogen; or a C1-4 heteroalkyl group;

[0013] R5is hydrogen or a methyl group;

[0014] L is CH2; CHR6; CH2CH2; or a bond; and

[0015] R3is hydrogen; an alkyl group; or a benzyl group; or L and R3together are part of a monocyclic or bicyclic cycloalkyl group; and

[0016] R6is a C1-4 alkyl group or a C1-4 heteroalkyl group; or a salt thereof; for use in the treatment or prophylaxis of Salmonella infections (salmonellosis).

[0017] Preferably, R4is hydrogen or an alkyl group.

[0018] Further preferably, Y is NR3.

[0019] Moreover preferably, R2is Br; Cl; I; or a C1-4 heteroalkyl group.

[0020] Further preferably, R6is methyl; CH2OH; CH2SH; or CH2CH2NH2.

[0021] Moreover preferably, L is CH2; CHMe; or CH2CH2.

[0022] Further preferably, R5is hydrogen.

[0023] The present invention moreover provides compounds of formula (I): wherein

[0024] Ar is an optionally substituted arylene group; or an optionally substituted heteroarylene group;

[0025] X is CHR4; NH; O; or a bond; R4is hydrogen; or an alkyl group;

[0026] R1is an optionally substituted aryl group; or an optionally substituted heteroaryl group;

[0027] R2is Br; Cl; or a C1-4 heteroalkyl group;

[0028] L is CH2; CHMe; or CH2CH2; and

[0029] R3is hydrogen; an alkyl group; or a benzyl group; or

[0030] L and R3together are part of a monocyclic or bicyclic cycloalkyl group; or a salt thereof; for use in the treatment or prophylaxis of Salmonella infections (salmonellosis).

[0031] The present invention further provides compounds of formula (II): wherein R1; R3; and R4are as defined above or below; or a salt thereof; for use in the treatment or prophylaxis of Salmonella infections (salmonellosis).

[0032] The present invention further provides compounds of formula (II): wherein

[0033] R1is an optionally substituted aryl group; or an optionally substituted heteroaryl group;

[0034] R3is hydrogen; an alkyl group; or a benzyl group; and

[0035] R4is hydrogen; or an alkyl group; or a salt thereof; for use in the treatment or prophylaxis of Salmonella infections (salmonellosis).

[0036] The present invention moreover provides compounds of formula (III): wherein

[0037] R1is an optionally substituted aryl group; or an optionally substituted heteroaryl group; or a salt thereof; for use in the treatment or prophylaxis of Salmonella infections (salmonellosis).

[0038] Preferably, Ar is an optionally substituted phenylene group; or an optionally substituted heteroarylene group comprising 5 or 6 ring atoms that are independently selected from C, O, S and N.

[0039] Further preferably, Ar is the following group:

[0040] Moreover preferably, R4is hydrogen; a CM alkyl group; or a C1-4 heteroalkyl group.

[0041] Further preferably, R4is hydrogen; or a C1-4 alkyl group.

[0042] Moreover preferably, R4is hydrogen; methyl; or CH2OH.

[0043] Further preferably, R4is hydrogen or methyl; especially hydrogen.

[0044] Moreover preferably, X is CH2; CHMe; O; or a bond.

[0045] Further preferably, X is CH2.

[0046] Moreover preferably, R1is an optionally substituted phenyl group; an optionally substituted naphthyl group; or an optionally substituted heteroaryl group comprising 5 to 10 ring atoms (one or two rings) that are independently selected from C, O, S and N.

[0047] Further preferably, R1is an optionally substituted phenyl group; or an optionally substituted heteroaryl group comprising 5 or 6 ring atoms that are independently selected from C, O, S and N.

[0048] Moreover preferably, R1is an optionally substituted phenyl group; or an optionally substituted naphthyl group.

[0049] Moreover preferably, R1is an optionally substituted phenyl group.

[0050] Further preferably, R2is Br; I; -OMe; or -SMe. Further preferably, R2is Br; Cl; or -SMe.

[0051] Moreover preferably, R2is Br.

[0052] Further preferably, L is CH2.

[0053] Moreover preferably, R3is hydrogen or a C1-4 alkyl group (especially hydrogen; or a methyl group).

[0054] Further preferably, R3is hydrogen; methyl; or ethyl.

[0055] Further preferably, R3is a methyl group.

[0056] The present invention moreover provides the following novel compounds:

[0057]

[0058] SW-C112 SW-C183

[0059]

[0060] The present invention further provides the following novel compounds:

[0061]

[0062]

[0063] The most preferred compounds of the present invention are the compounds disclosed in the examples, or a salt thereof.

[0064] It is further preferred to combine the preferred embodiments of the present invention in any desired manner (e.g., any embodiment for R1may be combined with any embodiment of Ar).

[0065] 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; further preferably by one) substituents.

[0066] If a group (e.g., group Ar and / or group R1) comprises more than one substituent, these substituents are independently selected, i.e. , they may be the same or different.

[0067] If a group (e.g., group Ar and / or group R1) is substituted by a cyclic group, such as e.g., a cycloalkyl group or a heterocycloalkyl group, this cyclic group may be bonded to this group (e.g., group Ar and / or group R1) via a single or double bond or this cyclic group may be annulated or fused to said group (e.g., group Ar and / or group R1).

[0068] Examples for substituents are fluorine, chlorine, bromine and iodine and OH, =0, SH, NH2, -SO3H, -SO2NH2, -COOH, -CONH2, -CN, -N3 and -NO2 groups. Further examples of substituents are C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C1-C10 heteroalkyl, C3-C18 cycloalkyl, C1-C17 heterocycloalkyl, C4-C20 alkylcycloalkyl, C1-C19 heteroalkylcycloalkyl, C6-C18 aryl, C1-C17 heteroaryl, C7-C20 aralkyl and C1-C19 heteroaralkyl groups; especially C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, C1-C9 heterocycloalkyl, C4-C12 alkylcycloalkyl, C1-C11 heteroalkylcycloalkyl, C6-C10 aryl, C1-C9 heteroaryl, C7-C12 aralkyl and C1-C11 heteroaralkyl groups, further preferably C1-C6 alkyl; C1-C6 heteroalkyl; and C1-C5 heterocycloalkyl groups.

[0069] Preferred substituents are F, Cl, Br, I, C1-6 alkyl groups, C1-6 heteroalkyl groups; and groups of formula -O-CH2-O- and -O-CF2-O-.

[0070] Further preferred substituents are F, Cl, Br, I, -OMe, -OEt, -Me, -CF3, -OCF3, and groups of formula -O-CH2-O- and -O-CF2-O-.

[0071] Moreover preferred substituents are F, Cl, Br, I, -OMe, -OEt, -Me, -OCF3, and groups of formula -O-CH2-O- and -O-CF2-O-.

[0072] The suffix "-ene" like e.g., in "phenylene" refers to the corresponding divalent group.

[0073] The expression alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 20 carbon atoms, preferably from 1 to 15 carbon atoms, especially from 1 to 10 (e.g., 1 , 2, 3 or 4) carbon atoms, for example a methyl (Me, CH3), ethyl (Et), n-propyl (nPr), / so-propyl ( / Pr), n-butyl (nBu), / so-butyl ( / Bu), sec-butyl (sBu), terf-butyl (fBu), n-pentyl, / so-pentyl, n-hexyl, 2,2-dimethylbutyl or n-octyl group.

[0074] Especially preferred alkyl groups are C1-6 alkyl groups; moreover preferred alkyl groups are C1-4 alkyl groups.

[0075] The expression C1-6 alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 6 carbon atoms. The expression C1-4 alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 4 carbon atoms. Examples are a methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, sec-butyl or tenf-butyl group. The expressions alkenyl and alkynyl refer to at least partially unsaturated, straight- chain or branched hydrocarbon groups that contain from 2 to 20 carbon atoms, pre- ferably from 2 to 15 carbon atoms, especially from 2 to 10 (e.g., 2, 3 or 4) carbon atoms, for example an ethenyl (vinyl), propenyl (allyl), isopropenyl, butenyl, ethynyl (acetylenyl), propynyl (e.g., propargyl), butynyl, isoprenyl or hex-2-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).

[0076] 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 2,2,2-trichloroethyl or a trifluoromethyl group.

[0077] The expression heteroalkyl refers to an alkyl, alkenyl or alkynyl group in which one or more (preferably 1 to 8; especially preferably 1 , 2, 3 or 4) 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 SO2 group. Accordingly, the expression heteroalkyl e.g. also refers to alkyl groups that are substituted by one or more OH, SH and / or NH2 groups. 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).

[0078] Preferably, a heteroalkyl group contains from 1 to 12 carbon atoms and from 1 to 8 heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen). Especially preferably, a heteroalkyl group contains from 1 to 6 (e.g., 1, 2, 3 or 4) carbon atoms and 1 , 2, 3 or 4 (especially 1 , 2 or 3) heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen). The term C1-C10 heteroalkyl refers to a heteroalkyl group containing from 1 to 10 carbon atoms and 1, 2, 3, 4, 5 or 6 heteroatoms selected from O, S and / or N (especially O and / or N). The term C1-C6 heteroalkyl refers to a heteroalkyl group containing from 1 to 6 carbon atoms and 1 , 2, 3 or 4 heteroatoms selected from O, S and / or N (especially O and / or N). The term C1-C4 heteroalkyl refers to a heteroalkyl group containing from 1 to 4 carbon atoms and 1 , 2 or 3 heteroatoms selected from O, S and / or N (especially O and / or N).

[0079] Further preferably, the expression heteroalkyl refers to an alkyl group as defined above (straight-chain or branched) in which one or more (preferably 1 to 6; especially preferably 1 , 2, 3 or 4) carbon atoms have been replaced by an oxygen, sulfur or nitrogen atom or a CO group or a SO group or a SO2 group; this group preferably contains from 1 to 6 (e.g. 1 , 2, 3 or 4) carbon atoms and 1 , 2, 3 or 4 (especially 1 , 2 or 3) heteroatoms selected from oxygen, nitrogen and sulfur (especially oxygen and nitrogen); this group may preferably be substituted by one or more (preferably 1 to 6; especially preferably 1 , 2, 3 or 4) fluorine, chlorine, bromine or iodine atoms or OH, =0, SH, =S, NH2, =NH, N3, CN or NO2 groups.

[0080] Examples of heteroalkyl groups are groups of formulae: Ra-0-Ya-, Ra-S-Ya-, Ra-SO-Ya-, Ra-SO2-Ya-, Ra-N(Rb)-SO2-Ya-, Ra-SO2-N(Rb)-Ya-, Ra-N(Rb)-Ya-, Ra-C0-Ya-, Ra-0-C0-Ya-, Ra-C0-0-Ya-, Ra-CO-N(Rb)-Ya-, Ra-N(Rb)-CO-Ya-, Ra-0-C0-N(Rb)-Ya-, Ra-N(Rb)-CO-O-Ya-, Ra-N(Rb)-CO-N(Rc)-Ya-, Ra-0-C0-0-Ya-, Ra-N(Rb)-C(=NRd)-N(Rc)-Ya-, Ra-CS-Ya-, Ra-O-CS-Ya-, Ra-CS-O-Ya-,

[0081] 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-,

[0082] 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 Rabeing a hydrogen atom, a C1-C6 alkyl, a

[0083] C2-C6 alkenyl or a C2-C6 alkynyl group; Rbbeing a hydrogen atom, a C1-C6 alkyl, a

[0084] C2-C6 alkenyl or a C2-C6 alkynyl group; Rcbeing a hydrogen atom, a C1-C6 alkyl, a

[0085] C2-C6 alkenyl or a C2-C6 alkynyl group; Rdbeing a hydrogen atom, a C1-C6 alkyl, a

[0086] C2-C6 alkenyl or a C2-C6 alkynyl group and Yabeing a bond, a C1-C6 alkylene, a C2-C6 alkenylene or a C2-C6 alkynylene group, wherein each heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms may be replaced by fluorine or chlorine atoms. Specific examples of heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, / so-propyloxy, n-butoxy, terf-butyloxy, methoxy methyl, ethoxymethyl, -CH2CH2OH, -CH2OH, -SCteMe, -NHAc, methoxyethyl, 1 -methoxyethyl, 1 -ethoxyethyl, 2-methoxyethyl or 2-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, A / -ethyl-A / -methyl- carbamoyl or A / -methylcarbamoyl. Further examples of heteroalkyl groups are nitrile (- CN), isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkylnitrile groups.

[0087] Especially preferred heteroalkyl groups are C1-6 heteroalkyl groups; moreover preferred heteroalkyl groups are C1-4 heteroalkyl groups.

[0088] The expression cycloalkyl refers to a saturated or partially unsaturated (for example, a cycloalkenyl group) cyclic group that contains one or more rings (preferably 1 or 2), and contains from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) 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, =0, SH, =S, NH2, =NH, N3 or NO2 groups, thus, for example, cyclic ketones such as, for example, cyclohexanone, 2-cyclohexenone or cyclopentanone. Further specific examples of cycloalkyl groups are a cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, propellane (e.g., [1.1.1]propellane) tetraline, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl group. Preferably, the expression cycloalkyl refers to a saturated cyclic group that contains one or more rings (preferably 1 or 2), and contains from 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms. The expression heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (preferably 1 , 2 or 3) ring carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or a SO group or a SO2 group. A heterocycloalkyl group has preferably 1 or 2 ring(s) and 3 to 10 (especially 3, 4, 5, 6 or 7) 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, =0, SH, =S, NH2, =NH, N3 or NO2 groups. Examples are a piperidyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl (e.g., -N(CH2CH2)2O), urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or2-pyrazolinyl group and also lactames, lactones, cyclic imides and cyclic anhydrides.

[0089] The expression alkylcycloalkyl refers to groups that contain both cycloalkyl and 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 and from 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms, and one or two alkyl, alkenyl or alkynyl groups (especially alkyl groups) having 1 or 2 to 6 carbon atoms.

[0090] The expression heteroalkylcycloalkyl refers to alkylcycloalkyl groups as defined above in which one or more (preferably 1 , 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxy- gen, sulfur or nitrogen atom) or a SO group or a SO2 group. A heteroalkylcycloalkyl group preferably contains 1 or 2 rings having from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups (especially alkyl or heteroalkyl groups) having from 1 or 2 to 6 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- unsatu rated. The expression aryl refers to an aromatic group that contains one or more rings and from 6 to 14 ring carbon atoms, preferably from 6 to 10 (especially 6) ring carbon atoms. The expression aryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by OH, SH, NH2, N3 or NO2 groups. Examples are the phenyl (Ph), naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.

[0091] The expression heteroaryl refers to an aromatic group that contains one or more rings and from 5 to 14 ring atoms, preferably from 5 to 10 (especially 5 or 6 or 9 or 10) ring atoms, comprising one or more (preferably 1, 2, 3 or 4) 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, N3, NH2 or NO2 groups. Examples are pyridyl (e.g. 4-pyridyl), imidazolyl (e.g. 2-imidazolyl), phenylpyrrolyl (e.g., 3-phenylpyrrolyl), thiazolyl, isothiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, 4-hydroxypyridyl (4-pyridonyl), 3,4- hydroxypyridyl (3, 4-pyridonyl), oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3'-bifuryl, pyrazolyl (e.g., 3-pyrazolyl) and isoquinolinyl groups.

[0092] 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, alkylarylcycloalkyl and alkylarylcycloalkenyl groups. Specific examples of aralkyls are phenylcyclopentyl, cyclohexylphenyl as well as groups derived from toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1 / - / -indene, tetraline, dihydronaphthalene, indanone, cumene, fluorene and indane. An aralkyl group preferably contains one or two aromatic ring systems (especially 1 or 2 rings), each containing from 6 to 10 carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups containing from 1 or 2 to 6 carbon atoms and / or a cycloalkyl group containing 3, 4, 5, 6 or 7 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 het- erocycloalkyl groups in accordance with the above definitions. A heteroaralkyl group preferably contains one or two aromatic ring systems (especially 1 or 2 rings), each containing from 5 or 6 to 9 or 10 ring atoms (preferably selected from C, N, O and S) and one or two alkyl, alkenyl and / or alkynyl groups containing 1 or 2 to 6 carbon atoms and / or one or two heteroalkyl groups containing 1 to 6 carbon atoms and 1 , 2 or 3 heteroatoms selected from O, S and N and / or one or two cycloalkyl groups each containing 3, 4, 5, 6 or 7 ring carbon atoms and / or one or two heterocycloalkyl groups, each containing 3, 4, 5, 6 or 7 ring atoms comprising 1, 2, 3 or 4 oxygen, sulfur or nitrogen atoms.

[0093] Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroaryl- heterocycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroaryl- alkylheterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkyl- cycloalkenyl and heteroarylheteroalkylheterocycloalkyl groups, the cyclic groups being saturated or mono-, di- or tri-unsatu rated. Specific examples are a tetrahydroisoquinolinyl, benzoyl, phthalidyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl group.

[0094] 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, =0, SH, =S, NH2, =NH, NS or NO? groups.

[0095] The term halogen refers to F, Cl, Br or I. 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 annotated or fused or bridged.

[0096] Owing to their substitution, the compounds of the present invention may contain one or more centers of chirality. The present invention therefore includes both all pure enantiomers and all pure diastereomers and also mixtures thereof in any mixing ratio. The present invention moreover also includes all c / s / frans-isomers of the compounds of the present invention and also mixtures thereof. The present invention moreover includes all tautomeric forms of the compounds of the present invention.

[0097] The present invention further provides pharmaceutical compositions comprising one or more compounds described herein or a pharmaceutically acceptable salt, solvate or hydrate thereof, optionally in combination with one or more carrier substances and / or one or more adjuvants.

[0098] The present invention furthermore provides compounds or pharmaceutical compositions as described herein for use in the treatment or prophylaxis of Salmonella infections (salmonellosis).

[0099] The present invention moreover provides a compound as described herein or a pharmaceutical composition as defined herein for the preparation of a medicament for the treatment or prophylaxis of Salmonella infections (salmonellosis).

[0100] The present invention further provides a compound as described herein for the preparation of a food additive or a feed additive for the treatment or prophylaxis of Salmonella infections (salmonellosis).

[0101] The present invention moreover provides the use of a compound as described herein in animal health, both as a pharmaceutical product and as a feed additive. The present invention further provides a method for the treatment or prophylaxis of Salmonella infections (salmonellosis) in a subject which comprises administering to the subject an effective amount of a compound as described herein. Thereby, the subject may be a human or an animal; especially a human.

[0102] Examples of salts (especially 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-(2-hydroxyethyl)amine, lysine or arginine salts; all of which are also further examples of salts of the compounds described herein.

[0103] The compounds described herein may be solvated, especially hydrated. The solvation / 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.

[0104] The therapeutic use of the compounds described herein, their pharmacologically acceptable salts, solvates and hydrates, respectively, as well as formulations and pharmaceutical compositions also lie within the scope of the present invention.

[0105] In general, the compounds and pharmaceutical compositions described herein will be administered by using the established and acceptable modes known in the art.

[0106] 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 drug delivery system (TDDS) 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 300 to 350 nm) preferred in phosphate buffered saline (pH = 7 to 8, preferred 7.4). 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, 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.

[0107] In general, in the case of oral or parenteral administration to adult humans weighing approximately 80 kg, a daily dosage of about 1 mg to about 10,000 mg, preferably from about 5 mg to about 1 ,000 mg, 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. EXAMPLES

[0108] Abbreviations and Acronyms

[0109] Abbreviations and Acronyms used in the description of the chemistry and in the Examples that follow are: aq. aqueous

[0110] Ar argon

[0111] Boc tert-Butyloxycarbonyl br. broad

[0112] CDCh deuterated chloroform

[0113] CD3OD deuterated methanol cHex cyclohexane cone. Concentrated d doublet

[0114] DCM dichloromethane

[0115] DI deionised

[0116] DIPEA Diisopropylethylamine

[0117] DMF dimethylformamide

[0118] DMSO dimethylsulfoxide

[0119] DMSO-de deuterated dimethylsulfoxide

[0120] ESI electrospray

[0121] EtsN triethylamine

[0122] EtOAc ethyl acetate

[0123] EtOH ethanol h hour hept heptet

[0124] HCI hydrochloric acid

[0125] HPLC high performance liquid chromatography H2O water

[0126] H2SO4 sulfuric acid iPrOH isopropanol m multiplet

[0127] MeCN acetonitrile

[0128] MeOH methanol min minutes

[0129] MS mass spectrometry

[0130] NaHCO3sodium hydrogencarbonate

[0131] NaCI sodium chloride

[0132] NaOH sodium hydroxide

[0133] Na2SO4sodium sulfate

[0134] NMR nuclear magnetic resonance q quartet quint quintet r. t. room temperature s singlet sat. saturated sfGFP super folder Green Fluorescent Protein t triplet

[0135] TFA trifluoroacetic acid

[0136] UPLC Ultra Performance Liquid Chromatography wt weight

[0137] In general, the compounds of the invention can 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 specific processes to be utilised in the preparation of the compounds of this invention depend 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 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.

[0138] Experimental procedures

[0139] LC-MS method

[0140] HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using an Agilent 6130 Single Quadrupole LC / MS System equipped with 1260 Infinity II LC System.

[0141] Column: Gemini® 3 pm NX-C18, LC Column 50 x 2 mm

[0142] Eluents: A: H2O with 0.1% formic acid and B: MeCN with 0.1% formic acid.

[0143] Flash chromatography method

[0144] Flash chromatography was performed using Pure C-850 FlashPrep system in a flash mode. Reversed phase (RP) separations were performed using FlashPure EcoFlex C18 cartridges from Biichi with H2O - MeCN eluent. Normal phase separations were performed using FlashPure silica cartridges from Buchi.

[0145] Preparative HPLC method

[0146] Preparative HPLC was performed using a Pure C-850 FlashPrep system in the HPLC mode.

[0147] Column: Luna® Prep C18 5 pm, 21.2 x 250 mm

[0148] Flow: 10 mL / min

[0149] Eluents: A: H2O with 0.1% formic acid and B: MeCN with 0.1% formic acid.

[0150] Accurate Mass method

[0151] High resolution masses were obtained using Maxis II TM HD mass spectrometer (Bruker).

[0152] NMR methods

[0153] Proton (1H) nuclear magnetic resonance (NMR) spectra were measured with a Bruker Avance III (500MHz) or a Bruker Avance III (700MHz) spectrometer with residual protonated solvent (CHCI357.26; MeOH 63.30; DMSO 62.49) as standard. The NMR data of the synthesized examples are in agreement with their corresponding structural assignments.

[0154] Synthesis of Compounds

[0155] For the synthesis of compounds two general schemes were developed:

[0156] Scheme 2

[0157] / V-(tert-butoxycarbonyl)-N-methylglycine (1 )

[0158] Sarcosine (1.00 g, 11.22 mmol, 1 eq) was dissolved in a mixture of H2O (11 mL) and 1 ,4-dioxane (25 mL) and the solution was cooled to 0 °C. KOH (2.73 g, 50.51 mmol, 4.5 eq), dissolved in 4 mL H2O, and di-fert-butyl dicarbonate (2.94g, 13.46mmol, 1 .2eq) was added and the solution was stirred overnight at r.t.. Then 1 ,4-dioxane was rotary evaporated and the aqueous residue was acidified with 1 N HCI to pH = 3. The solution was extracted with EtOAc (3 x 40 mL) and combined organic phased were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to obtain compound 1 as a brownish oil (1.2 g, 6.33 mmol, 57 %). The crude product was used for the next step without further purification. The experimental NMR data correspond with those from the literature.

[0159] 1H NMR (500 MHz, CDCI3) δ 4.02 (s, 1H), 3.95 (s, 1H), 2.94 (s, 3H), 1.46 (d, J = 18.7 Hz, 9H). LCMS (ESI): m / z 190 (M + H+). tert-Butyl (2-((Benzo[d][1 ,3]dioxol-5-ylmethyl)amino)-2- oxoethyl)(methyl)carbamate (2)

[0160] To an ice-cooled and stirring solution of N-Boc-sarcosine 1 (1.20 g, 6.33 mmol, 1 eq) in dry THF (10 mL) was added TEA (2.54 mL, 1.36 g, 18.99 mmol, 3 eq) and isobutyl chloroformate (0.95 g, 6.96 mmol, 1 .2 eq). The solution was allowed to come to r.t. and was stirred for 2 h at r.t. under nitrogen atmosphere. After 2 h, piperonylamine (0.76 mL, 0.95 g, 6.33 mmol, 1 eq) was added and the reaction mixture was stirred for another 2 h under same conditions. The solution was quenched with an aqueous, saturated NaHCO3solution (50 mL) and extracted with DCM (3 x 40 mL). Combined organic phases were washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (2 - 4 % MeOH in DCM) to afford compound 2 (1.71 g, 5.32 mmol, 84 %).

[0161] 1H NMR (500 MHz, CDC13) δ 6.76 - 6.74 (m, 2H), 6.72 (d, J = 7.9, 1.6 Hz, 1H), 5.94 (s, 2H), 4.37 (d, J = 5.7 Hz, 2H), 3.88 (s, 2H), 2.94 (s, 3H), 1.43 (s, 9H).

[0162] LCMS (ESI): m / z 345 (M + Na).

[0163] TLC: Rf= 0.38 (DCM / MeOH 50:1).

[0164] / V-(Benzo[d][1,3]dioxol-5-ylmethyl)-2-(methylamino)acetamide (3)

[0165] Compound 2 (629 g, 1 .95 mmol, 1 eq) was dissolved in DCM (10 mL). TEA (5mL) was added and the reaction mixture was stirred overnight at r.t.. The solution was quenched with an aqueous, saturated NaHCO3solution (50 mL) and extracted with DCM (3 x 40 mL). Combined organic phases were washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the compound 3 (311 mg, 1.40 mmol, 72 %). The crude product was used for the next step without further purification.

[0166] 1H NMR (500 MHz, CDC13) δ 6.78 - 6.75 (m, 3H), 5.94 (s, 2H), 4.38 (d, J = 5.9 Hz, 2H), 3.93 (d, J = 6.7 Hz, 2H), 2.46 (s, 3H).

[0167] LCMS (ESI): m / z 223 (M + H+).

[0168] W-(benzo[d][1,3]dioxol-5-ylmethyl)-2-(((5-bromothiophen-2- yl)methyl)(methyl)amino)acetamide (SW-C26)

[0169] SW-C26

[0170] To a stirring solution of compound 3 (202 mg, 0.90 mmol, 1 eq) in dry THF (6 mL) was added 5-bromothiophene-2-carbaldehyde (83 μL, 146 mg, 0.76 mmol, 0.84 eq) and acetic acid (104 μL, 109 mg, 1.80μmol, 2 eq). After 10 minutes, sodium triacetoxyborohydride (288 mg, 1.35 mmol, 1.5 eq) was added and the solution was stirred for 18 h at r. t. under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, the crude product was purified by RP flash chromatography and product containing fractions were lyophilised. The residue was taken up in MeOH and purified by HPLC to afford compound SW-C26 (58 mg, 0.14μmol, 20 %).

[0171] 1H NMR (500 MHz, DMSO-d6) δ 8.19 (t, J = 5.8 Hz, 1H), 7.06 (d, J = 3.7 Hz, 1 H), 6.86 - 6.83 (m, 3H), 6.73 (dd, J = 8.1 , 1 .4 Hz, 1 H), 5.97 (s, 2H), 4.20 (d, J = 6.1 Hz, 2H), 3.79 (s, 2H), 3.05 (s, 2H), 2.25 (s, 3H).

[0172] 13C NMR (126 MHz, DMSO-d6) δ 169.1 , 147.23, 147.21 , 146.0, 133.4, 129.8, 127.0, 120.4, 110.5, 107.9, 100.8, 59.1, 55.5, 42.0, 41.6.

[0173] HRMS (ESI) calculated for Ci6Hi7BrN2O3S (M (79Br) + H+): 397.0222, found: 397.0214; calculated for CieHvBrNsOsS (M (81Br) + H+): 399.0201 , found: 399.0194.

[0174] N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-(((5-bromothiazol-2- yl)methyl)(methyl)amino)acetamide (SW-C282)

[0175] SW-C282

[0176] To a stirring solution of compound 3 (110 mg, 0.40 mmol, 1 eq) in dry THF (2 mL) was added 5-bromo-1 ,3-thiazole-2-carbaldehyde (77 mg, 0.40 mmol, 1 eq) and acetic acid (46 μL, 48 mg, 0.80 mmol, 2 eq). After 10 minutes, NaBH(OAc)3 (128 mg, 0.60 mmol, 1 .5 eq) was added and the solution was stirred for 18 h at r. t. under argon atmosphere. The reaction mixture was concentrated under reduced pressure, the crude product was purified by RP flash chromatography and product containing fractions were lyophilised to give the product SW-C282 (47 mg, 30 %).

[0177] 1H NMR (500 MHz, MeOH-d4) δ 7.64 (s, 1 H), 6.80 - 6.74 (m, 3H), 5.91 (s, 2H), 4.32 (s, 2H), 3.93 (s, 2H), 3.20 (s, 2H), 2.39 (s, 3H).

[0178] 13C NMR (126 MHz, MeOH-d4) δ 173.7, 172.5, 149.3, 148.3, 144.6, 133.8, 122.1 , 110.8, 109.2, 109.1 , 102.4, 61.2, 59.7, 43.6, 43.5.

[0179] MS (ESI) calculated for CisHnBrNsOsS (M + H+): 398 / 400, found: 398 / 400.

[0180] N-(Benzo[d][1,3]dioxol-5-ylmethyl)-2-(methyl((5-(methylthio)thiophen-2- yl)methyl)amino)acetamide (SW-C255)

[0181] To a stirring solution of compound 3 (114 mg, 0.42 mmol, 1 eq) in dry THF (1 mL) was added 5-(methylthio)thiophene-2-carbaldehyde (66 mg, 0.42 mmol, 1 eq) and acetic acid (48 μL, 50 mg, 0.83 mmol, 2 eq). After 10 minutes, NaBH(OAc)3(132 mg, 0.63 mmol, 1.5 eq) was added and the solution was stirred for 18 h at r. t. under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, the crude product was purified by RP flash chromatography (C18; MeCN : H2O) and product containing fractions were lyophilised to afford the product SW-C255 (37 mg, 0.11 mmol, 25 %).

[0182] 1H NMR (700 MHz, CD3CN) δ 7.52 (s, 1 H), 6.91 (d, J = 3.5 Hz, 1 H), 6.80 (dt, J = 3.5, 0.9 Hz, 1 H), 6.80 - 6.79 (m, 1 H), 6.78 - 6.74 (m, 2H), 5.92 (s, 2H), 4.28 (d, J = 6.3 Hz, 2H), 3.70 (d, J = 0.7 Hz, 2H), 3.00 (s, 2H), 2.44 (s, 3H), 2.27 (s, 3H).13C NMR (176 MHz, CD3CN) δ 170.9, 148.8, 147.6, 145.7, 137.7, 134.5, 131.2, 127.8, 121.6, 108.92, 108.90, 102.3, 60.8, 57.2, 43.2, 43.0, 22.0.

[0183] MS (ESI) calculated for Ci7H2iBrN20sS2 (M + H+): 365, found: 365.

[0184] / V-(benzo[d][1,3]dioxol-5-ylmethyl)-2-((4-bromo-2- fluorobenzyl)(methyl)amino)acetamide (SW-C259)

[0185] To a stirring solution of the compound 3 (105 mg, 0.38 mmol, 1 eq) in dry THF (2 mL) was added 4-bromo-2-fluorobenzaldehyde (78 mg, 0.38 mmol, 1 eq) and acetic acid (44 μL, 46 mg, 0.77 mmol, 2 eq). After 10 minutes, NaBH(OAc)3 (122 mg, 0.57 mmol, 1 .5 eq) was added and the solution was stirred for 18 h at r. t. under argon atmosphere. The reaction mixture was concentrated under reduced pressure, the crude product was purified by RP flash chromatography (C18; MeCN : H2O) and product containing fractions were lyophilised to give the product SW-C259 (38 mg, 94μmol, 25 %).

[0186] 1H NMR (700 MHz, DMSO-d6) δ 8.21 (d, J = 6.2 Hz, 1 H), 7.49 (dd, J = 9.7, 2.0 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.38 (dd, J = 8.2, 1.9 Hz, 1 H), 6.82 (d, J = 7.9 Hz, 1H), 6.81 (d, J = 1.6 Hz, 1 H), 6.74 - 6.69 (m, 1 H), 5.97 (s, 2H), 4.19 (d, J = 6.2 Hz, 2H), 3.60 (s, 2H), 3.03 (s, 2H), 2.18 (s, 3H).

[0187] 13C NMR (126 MHz, MeOH-d4) δ 173.0, 163.6, 149.3, 148.3, 134.2, 133.8, 128.6, 125.4, 122.6, 122.0, 120.0, 109.11 , 109.05, 102.4, 61.1 , 55.2, 43.6, 43.2.

[0188] MS (ESI) calculated for C18H19FBrN2O3 (M + H+): 409 / 411, found: 409 / 411 .

[0189] W-(Benzo[d][1,3]dioxol-5-ylmethyl)-2-((4-bromo-3- fluorobenzyl)(methyl)amino)acetamide (SW-C262) To a stirring solution of the compound 3 (111 mg, 0.40 mmol, 1 eq) in dry THF (2 mL) was added 4-bromo-3-fluorobenzaldehyde (82 mg, 0.40 mmol, 1 eq) and acetic acid (46 μL, 49 mg, 0.81 mmol, 2 eq). After 10 minutes, NaBH(OAc)s (129 mg, 0.61 mmol, 1.5 eq) was added and the solution was stirred for 18 h at r. t. under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, the crude product was purified by RP flash chromatography (C18; MeCN : H2O) and product containing fractions were lyophilised to afford the product SW-C262 (46 mg, 0.11 mmol, 27 %).

[0190] 1H NMR (700 MHz, CD3CN) δ 7.60 (s, 1 H), 7.54 (dd, J = 8.1 , 7.4 Hz, 1 H), 7.24 (d, J = 10.0, 1.9 Hz, 1 H), 7.07 (ddd, J = 8.2, 1.9, 0.4 Hz, 1 H), 6.78 - 6.71 (m, 3H), 5.92 (s, 2H), 4.27 (d, J = 6.4 Hz, 2H), 3.52 (s, 2H), 2.99 (s, 2H), 2.21 (s, 3H).

[0191] 13C NMR (176 MHz, CD3CN) δ 170.9, 148.7, 147.6, 134.6, 134.2, 127.10, 127.08, 121.5, 117.8, 117.7, 108.9, 108.8, 102.2, 61.59, 61.55, 43.3, 42.9.

[0192] MS (ESI) calculated for Ci8Hi9FBrN2O3 (M + H+): 409 / 411, found: 409 / 411 .

[0193] A / -((5-bromothiophen-2-yl)methyl)-A / -methylglycine (4)

[0194] To a solution of sarcosine (200 mg, 2.24 mmol, 2 eq) in dry MeOH (5 mL) was added TEA (313 μL, 227 mg, 2.24 mmol, 2 eq) and 5-bromothiophene-2-carboxaldehyde (121 μL, 214 mg, 1.12 mmol, 1 eq). The reaction mixture was stirred for 14 h at r. t. under argon atmosphere, then NaBH4(169 mg, 4.48 mmol, 4 eq) was added and the solution was stirred for another 16 h at the same conditions. All volatile components were removed under reduced pressure and the crude product was purified by RP flash chromatography (C18; MeCN : H2O) to afford the compound 4 as a white solid (286 mg, 1.08 mmol, 97 %).

[0195] 1H NMR (500 MHz, MeOH-d4) δ 6.92 (d, J = 3.7 Hz, 1 H), 6.77 (dt, J = 3.7, 0.8 Hz, 1H), 3.82 (d, J = 0.6 Hz, 2H), 3.03 (s, 2H), 2.32 (s, 3H).

[0196] 13C NMR (126 MHz, MeOH-d4) δ 178.1 , 145.0, 130.5, 128.2, 112.1 , 61.2, 56.4, 42.4, 35.9. HRMS (ESI) calculated for C8H10BrNO2S (M (79Br) + H+): 263.9694, found:

[0197] 263.9704; calculated for C8H10BrNO2S (M (81Br) + H+): 265.9673, found: 265.9683

[0198] 2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)- / \ / -((2,2- difluorobenzo[d][1 ,3]dioxol-5-yl)methyl)acetamide (SW-C182)

[0199] To a stirring solution of compound 4 (60 mg, 227μmol, 1 eq) in dry DMF (1.5 mL). was added HATU (172 mg, 454 μmol, 1.2 eq) and DIPEA (118 μL, 88 mg, 681μmol, 3 eq). After 10 minutes, 2,2-difluoro-1 ,3-benzodioxole-5-methanamine (32 μL, 46 mg, 249μmol, 1.2 eq) was added and the solution was stirred for 3 h at r. t. under nitrogen atmosphere. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3x20 mL). Combined organic phases were washed with brine (20 mL), dried over sodium sulfate, filtered, washed with DCM and concentrated under reduced pressure. The residue was taken up in MeOH and purified by HPLC. Product containing fractions were lyophilised to yield compound SW-C182 (19 mg, 44μmol, 20 %) as a yellow oil.

[0200] 1H NMR (700 MHz, DMSO-de) 3 8.95 (s, br, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 1.1 Hz, 1 H), 7.26 (d, J = 2.8 Hz, 1 H), 7.14 - 7.12 (m, 2H), 4.49 (s, br, 2H), 4.35 (d, J = 5.9 Hz, 2H), 3.85 (s, br, 2H), 2.75 (s, br, 3H).

[0201] 2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)-M-(4-chlorobenzyl)acetamide (SW-C202)

[0202] To a stirring solution of compound 4 (200 mg, 0.75 mmol, 1 eq) in dry DMF (6 mL) was added DIPEA (395 μL, 293 mg, 2.27 mmol, 3 eq) and HATU (345 mg, 0.90 mmol, 2 eq). After 10 minutes, 4-chlorobenzylamine (110 μL, 128 mg, 0.90 mmol, 1.2 eq) was added and the solution was stirred for 3 h at r. t. under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3x30 mL). Combined organic phases were washed with brine (20 mL), dried over sodium sulfate, filtered, washed with DCM and concentrated under reduced pressure. The residue was taken up in DMSO and purified by HPLC twice. Product containing fractions were lyophilised to yield compound SW-C202 (50 mg, 128μmol, 17 %) as a yellow oil.

[0203] 1H NMR (500 MHz, DMSO-d6) δ 8.41 (s, 1 H), 7.39 - 7.36 (m, 2H), 7.29 - 7.26 (m, 2H), 7.10 (d, J = 3.3 Hz, 1 H), 6.90 (s, br, 1 H), 4.29 (d, J = 6.1 Hz, 2H), 3.90 (s, 2H), 3.19 (s, 2H), 2.34 (s, 3H).

[0204] 13C NMR (176 MHz, DMSO-d6) δ 158.1, 140.4, 138.5, 131.3, 130.8, 129.9, 129.1 , 128.8, 128.2, 127.9, 55.2, 42.9, 35.8.

[0205] HRMS (ESI) calculated for C15H16BrCIN2OS (M (79Br) + H+): 386.9933, found: 386.9954; calculated for C15H16BrCIN2OS (M (81Br) + H+): 388.9913, found: 388.9905.

[0206] 2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)-N-(3-methylbenzyl)acetamide (SW-C278)

[0207] To a stirring solution of compound 4 (91 mg, 344μmol, 1 eq) in dry DMF (4 mL) was added DIPEA (180 μL, 134 mg, 1030μmol, 3 eq) and HATU (157 mg, 413μmol, 1.2 eq). After 10 minutes, 3-methylbenzylamine (50 mg, 413μmol, 1.2 eq) was added and the solution was stirred for 20 h at r. t. under argon atmosphere. The mixture was diluted with water (10 mL) and extracted with DCM. Phases were separated and combined organic phases were washed with brine and dried over sodium sulfate. The solution was filtered, washed with DCM and concentrated under reduced pressure. The residue was purified by C18 flash (MeCN:H2O) and then by preparative HPLC (MeCN:H2O+0.1% HCOOH). Product containing fractions were lyophilised to yield compound SW-C278 (27.6 mg, 22%).1H NMR (700 MHz, CD3OD) δ 7.20 (t, J = 7.5 Hz, 1 H), 7.11 (s, 1 H), 7.07 (s, 1 H), 7.06 (s, 1H), 6.93 (d, J = 3.7 Hz, 1H), 6.76 (d, J = 3.7 Hz, 1H), 4.38 (s, 2H), 3.78 (s, 2H), 3.09 (s, 2H), 2.34 (s, 3H), 2.32 (s, 3H).

[0208] 13C NMR (176 MHz, CD3OD) δ 173.16, 145.18, 139.89, 139.51 , 130.86, 129.66, 129.33, 129.12, 128.32, 125.78, 112.71, 60.58, 57.43, 43.93, 43.34, 21.64.

[0209] MS (ESI) calculated for Ci6H2oBrN2OS (M + H+): 367, found: 367.

[0210] 2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)-N-(3,4- dichlorobenzyl)acetamide (SW-C230)

[0211] SW-C230

[0212] To a stirring solution of compound 4 (50 mg, 180 μmol, 1 eq) in dry DMF (3 mL) was added DIPEA (98 μL, 73.3 mg, 560μmol, 3 eq) and HATU (86 mg, 220 μmol, 1.2 eq). After 10 minutes, 3,4-dichlorobenzylamine (30 μL, 40 mg, 220μmol, 1.2 eq) was added and the solution was stirred for 20 h at r. t. under nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with DCM (3x30 mL). Phases were separated and combined organic phases were washed with brine (20 mL) and dried over sodium sulfate. The solution was filtered, washed with DCM and concentrated under reduced pressure. The residue was taken up in DMSO and purified by HPLC twice. Product containing fractions were lyophilised to yield compound SW- C230 (22 mg, 52μmol, 28 %) as a white solid.

[0213] 1H NMR (700 MHz, DMSO-d6) δ 8.37 (t, J = 6.2 Hz, 1 H), 7.57 (d, J = 8.2 Hz, 1 H), 7.50 (d, J = 2.0 Hz, 1 H), 7.25 (dd, J = 8.3, 2.0 Hz, 1 H), 7.06 (d, J = 3.7 Hz, 1 H), 6.84 (d, J = 3.7 Hz, 1H), 4.29 (d, J = 6.2 Hz, 2H), 3.77 (s, 2H), 3.04 (s, 2H), 2.25 (s, 3H).13C NMR (176 MHz, DMSO-d6) δ 169.7, 144.2, 141.0, 130.8, 130.4, 129.7, 129.2, 129.1 , 127.6, 127.0, 110.4, 59.1 , 55.5, 42.1 , 40.8.

[0214] HRMS (ESI) calculated for C15H15BrC12N2OS (M (79Br) + H+): 420.9544, found: 420.9554; calculated for C15H15BrC12N2OS (M (81Br) + H+): 422.9523, found: 422.9514. 2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)-N-(3,5- dichlorobenzyl)acetamide (SW-C250)

[0215] To a stirring solution of compound 4 (100 mg, 379μmol, 1 eq) in dry DMF (6 mL) was added DIPEA (198 μL, 147 mg, 1140μmol, 3 eq) and HATU (173 mg, 454μmol, 1.2 eq). After 10 minutes, 3,4-dichlorobenzylamine (61 μL, 80 mg, 454μmol, 1.2 eq) was added and the solution was stirred for 20 h at r. t. under argon atmosphere. The mixture was diluted with water (10 mL) and extracted with DCM (3x30 mL). Phases were separated and combined organic phases were washed with brine (20 mL) and dried over sodium sulfate. The solution was filtered, washed with DCM and concentrated under reduced pressure. The residue was purified by C18 flash (MeCN:H2O) and then by preparative HPLC (MeCN:H2O+0.1% HCOOH). Product containing fractions were lyophilised to yield compound SW-C250 (28.5 mg, 18%).

[0216] 1H NMR (500 MHz, CD3OD) δ 7.33 (t, J = 2.0 Hz, 1 H), 7.33 (t, J = 2.0 Hz, 1 H), 7.27 (d, J = 2.0 Hz, 2H), 6.94 (d, J = 3.7 Hz, 1 H), 6.79 (dt, J = 3.7, 0.9 Hz, 1 H), 4.39 (s, 2H), 3.79 (d, J = 0.9 Hz, 2H), 3.10 (s, 2H), 2.36 (s, 3H).

[0217] 13C NMR (126 MHz, CD3OD) δ 173.64, 145.03, 144.45, 136.29, 130.88, 128.43, 128.26, 127.33, 112.85, 60.33, 57.43, 43.48, 42.91.

[0218] MS (ESI) calculated for C15H15BrC12N2OS (M + H+): 421 / 423, found: 421 / 423.

[0219] 2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)- / V-(4-ethoxybenzyl)acetamide (SW-C279)

[0220] SW-C279

[0221] To a stirring solution of compound 4 (73 mg, 276μmol, 1 eq) in dry DMF (4 mL) was added DIPEA (144 μL, 107 mg, 829μmol, 3 eq) and HATU (126 mg, 829μmol, 1.2 eq). After 10 minutes, 4-ethoxybenzylamine (50 mg, 331 μmol, 1.2 eq) was added and the solution was stirred for 20 h at r. t. under argon atmosphere. The mixture was diluted with water (10 mL) and extracted with DCM (3x30 mL). Phases were separated and combined organic phases were washed with brine (20 mL) and dried over sodium sulfate. The solution was filtered, washed with DCM and concentrated under reduced pressure. The residue was purified by C18 flash (MeCN:H2O) and then by preparative HPLC (MeCN:H2O+0.1% HCOOH). Product containing fractions were lyophilised to yield compound SW-C279 (48.4 mg, 44%).

[0222] 1H NMR (500 MHz, CD3OD) δ 7.20 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 3.7 Hz, 1 H), 6.86 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 3.7 Hz, 1 H), 4.34 (s, 2H), 4.01 (q, J = 7.0 Hz, 2H), 3.76 (s, 2H), 3.07 (s, 2H), 2.33 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H).

[0223] 13C NMR (126 MHz, CD3OD) δ 173.04, 159.89, 145.14, 131.90, 130.84, 130.07, 128.35, 115.67, 112.72, 64.59, 60.49, 57.40, 43.43, 43.34, 15.32.

[0224] MS (ESI) calculated for C17H22BrN2O2S (M + H+): 397 / 399, found: 397 / 399.

[0225] 2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)- / V-(3- methoxybenzyl)acetamide (SW-C280)

[0226] SW-C280

[0227] To a stirring solution of compound 4 (80 mg, 303μmol, 1 eq) in dry DMF (4 mL) was added DIPEA (158 μL, 117 mg, 909μmol, 3 eq) and HATU (138 mg, 346μmol, 1.2 eq). After 10 minutes, 3-methoxybenzylamine (50 mg, 364μmol, 1.2 eq) was added and the solution was stirred for 20 h at r. t. under argon atmosphere. The mixture was diluted with water (10 mL) and extracted with DCM (3x30 mL). Phases were separated and combined organic phases were washed with brine (20 mL) and dried over sodium sulfate. The solution was filtered, washed with DCM and concentrated under reduced pressure. The residue was purified by C18 flash (MeCN:H2O) and then by preparative HPLC (MeCN:H2O+0.1 % HCOOH). Product containing fractions were lyophilised to yield compound SW-C280 (39.6 mg, 34%).1H NMR (500 MHz, CD3OD) δ 7.23 (t, J = 8.0 Hz, 1 H), 6.93 (d, J = 3.7 Hz, 1 H), 6.88 - 6.84 (m, 2H), 6.83 - 6.79 (m, 1 H), 6.77 (dt, J = 3.7, 0.9 Hz, 1 H), 4.39 (s, 2H), 3.77 (d, J = 0.9 Hz, 2H), 3.77 (s, 3H), 3.09 (s, 2H), 2.34 (s, 3H).

[0228] 13C NMR (126 MHz, CD3OD) δ 173.24, 161.53, 145.12, 141.59, 130.86, 130.75, 128.37, 120.85, 114.10, 113.95, 112.74, 60.49, 57.41, 55.76, 43.87, 43.35.

[0229] MS (ESI) calculated for Ci6H2oBrN202S (M + H+): 383 / 385, found: 383 / 385.

[0230] 2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)- / V-(4- (trifluoromethoxy)benzy l)acetamide (SW-C251 )

[0231] SW-C251

[0232] To a stirring solution of compound 4 (91 mg, 345μmol, 1 eq) in dry DMF (2 mL) was added DIPEA (180 μL, 134 mg, 1036μmol, 3 eq) and HATU (157 mg, 414μmol, 1.2 eq). After 10 minutes, 4-(trifluoromethoxy)benzylamine (63 mg, 414μmol, 1.2 eq) was added and the solution was stirred for 20 h at r. t. under argon atmosphere. The mixture was diluted with water (10 mL) and extracted with DCM (3x30 mL). Phases were separated and combined organic phases were washed with brine (20 mL) and dried over sodium sulfate. The solution was filtered, washed with DCM and concentrated under reduced pressure. The residue was purified by C18 flash (MeCN:H2O). Product containing fractions were lyophilised to yield compound SW- C251 (15.8 mg, 11%).

[0233] 1H NMR (500 MHz, CD3OD) δ 7.38 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 3.7 Hz, 1 H), 6.77 (dt, J = 3.7, 0.9 Hz, 1 H), 4.43 (s, 2H), 3.79 (s, 2H), 3.10 (s, 2H), 2.35 (s, 3H).

[0234] MS (ESI) calculated for C16H17BrF3N2O2S (M + H+): 437 / 439, found: 437 / 439.

[0235] (R)-2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)-N-(1-(4- chlorophenyl)ethyl)acetamide (SW-C271)

[0236] To a stirring solution of compound 4 (71 mg, 268 μmol, 1 eq) in dry DMF (4 mL) was added DIPEA (140 μL, 104 mg, 806μmol, 3 eq) and HATU (123 mg, 321μmol, 1.2 eq). After 10 minutes, (R)-1-(4-chlorophenyl)ethan-1 -amine (50 mg, 321μmol, 1 .2 eq) was added and the solution was stirred for 20 h at r. t. under argon atmosphere. The mixture was diluted with water and extracted with DCM. Phases were separated and combined organic phases were washed with brine and dried over sodium sulfate. The solution was filtered, washed with DCM and concentrated under reduced pressure. The residue was purified by C18 flash (MeCN.TW) and then by preparative HPLC (MeCN:H2O+0.1 % HCOOH). Product containing fractions were lyophilised to yield compound SW-C271 (20.4 mg, 19%).

[0237] 1H NMR (700 MHz, CD3OD) δ 7.34 - 7.30 (m, 4H), 6.94 (d, J = 3.7 Hz, 1 H), 6.76 (dt, J = 3.7, 0.9 Hz, 1 H), 5.02 (q, J = 7.0 Hz, 1 H), 3.77 (s, 2H), 3.07 (s, 2H), 2.34 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H).

[0238] 13C NMR (176 MHz, CD3OD) δ 172.27, 145.13, 143.87, 134.08, 130.92, 129.79, 129.01 , 128.43, 112.73, 60.49, 57.33, 43.28, 22.25.

[0239] MS (ESI) calculated for CieHi9BrN2OS (M + H+): 401 , found: 401.

[0240] (S)-2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)-N-(1-(4- chlorophenyl)ethyl)acetamide (SW-C272)

[0241] To a stirring solution of compound 4 (57 mg, 217μmol, 1 eq) in dry DMF (3.5 mL) was added DIPEA (113 μL, 84 mg, 647 μmol, 3 eq) and HATU (98 mg, 260μmol, 1.2 eq). After 10 minutes, (S)-1-(4-chlorophenyl)ethan-1 -amine hydrochloride (50 mg, 260μmol, 1.2 eq) was added and the solution was stirred for 20 h at r. t. under argon atmosphere. The mixture was diluted with water (10 mL) and extracted with DCM. Phases were separated and combined organic phases were washed with brine and dried over sodium sulfate. The solution was filtered, washed with DCM and concentrated under reduced pressure. The residue was purified by C18 flash (MeCN:H2O) and then by preparative HPLC (MeCN:H2O+0.1% HCOOH). Product containing fractions were lyophilised to yield compound SW-C272 (9.5 mg, 11%).

[0242] 1H NMR (700 MHz, CD3OD) δ 7.34 - 7.29 (m, 4H), 6.94 (d, J = 3.7 Hz, 1 H), 6.76 (dt, J = 3.7, 0.9 Hz, 1 H), 5.01 (q, J = 7.0 Hz, 1H), 3.77 (s, 2H), 3.07 (s, 2H), 2.34 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H).

[0243] 13C NMR (176 MHz, CD3OD) δ 172.28, 145.14, 143.87, 134.07, 130.91 , 129.78, 129.00, 128.42, 112.73, 60.49, 57.33, 43.28, 22.25.

[0244] MS (ESI) calculated for C16H19BrN2OS (M + H+): 401 , found: 401.

[0245] 2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)- / V-(4-iodobenzyl)acetamide (SW-C204)

[0246] SW-C204

[0247] To the compound 4 (0.040 g, 0.161 mmol, 1.50 eq.) in CH2CI2 (1 mL) was added TEA (0.068 mL, 0.482 mmol, 3.0 eq.) under nitrogen atmosphere at 0 °C. T3P (50% in DMF) (0.102 mL, 0.161 mmol, 1.50 eq.) was added drop wise at 0 °C. Stirred for 10 min at room temperature and 4-iodobenzylamine (0.025 mg, 0.107 mmol, 1.0 eq.) was added at room temperature in a single portion and stirred at room temp for 16 h. Reaction mixture was quenched with saturated NaHCO3 solution (20 mL) and extracted with Et20 (2 x 20 mL). Combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under vacuum. Crude compound was purified using column chromatography (1 :2, EtOAc: PE) to obtain compound SW-C204 (0.025 g, 35%) as white solid.

[0248] TLC analysis: 1 :1 , EtOAc: PE, Rf : 0.50 (Stain: Ninhydrin / UV).

[0249] 1H NMR (400 MHz, CDCI3): δ= 7.63-7.69 (m, 2H), 7.51 (bs, 1 H), 7.04 (d, J = 8.1 Hz), 6.88 (d, J = 3.6 Hz, 1 H), 6.68 (d, J = 3.1 Hz, 1H), 4.40 (d, J = 5.9 Hz, 1 H), 3.75 (s, 2H), 3.15 (s, 2H), 2.37 (s, 3H).13C NMR (101 MHz, CDC13): δ= 170.0, 138.1 , 137.9, 137.8, 129.9, 129.8, 129.7, 129.3, 93.0, 59.7, 56.8, 43.2, 42.7.

[0250] ESI-HRMS: C15H16BrlN2OS [M+H]+ calc. 478.9290, found 472.9283.

[0251] N-(4-Bromobenzyl)-2-(((5-bromothiophen-2-yl)methyl)(methyl)amino)acetamide (SW-C205)

[0252] SW-C205

[0253] To the compound 4 (0.050 g, 0.201 mmol, 1.50 eq.) in CH2CI2 (1 mL) was added TEA (0.056 mL, 0.403 mmol, 3.0 eq.) under nitrogen atmosphere at 0 °C. T3P (50% in DMF) (0.130 mL, 0.201 mmol, 1.50 eq.) was added drop wise at 0 °C. Stirred for 10 min at room temperature and 4-bromobenzylamine (0.025 mg, 0.134 mmol, 1.0 eq.) was added at room temperature in a single portion and stirred at room temp for 16 h. Reaction mixture was quenched with saturated NaHCO3solution (20 mL) and extracted with Et2O (2 x 20 mL). Combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under vacuum. Crude compound was purified using column chromatography (1 :2, EtOAc: PE) to obtain compound SW-C205 (0.032 g, 39%) as colorless oil.

[0254] TLC analysis: 1 :1 , EtOAc: PE, Rf 0.50 (Stain: Ninhydrin / UV).

[0255] 1H NMR (400 MHz, CDC13): δ= 7.42-7.52 (m, 3H), 7.13-7.19 (m, 2H), 6.87 (d, J = 3.6 Hz, 1 H), 6.66 (d, J = 3.6 Hz, 1 H), 4.42 (d, J = 6.3 Hz, 2H), 3.75 (s, 2H), 3.13 (s, 2H), 2.35 (s, 3H).

[0256] 13C NMR (101 MHz, CDC13): δ= 170.1 , 137.9, 131.9, 131.8, 129.6, 129.5, 129.0, 127.0, 121.5, 112.2, 59.8, 56.9, 44.4, 43.3, 42.6.

[0257] ESI-HRMS: C15H16Br2N2OS [M+H]+ calc. 430.9428, found 430.9435.

[0258] 2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)-N-(4-fluorobenzyl)acetamide (SW-C206)

[0259] To a stirring solution of compound 4 (70 mg, 0.26 mmol, 1 eq) in dry DMF (3 mL). was added DIPEA (138 μL, 102 mg, 0.79 mmol, 3 eq) and HATU (120 mg, 0.31 mmol, 1.2 eq). After 10 minutes, 4-fluorobenzylamine (27 μL, 29 mg, 0.31 mmol, 1.2 eq) was added and the solution was stirred for 2 h at r. t. under nitrogen atmosphere. The orangish reaction mixture was diluted with water (5 mL) and extracted with DCM (3x20 mL). Phases were separated and combined organic phases were washed with brine (20 mL), dried over sodium sulfate, filtered, washed with DCM and concentrated under reduced pressure. The residue was taken up in DMSO and purified by HPLC twice. Product containing fractions were lyophilised to yield compound SW-C206 (29 mg, 128 μmol, 17 %) as a yellow oil.

[0260] 1H NMR (500 MHz, DMSO-d6) δ 8.94 (s, br, 1 H), 7.31 - 7.27 (m, 2H), 7.15 - 7.11 (m, 2H), 7.07 (d, J = 9.4 Hz, 1 H), 6.86 (s, br, 1 H), 4.28 (d, J = 6.2 Hz, 2H), 3.82 (s, 2H), 3.09 (s, 2H), 2.31 (s, br, 3H).

[0261] 13C NMR (176 MHz, CD3CN) δ 163.0, 160.1 , 140.9, 135.8, 129.8, 129.2, 129.1 , 115.0, 114.8, 59.1 , 55.5, 42.0, 41.1.

[0262] HRMS (ESI) calculated for Ci5Hi6BrFN2OS (M (79Br) + H+): 371.0229, found: 371.0231; calculated for Ci5Hi6BrFN2OS (M (81Br) + H+): 373.0209, found: 373.0202. tert-Butyl (2-((3-Fluorobenzyl)amino)-2-oxoethyl)(methyl)carbamate (5)

[0263] To the solution of Boc-sarcosine 1 (0.100 g, 0.528 mmol, 1.0 eq.) in THF (2.5 mL) was added TEA (0.22 mL, 1.584 mmol, 3.0 eq.) under nitrogen atmosphere at 0 °C. T3P (50% in DMF) (0.504 mL, 0.792 mmol, 1.50 eq.) was added drop wise at 0 °C. Stirred for 10 min at room temperature and 3-fluorobenzylamine (0.060 mL, 0.528 mmol, 1.0 eq.) was added at room temperature in a single portion and stirred at room temp for 16 h. The reaction mixture was quenched with saturated NaHCO3solution (20 mL) and extracted with CH2CI2 (2 x 20 mL). Combined organic layers are dried over anhydrous Na2SO4, filtered and concentrated under vacuum. Crude compound was purified using column chromatography (1 :1 , EtOAc: PE) to obtain compound 5 (0.166 g, quant.) as off-white solid.

[0264] TLC analysis: 1 :1 , EtOAc: PE, Rf : 0.50 (Stain: Ninhydrin / UV).

[0265] 1H NMR (400 MHz, CDCI3): δ= 7.19-7.32 (m, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 6.93 (d, J = 8.8 Hz, 2H), 6.56 (bs, 1 H), 4.43 (d, J = 5.8 Hz, 2H), 3.87 (s, 2H), 2.93 (s, 2H), 1.41 (s, 9H).

[0266] 13C NMR (101 MHz, CDCI3): δ= 169.6, 154.3, 161.8, 140.8, 130.3, 130.3, 130.2,

[0267] 123.4, 123.4, 123.1 , 122.7, 118.7, 118.5, 114.8, 114.7, 114.6, 114.5, 114.4, 81.0,

[0268] 53.4, 43.6, 43.6, 42.7, 42.7, 36.0, 28.3

[0269] ESI-HRMS: C15H21FN2O3 [M+Na]+ calc. 319.1431 , found 319.1432.

[0270] N-(3-fluorobenzyl)-2-(methylamino)acetamide (6)

[0271] To the compound 5 (0.100 g, 0.337 mmol, 1.0 eq) in dichloromethane (3 mL) was added TFA (0.3 mL) at room temperature and stirred for 16 h. The reaction mixture was quenched into saturated NaHCO3 solution (50 mL), extracted with CH2CI2 (2 x 50 mL). Combined organic layers are dried over anhydrous Na2SO4, filtered, concentrated on vacuum. Compound 6 (55 mg, 83%) was isolated as colorless liquid.

[0272] TLC analysis: 10:1 , CH2CI2: MeOH, Rf: 0.15 (Stain: Ninhydrin / UV).

[0273] 2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)-N-(3-fluorobenzyl)acetamide

[0274] (SW-C203)

[0275] SW-C203

[0276] To the solution of the compound 6 (0.055 g, 0.280 mmol, 1.0 eq.) in THF (1.5 mL) was added 2-bromothiophene-5-aldehyde (0.033 mL, 0.280 mmol, 1.0 eq.) and acetic acid (0.033 mL, 0.560 mmol, 2.0 eq.) at room temperature under nitrogen. The reaction mixture was stirred for 5 min and NaBH(OAc)3 (0.089 g, 0.420 mmol, 1.5 eq.) was added in one portion and stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 solution (30 mL), extracted with diethylether (2 x 25 mL). Combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated on vacuum. Crude compound purified using column chromatography (PE: EtOAc, 2:1) to obtain compound SW-C203 (47 mg, 50%) as colorless liquid.

[0277] TLC analysis: 3:1 , EtOAc: PE Rt: 0.35 (Stain: UV / KMnO4).

[0278] 1H NMR (400 MHz, CDC13): δ= 7.45 (bs, 1 H), 7.26-7.34 (m, 1 H), 7.05 (d, J = 7.7 Hz, 1 H), 6.93-7.00 (m, 2H), 6.87 (d, J = 3.6 Hz, 1H), 6.66 (d, J = 3.4 Hz, 1 H), 4.46 (d, J = 6.0 Hz, 2H), 3.71 (s, 2H), 3.13 (s, 2H), 2.35 (s, 3H).

[0279] 13C NMR (101 MHz, CDC13): δ= 170.3, 164.3, 161.9, 143.2, 141.0, 140.9, 130.4, 130.3, 129.6, 126.9, 123.2, 114.7, 114.6, 114.5, 114.4, 112.1 , 59.9, 57.0, 43.3, 42.6.

[0280] ESI-HRMS: C15H16BrFN2OS [M+H]+ calc. 371.0229, found 371.0228.

[0281] 2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)-A / -phenoxyacetamide (SW- C238)

[0282] To a stirring solution of compound 4 (60 mg, 227μmol, 1 eq) in dry DMF (3 mL) was added DIPEA (118 μL, 88 mg, 681μmol, 3 eq) and HATU (103 mg, 272μmol, 1.2 eq). After 10 minutes, O-phenylhydroxylamine (24 μL, 29 mg, 272μmol, 1.2 eq) was added and the solution was stirred for 4 h at r. t. under nitrogen atmosphere. The orange - red reaction mixture was diluted with water (5 mL) and extracted with DCM (3x20 mL). combined organic phases were washed with brine (20 mL), dried over sodium sulfate, filtered, washed with DCM and concentrated under reduced pressure. The residue was taken up in DMSO and purified by HPLC twice. Product containing fractions were lyophilised to yield compound SW-C238 (18 mg, 50 μmol, 22 %) as a white solid.

[0283] 1H NMR (500 MHz, DMSO-d6) δ 7.33 (t, J = 8.0 Hz, 2H), 7.10 (d, J = 3.3 Hz, 1H), 7.04 - 7.00 (m, 3H), 6.89 (s, br, 1 H), 3.89 (s, 2H), 3.25 (s, 2H), 2.36 (s, 3H).

[0284] 13C NMR (176 MHz, DMSO-d6) δ 159.4, 145.0, 138.6, 129.8, 129.7, 129.4, 122.3, 112.8, 110.7, 56.3, 55.2, 41.3.

[0285] HRMS (ESI) calculated for C14H15BrN2O2S (M (79Br) + H+): 355.0116, found: 355.0092; calculated for C14H15BrN2O2S (M (81Br) + H+): 357.0095, found: 357.0089.

[0286] 2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)-N-(4-methylbenzyl)acetamide

[0287] SW-C207

[0288] To the compound 4 (0.068 g, 0.258 mmol, 1.25 eq.) in CH2CI2(2 mL) was added TEA (0.086 mL, 0.669 mmol, 3.0 eq.) under nitrogen atmosphere at 0 °C. T3P (50% in DMF) (0.196 mL, 0.309 mmol, 1.50 eq.) was added drop wise at 0 °C. Stirred for 10 min at room temperature and 4-methylbenzylamine (0.025 mg, 0.206 mmol, 1.0 eq.) was added at room temperature in a single portion and stirred at room temp for 16 h. The reaction mixture was quenched with saturated NaHCO3 solution (20 mL) and extracted with Et2O (2 x 20 mL). Combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude compound was purified by column chromatography (1 :2, EtOAc: PE) to obtain compound SW-C207 (0.038 g, 40%) as colorless oil.

[0289] TLC analysis: 1 :1. EtOAC: PE, Rf: 0.50 (Stain: Ninhydrin / UV).

[0290] 1H NMR (400 MHz, CDCI3): δ= 7.40 (bs, 1 H), 7.21-7.28 (m, 2H), 6.98-7.01 (d, 2H), 6.86 (d, J = 3.6 Hz, 1 H), 6.65 (d, J = 3.6 Hz, 1 H), 4.44 (d, J = 6.0 Hz, 2H), 3.70 (s, 2H), 3.11 (s, 2H), 2.34 (s, 3H).13C NMR (101 MHz, CDC13): δ= 170.2, 163.5, 161.1 , 143.3, 134.2, 129.6, 129.5, 129.4, 126.9, 115.8, 115.6, 112.1 , 59.0, 57.0, 43.3, 42.5.

[0291] ESI-HRMS: Ci5Hi9BrN2O [M+H]+ calc. 367.0480, found 367.0482.

[0292] ((R)-2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)-N-(1- phenylethyl)acetamide (SW-C246)

[0293] To a stirring solution of compound 4 (55 mg, 210μmol, 1 eq) in dry DMF (2 mL) was added DIPEA (110 μL, 82 mg, 633μmol, 3 eq) and HATU (96 mg, 252μmol, 1.2 eq). After 10 minutes, (R)-1 -phenylethylamine (31 mg, 252μmol, 1.2 eq) was added and the solution was stirred for 20 h at r. t. under argon atmosphere. The mixture was diluted with water and extracted with DCM. Phases were separated and combined organic phases were washed with brine and dried over sodium sulfate. The solution was filtered, washed with DCM and concentrated under reduced pressure. The residue was purified by C18 flash (MeCN:H2O). Product containing fractions were lyophilised to yield compound SW-C246 (20 mg, 26%).

[0294] 1H NMR (500 MHz, CD3OD) δ 7.36 - 7.32 (m, 4H), 7.29 - 7.23 (m, 1 H), 6.95 (d, J = 3.7 Hz, 1H), 6.77 (d, J = 3.7 Hz, 1 H), 5.05 (q, J = 7.0 Hz, 1 H), 4.61 (br. s, 1H), 3.79 (s, 2H), 3.09 (s, 2H), 2.35 (s, 3H), 1.50 (d, J = 7.0 Hz, 3H).

[0295] 13C NMR (126 MHz, CD3OD) δ 170.64, 143.63, 143.37, 129.38, 128.26, 126.91 , 126.86, 125.72, 111.17, 59.03, 55.81 , 48.66, 41.72, 20.99.

[0296] (S)-2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)-N-(1- phenylethyl)acetamide (SW-C245)

[0297] To a stirring solution of compound 4 (64 mg, 243μmol, 1 eq) in dry DMF (2 mL) was added DIPEA (127 μL, 94 mg, 729 μmol, 3 eq) and HATU (111 mg, 291μmol, 1 .2 eq). After 10 minutes, (S)-1 -phenylethylamine (35 mg, 291μmol, 1.2 eq) was added and the solution was stirred for 20 h at r. t. under argon atmosphere. The mixture was diluted with water (10 mL) and extracted with DCM. Phases were separated and combined organic phases were washed with brine and dried over sodium sulfate. The solution was filtered, washed with DCM and concentrated under reduced pressure. The residue was purified by C18 flash (MeCN:H2O). Product containing fractions were lyophilised to yield compound SW-C245 (18 mg, 20%).

[0298] 1H NMR (500 MHz, CD3OD) δ 7.34 - 7.30 (m, 4H), 7.26 - 7.22 (m, 1 H), 6.93 (d, J = 3.7 Hz, 1 H), 6.75 (d, J = 3.7 Hz, 1 H), 5.04 (q, J = 7.0 Hz, 1 H), 3.76 (s, 2H), 3.07 (s, 2H), 2.33 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H).

[0299] 13C NMR (126 MHz, CD3OD) δ 170.62, 143.66, 143.39, 129.38, 128.26, 126.90, 126.84, 125.73, 111.16, 59.05, 55.82, 48.65, 41.72, 20.99. tert-Butyl (2-(Benzylamino)-2-oxoethyl)(methyl)carbamate (7)

[0300] To the solution of the compound 1 (1.00 g, 5.285 mmol, 1.0 eq.) in THF (7 mL) was added TEA (2.20 mL, 15.855 mmol, 3.0 eq.) under nitrogen atmosphere at 0 °C. Isobutylchloroformate (0.76 mL, 5.813 mmol, 1.10 eq.) was added dropwise at 0 °C. The reaction mixture was stirred for 2 h at room temperature and benzyl amine (0.57 mL, 5.285 mmol, 1.0 eq.) was added at room temperature in a single portion and stirred at room temp for additional 2 h. The reaction mixture was quenched with saturated

[0301] NaHCO3solution (50 mL) and extracted with CH2CI2 (2 x 50 mL). Combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. Crude compound was purified using column chromatography (2-5% MeOH in dichloromethane) to obtain the compound 7 (0.93 g, 64%) as light yellow liquid.

[0302] TLC analysis: 20:1 , CH2CI2: MeOH, Rr 0,20 (Stain: Ninhydrin).

[0303] 1H NMR (400 MHz, CDCI3): δ = 7.20-7.36 (m, 5H), 6.43 (bs, 1 H), 4.46 (d, J = 5.96 Hz, 2H), 3.89 (s, 2H), 2.93 (s, 3H), 1.40 (s, 9H).13C NMR (101 MHz, CDCI3): δ = 171.3, 169.4, 138.1 , 128.8, 127.6, 80.9, 60.5, 43.3, 35.9, 28.3.

[0304] ESI-HRMS: C15H22N2O3 [M+Na]+ calc. 301.1528, found 301.1529.

[0305] A / -Benzyl-2-(methylamino)acetamide (8)

[0306] To the compound 7 (0.500 g, 1.796 mmol, 1.0 eq) in dichloromethane (15 mL) was added TFA (6 mL) at room temperature and stirred for 16 h. The reaction mixture was quenched into saturated NaHCO3solution (50 mL), extracted with CH2CI2 (2 x 50mL). Combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The compound 8 (200 mg, 62%) was isolated as a colorless liquid.

[0307] TLC analysis: 20:1. CH2CI2: MeOH, Rf: 0,15 (Stain: Ninhydrin / UV).

[0308] W-Benzyl-2-(((5-bromothiophen-2-yl)methyl)(methyl)amino)acetamide (SW- C103)

[0309] H / ^ N^N-Phvs10

[0310] Br SW-C103

[0311] To the compound 8 (0,050 g, 0.253 mmol, 1.0 eq.) in THF (1 mL) was added 2- bromothiophene-5-aldehyde (0.030 mL, 0.253 mmol, 1.0 eq.) and acetic acid (0.030 mL, 0.506 mmol, 2.0 eq.) at room temperature under nitrogen. The reaction mixture was stirred for 5 min and NaBH(OAc)3 (0.083 g, 0.379 mmol, 1.5 eq.) was added in one portion and stirred overnight at room temperature. The reaction was quenched by saturated NaHCO3solution (25 mL), extracted with diethyl ether (2 x 25 mL). Combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The crude compound was purified by column chromatography (PE: EtOAc, 2:1) to obtain the compound SW-C103 (63 mg, 64%) as a colorless liquid. TLC analysis: 2:1 , EtOAc: PE Rt: 0,35 (Stain: UV / KMnO4).

[0312] 1H NMR (400 MHz, CDCI3): δ = 7.32-7.44 (m, 3H), 7.22-7.31 (m, 2H), 6.87 (d, J = 3.6 Hz, 1 H), 6.64 (d, J = 4.0 Hz, 1 H), 4.48 (d, J = 5.9 Hz, 2H), 3.69 (s, 2H), 3.11 (s, 2H), 2.33 (s, 3H).

[0313] 13C NMR (101 MHz, CDC13): δ = 170.2, 143.5, 138.3, 129.5, 128.8, 127.7, 127.6, 126.7, 111.9, 60.1 , 57.0, 43.3, 43.1.

[0314] ESI-HRMS: Ci5Hi7BrN2OS [M+H]+ calc. 353.0324, found 353.0327.

[0315] (R)-N-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-(((5-bromothiophen-2- yl)methyl)(methyl)amino)acetamide (SW-C277)

[0316] To a stirring solution of compound 4 (67 mg, 252μmol, 1 eq) in dry DMF (3.5 mL) was added DIPEA (132 μL, 98 mg, 756μmol, 3 eq) and HATU (115 mg, 303 μmol, 1.2 eq). After 10 minutes, (R)-1-(benzo[d][1 ,3]dioxol-5-yl)ethanamine (50 mg, 303μmol, 1 .2 eq) was added and the solution was stirred for 20 h at r. t. under argon atmosphere. The mixture was diluted with water and extracted with DCM. Phases were separated and combined organic phases were washed with brine and dried over sodium sulfate. The solution was filtered, washed with DCM and concentrated under reduced pressure. The residue was purified by C18 flash (MeCN:H2O) and then by preparative HPLC (MeCN:H2O+0.1 % HCOOH). Product containing fractions were lyophilised to yield compound SW-C277 (17.3 mg, 17%).

[0317] 1H NMR (700 MHz, CD3OD) δ = 6.93 (d, J = 3.7 Hz, 1 H), 6.84 (d, J = 1 .7 Hz, 1 H), 6.80 (dd, J = 8.0, 1 .7 Hz, 1 H), 6.77 - 6.74 (m, 2H), 5.92 (s, 2H), 4.95 (q, J = 7.0 Hz, 1 H), 3.76 (s, 2H), 3.10 - 3.03 (m, 2H), 2.33 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H).

[0318] 13C NMR (176 MHz, CD3OD) δ = 172.03, 149.48, 148.36, 145.12, 138.91 , 130.90, 128.38, 120.56, 112.74, 109.22, 107.84, 102.52, 60.60, 57.31, 49.90, 43.20, 22.41. MS (ESI) calculated for C17H20BrN203S (M + H+): 411 , found: 411 . (S)- / V-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-(((5-bromothiophen-2- yl)methyl)(methyl)amino)acetamide (SW-C276)

[0319] To a stirring solution of compound 4 (67 mg, 252 μmol, 1 eq) in dry DMF (3.5 mL) was added DIPEA (132 μL, 98 mg, 756μmol, 3 eq) and HATU (115 mg, 303μmol, 1 .2 eq). After 10 minutes, (S)-1-(benzo[d][1,3]dioxol-5-yl)ethanamine (50 mg, 303μmol, 1.2 eq) was added and the solution was stirred for 20 h at r. t. under argon atmosphere. The mixture was diluted with water and extracted with DCM. Phases were separated and combined organic phases were washed with brine and dried over sodium sulfate. The solution was filtered, washed with DCM and concentrated under reduced pressure. The residue was purified by C18 flash (MeCN:H2O) and then by preparative HPLC (MeCN:H2O+0.1 % HCOOH). Product containing fractions were lyophilised to yield compound SW-C276 (24.1 mg, 23%).

[0320] 1H NMR (700 MHz, CD3OD) δ = 6.92 (d, J = 3.7 Hz, 1H), 6.84 (d, J = 1.7 Hz, 1H), 6.80 (dd, J = 8.0, 1.7 Hz, 1 H), 6.77 - 6.74 (m, 2H), 5.92 (s, 2H), 4.95 (q, J = 7.0 Hz, 1 H), 3.75 (s, 2H), 3.09 - 3.03 (m, 2H), 2.32 (s, 3H), 1 .45 (d, J = 7.0 Hz, 3H).

[0321] 13C NMR (176 MHz, CD3OD) δ 172.08, 149.48, 148.36, 145.20, 138.91 , 130.89, 128.33, 120.56, 112.71 , 109.22, 107.84, 102.51 , 60.63, 57.33, 49.90, 43.21 , 22.42. MS (ESI) calculated for C17H20BrN203S (M + H+): 411 , found: 411.

[0322] Methyl / V-((5-Bromothiophen-2-yl)methyl)- / V-methyl-L-alaninate (9)

[0323] To a solution of L-alanine methyl ester hydrochloride (1.95 g, 14.0 mmol, 2 eq) in MeOH (20 mL) was added TEA (1.91 mL, 1.41 g, 14.0 mmol, 2 eq) and 5- bromothiophene-2-carboxaldehyde (0.76 mL, 1.33 g, 7.0 mmol, 1 eq). After stirring for 14 h at r. t. under nitrogen atmosphere, sodium borohydride (397 mg, 10.5 mmol, 1.5 eq) was added and the reaction mixture was stirred for another 16 h at the same conditions. The solution was diluted with water (60 mL) and extracted with DCM (3x50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (PE I EtOAc 10 : 1 to 3 : 1) to afford compound 9 as a yellow oil (821 mg, 2.95 mmol, 43 %).

[0324] 1H NMR (500 MHz, CDC13) δ 6.87 (d, J = 3.7 Hz, 1 H), 6.66 (dt, J = 3.7, 1.0 Hz, 1 H), 3.97 (dd, J = 14.2, 1.0 Hz, 1 H), 3.78 (dd, J = 14.1 , 0.9 Hz, 1 H), 3.73 (s, 3H), 3.41 (q, J = 7.0 Hz, 1 H), 1.31 (d, J = 7.0 Hz, 3H).

[0325] LCMS (ESI): m / z 278 (M (79Br)+H+), 280 (M (81Br)+H+).

[0326] TLC: Rf= 0.38 (PE / EtOAc 5:1).

[0327] Methyl A / -((5-Bromothiophen-2-yl)methyl)-A / -methyl-L-alaninate (10)

[0328] To a stirring solution of compound 9 (815 mg, 2.93 mmol, 1 eq) in MeCN (20 mL) was added K2CO3 (809 mg, 5.86 mmol, 2 eq). The reaction mixture was cooled to 0 °C and iodomethane (218 μL, 3.51 mmol, 1.2 eq) was added dropwise. The solution was stirred for 19 h at r.t., diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). Combined organic phases were dried over sodium sulfate, filtered, washed with EtOAc and concentrated under reduced pressure. The crude product was purified by column chromatography (PE I EtOAc 10:1 to 4:1) to obtain compound 10 as a yellow-orang ish oil (491 mg, 1.68 mmol, 58 %).

[0329] 1H NMR (500 MHz, CDC13) δ 6.86 (d, J = 3.7 Hz, 1 H), 6.66 (d, J = 3.7 Hz, 1 H), 3.83 (dd, J = 14.5, 10.2 Hz, 2H), 3.72 (s, 3H), 3.50 (q, J = 7.1 Hz, 1 H), 2.34 (s, 3H), 1.33 (d, J = 7.1 Hz, 3H).

[0330] LCMS (ESI): m / z 292 (M (79Br)+H+), 294 (M (81Br)+H+).

[0331] TLC: Rf= 0.32 (PE / EtOAc 10:1).

[0332] N-((5-Bromothiophen-2-y l)methy l)-N-methy l-L-alanine (11 )

[0333] Compound 10 (489 mg, 1 .67 mmol, 1 eq) was dissolved in MeOH (9 mL). THF (12 mL) was added and the solution was cooled to 0 °C. An aqueous solution of KOH (12 mL, 4 M) was added and the reaction mixture was stirred for 14 h at r.t.. The solution was acidified with cone. HCI (9 mL) until pH = 1 and concentrated in vacuo. The crude product was purified by RP flash chromatography and product containing fractions were lyophilised to afford compound 11 as a white solid (743 mg, 2.67 mmol, quant.).1H NMR (500 MHz, DMSO-d6) δ 7.06 (d, J = 3.5 Hz, 1H), 6.87 (s, br, 1H), 3.93 (s, br, 2H), 3.50 (s, br, 1 H), 2.31 (s, 3H), 1.25 (d, J = 6.8 Hz, 3H).

[0334] 13C NMR (126 MHz, DMSO-d6) δ 173.2, 142.5, 129.9, 129.8, 114.7, 59.7, 52.5, 37.2, 14.3.

[0335] HRMS (ESI) calculated for C9Hi2BrNO2S (M (79Br) +H+): 277.9850, found: 277.9845, C9Hi2BrNO2S (M (81Br) +H+): 279.9830, found: 279.9824.

[0336] (S)- / V-(benzo[d][1,3]dioxol-5-ylmethyl)-2"(((5-bromothiophen-2- yl)methyl)(methyl)amino)propanamide (SW-C225)

[0337] SW-C225

[0338] To a solution of the L-alanine derivative 11 (200 mg, 0.719 mmol, 1 eq) in dry DMF (4 mL) was added DIPEA (375 μL, 2.15 mmol, 3 eq) and HATU (328.1 mg, 0.86 mmol, 1 .2 eq). After 10 minutes piperonylamine (107 μL, 0.863 mmol, 1.2 eq) was added and the solution was stirred for 15 h at r.t. under argon atmosphere. The reaction mixture was diluted with water (20 mL), phases were separated and the aqueous phase was extracted with EtOAc (3x20 mL). Combined organic phases were washed with brine (30 mL) and dried over sodium sulfate. The solution was filtered and concentrated in vacuo. The crude product was purified by reversed phase flash chromatography and further purified by HPLC. Product containing fractions were lyophilised to afford compound SW-C225 (28.5 mg, 69.5μmol, 10 %).

[0339] 1H NMR (500 MHz, CDC13) δ 8.03 (s, 1 H), 6.85 (d, J = 3.7 Hz, 1 H), 6.78 - 6.74 (m, 3H), 6.63 (d, J = 3.7 Hz, 1H), 5.95 (s, 2H), 4.36 (d, J = 5.9 Hz, 2H), 3.66 (s, 2H), 3.34 (q, J = 6.9 Hz, 1 H), 2.24 (s, 3H), 1.26 (d, J = 7.0 Hz, 3H).

[0340] 13C NMR (126 MHz, DMSO-d6) δ 172.0, 147.2, 146.2, 146.0, 133.5, 129.7, 126.0, 120.4, 110.0, 107.94, 107.91 , 100.7, 60.8, 52.6, 41.7, 37.9, 12.2.

[0341] HRMS (ESI) calculated for CiyHwBrNaOsS (M (79Br) +H+): 411 .0378, found: 411.0373; calculated for Ci7Hi9BrN2O3S (M (81Br) +H+): 413.0358, found: 413.0352.

[0342] Methyl ((5-Bromothiophen-2-yl)methyl)-D-alaninate (12)

[0343] To a solution of D-alanine methyl ester hydrochloride (771 mg, 5.52 mmol, 2 eq) in MeOH (10 mL) was added TEA (0.77 mL, 559 mg, 5.52 mmol, 2 eq) and 5- bromothiophene-2-carboxaldehyde (0.30 mL, 528 g, 2.76 mmol, 1 eq). After stirring for 14 h at r. t. under nitrogen atmosphere, sodium borohydride (156 mg, 4.14 mmol, 1.5 eq) was added and the reaction mixture was stirred for another 16 h at the same conditions. The solution was diluted with water (30 mL) and extracted with DCM (3x40 mL). The combined organic phases were washed with brine (30mL), dried over sodium sulfate, filtrated and concentrated under reduced pressure. The crude product was purified by column chromatography (PE / EtOAc 10 : 1 to 5 : 1) to afford compound 12 as a yellow-orangish oil (316 mg, 1.13 mmol, 42 %).

[0344] 1H NMR (500 MHz, CDC13) δ 6.87 (d, J = 3.7 Hz, 1 H), 6.66 (dt, J = 3.7, 0.9 Hz, 1 H), 3.97 (dd, J = 14.2, 1.0 Hz, 1 H), 3.78 (dd, J = 14.2, 0.9 Hz, 1 H), 3.73 (s, 3H), 3.41 (q, J = 7.0 Hz, 1 H), 1.31 (d, J = 7.0 Hz, 3H).

[0345] LCMS (ESI): m / z 278 (M (79Br)+H+), 280 (M (81Br)+H+).

[0346] TLC: Rf= 0.36 (PE / EtOAc 5:1).

[0347] Methyl N-((5-Bromothiophen-2-yl)methyl)- / V-methyl-D-alaninate (13)

[0348] To a stirring solution of compound 12 (316 mg, 1.13 mmol, 1 eq) in MeCN (15 mL) was added K2CO3 (314 mg, 2.27 mmol, 2 eq). The reaction mixture was cooled to 0 °C and iodomethane (84 μL, 1 .36 mmol, 1 .2 eq) was added dropwise. The solution was stirred for 18 h at r.t., diluted with water (40 mL) and extracted with EtOAc (3x40 mL). Phases were separated and combined organic phases were dried over sodium sulfate, filtered, washed with EtOAc and concentrated under reduced pressure. The crude product was purified by column chromatography (PE I EtOAc 10:1 to 4:1) to obtain compound 13 as a yellow-orangish oil (193 mg, 0.66 mmol, 58 %).

[0349] 1H NMR (500 MHz, CDCI3) δ 6.86 (d, J = 3.7 Hz, 1 H), 6.66 (d, J = 3.7 Hz, 1 H), 3.83 (dd, J = 14.3, 10.1 Hz, 2H), 3.72 (s, 3H), 3.50 (q, J = 7.1 Hz, 1H), 2.34 (s, 3H), 1.33 (d, J = 7.1 Hz, 3H).

[0350] LCMS (ESI): m / z 292 (M (79Br)+H+), 294 (M (81Br)+H+).

[0351] TLC: Rf= 0.32 (PE / EtOAc 10:1).

[0352] JV-((5-Bromothiophen-2-yl)methyl)-A / -methyl-D-alanine (14)

[0353] The compound 13 (189 mg, 0.64 mmol, 1 eq) was dissolved in MeOH (4 mL). THF (5 mL) was added and the solution was cooled to 0 °C. An aqueous solution of KOH (5 mL, 4 M) was added and the reaction mixture was stirred for 16 h at r.t.. The solution was acidified with cone. HCI (4 mL) until pH = 1 and concentrated in vacuo. The crude product was purified by RP flash chromatography and product containing fractions were lyophilised to afford compound 14 as a white solid (431 mg, 1.55 mmol, quant).1H NMR (500 MHz, DMSO-d6) δ 7.17 (s, br, 1 H), 7.08 (s, br, 1 H), 4.27 (s, br, 3H), 3.84 (s, br, 2H), 2.55 (s, br, 1 H), 1.41 (s, br, 3H). HRMS (ESI) calculated for C9Hi2BrNO2S (M (79Br) +H+): 277.9850, found: 277.9849; calculated for C9H12BrNO2S (M (81Br) +H+): 279.9830, found: 279.9850.

[0354] ( / ?)-A / -(Benzo[d][1,3]dioxol-5-ylmethyl)-2-(((5-bromothiophen-2- y l)methyl)(methy l)amino)propanamide (SW-C219)

[0355] SW-C219

[0356] To a stirring solution of the acid 14 (253 mg, 0.91 mmol, 1 eq) in dry DMF (10 mL) was added DIPEA (477 μL, 353 mg, 2.73 mmol, 3 eq) and HATU (416 mg, 1.09 mmol, 1.2 eq). After 10 minutes piperonylamine (136 μL, 165 mg, 1.09 mmol, 1.2 eq) was added and the solution was stirred for 18 h at r.t. under nitrogen atmosphere. The reactions mixture was diluted with water (20 mL), phases were separated and the aqueous phase was extracted with DCM (3x30 mL). Combined organic phases were washed with brine (30 mL) and dried over sodium sulfate. The solution was filtered, washed with DCM and concentrated in vacuo. The crude product was purified by RP flash chromatography. Product containing fractions were lyophilised to afford compound SW-C219 (73 mg, 0.17 mmol, 20 %).

[0357] 1H NMR (700 MHz, DMSO-d6) δ 8.18 (t, J = 6.0 Hz, 1 H), 7.02 (d, J = 3.7 Hz, 1H), 6.83 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 3.7 Hz, 1 H), 6.73 (dd, J = 7.8, 1.7 Hz, 1 H), 5.97 (s, 2H), 4.23 (dd, J = 14.7, 6.2 Hz, 1 H), 4.17 (d, J = 14.7, 5.9 Hz, 1 H), 3.76 (d, J = 14.6 Hz, 1 H), 3.69 (d, J = 14.6 Hz, 1 H), 3.2 (q, J = 6.9 Hz, 1 H), 2.17 (s, 3H), 1.13 (d, J = 6.9 Hz, 3H).

[0358] 13C NMR (126 MHz, MeOH-d4) δ 175.7, 149.3, 148.3, 146.3, 133.9, 130.6, 127.4, 122.1, 112.2, 109.2, 109.0, 102.3, 62.9, 54.4, 43.7, 38.4, 11.9.

[0359] HRMS (ESI) calculated for C17H19BrN2O3S (M (79Br) +H+): 411.0378, found: 411.0355; calculated for C17H19BrN2O3S (M (81Br) +H+): 413.0358, found: 413.0335.

[0360] 2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)-N-(3,4- difluorobenzyl)acetamide (SW-C231 )

[0361] To a stirring solution of the compound 4 (50 mg, 180μmol, 1 eq) in dry DMF (3 mL). was added DIPEA (98 μL, 73.3 mg, 560μmol, 3 eq) and HATU (86 mg, 220μmol, 1.2 eq). After 10 minutes, 3,4-difluorobenzylamine (27 μL, 32.5 mg, 220μmol, 1.2 eq) was added and the solution was stirred for 20 h at r. t. under nitrogen atmosphere. The red reaction mixture was diluted with water (10 mL) and extracted with DCM (3x30 mL). Combined organic phases were washed with brine (20 mL) and dried over sodium sulfate. The solution was filtered, washed with DCM and concentrated under reduced pressure. The residue was taken up in DMSO and purified by HPLC. Product containing fractions were lyophilised to yield compound SW-C231 (22 mg, 57μmol, 31 %) as a white solid.

[0362] 1H NMR (700 MHz, CD3CN) δ 7.59 (s, br, 1 H), 7.23 - 7.17 (m, 2H), 7.08 - 7.06 (m, 1 H), 6.98 (d, J = 3.7 Hz, 1 H), 6.80 (d, J = 3.7 Hz, 1 H), 4.34 (d, J = 6.4 Hz, 2H), 3.82 (s, 2H), 3.11 (s, 2H), 2.36 (s, 3H).

[0363] 13C NMR (176 MHz, CD3CN) δ 170.4, 151.5, 150.7, 149.3, 138.1 , 130.8, 128.6, 124.7, 117.2, 117.1 , 112.3, 60.1 , 56.9, 43.1 , 42.2.

[0364] HRMS (ESI) calculated for Ci5Hi5BrF2N2OS (M (79Br) + H+): 389.0135, found: 389.0128; calculated for Ci5Hi5BrF2N2OS (M (81Br) + H+): 391.0114, found: 391.0108.

[0365] N-Benzy l-2-((4-bromobenzyl)(methy l)amino)acetamide (SW-C107)

[0366] To the compound 8 (0,050 g, 0.253 mmol, 1.0 eq.) in THF (1 mL) was added 4- bromobenzaldehyde (0.047 g, 0.253 mmol, 1.0 eq.) and acetic acid (0.030 mL, 0.506 mmol, 2.0 eq.) at room temperature under nitrogen. The reaction mixture was stirred for 5 min and NaBH(OAc)3(0.083 g, 0.379 mmol, 1.5 eq.) was added in one portion and stirred overnight at room temperature. The reaction was quenched by saturated

[0367] NaHCO3solution (25 mL), extracted with diethyl ether (2 x 25 mL). Combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The crude compound was purified by column chromatography (PE: EtOAc, 2:1) to obtain compound SW-C107 (55 mg, 55%) as colorless liquid.

[0368] TLC analysis: 2:1 , EtOAc: PE Rf : 0,35 (Stain: UV / KMnO4).

[0369] 1H NMR (400 MHz, CDC13): δ = 7.22-7.47 (m, 8H), 7.03-7.12 (m, 2H), 4.47 (d, J = 6.5 Hz, 2H), 3.50 (s, 2H), 3.1 (s, 2H), 2.27 (s, 3H).

[0370] 13C NMR (101 MHz, CDC13): δ = 170.5, 138.4, 136.9, 131.7, 130.7, 128.9, 127.8, 127.7, 121.5, 61.8, 60.6, 43.5, 43.1.

[0371] ESI-HRMS: Ci7Hi9BrN2O [M+H]+ calc. 347.0759, found 347.0759.

[0372] Methyl 3-(((5-Bromothiophen-2-yl)methyl)amino)propanoate (15)

[0373] 15

[0374] To a solution of p-alanine methyl ester (2.68 g, 19.2 mmol, 2 eq) in dry MeOH (20 mL) was added TEA (2.68 mL, 1.94 g, 19.2 mmol, 2 eq) and 5-bromothiophene-2- carboxaldehyde (1.04 mL, 1.83 g, 9.6 mmol, 1 eq). After stirring for 14 h at r. t. under nitrogen atmosphere, sodium triacetoxyborohydride (3.05 g, 14.4 mmol, 1.5 eq) was added and the reaction mixture was stirred for another 16 h under the same conditions. The solution was diluted with water (50 mL) and extracted with DCM (3x60 mL). the combined organic phases were dried over sodium sulfate, filtrated and concentrated under reduced pressure. The crude product was purified by normal phase flash chromatography (0 - 50 % EtOAc in PE) to afford compound 15 as a yellow oil (680 mg, 2.44 mmol, 26 %).

[0375] 1H NMR (500 MHz, CDC13) δ 6.87 (d, J = 3.7 Hz, 1 H), 6.67 (dt, J = 3.7, 0.9 Hz, 1 H), 3.92 (d, J = 0.9 Hz, 2H), 3.69 (s, 3H), 2.90 (t, J = 6.4 Hz, 2H), 2.52 (t, J = 6.4 Hz, 2H).13C NMR (126 MHz, CDC13) δ 173.2, 146.2, 129.5, 125.1 , 111.0, 51.8, 48.7, 44.2, 34.5. HRMS (ESI) calculated for C9H12BrNO2S (M (79Br) + H): 277.9850, found: 277.9856; calculated for C9H12BrNO2S (M (81Br) + H+): 279.9830, found: 279.9823.

[0376] TLC: Rf= 0.28 (PE / EtOAc 5:1).

[0377] Methyl 3-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)propanoate (16)

[0378] To a stirring solution of compound 15 (676 mg, 2.43 mmol, 1 eq) in MeCN (15 mL) was added K2COs (671 mg, 4.86 mmol, 2 eq). The reaction mixture was cooled to 0 °C and iodomethane (181 μL, 413 mg, 2.91 mmol, 1.2 eq) was added dropwise. The yellow solution was stirred for 16 h at r.t., diluted with water (60 mL) and extracted with EtOAc (3x80 mL). and combined organic phases were dried over sodium sulfate, filtered, washed with EtOAc and concentrated under reduced pressure. The crude product was purified by column chromatography (PE I EtOAc 10 : 1 to 1 : 1) to obtain compound 16 as a yellow - orangish oil (142 mg, 0.48 mmol, 21 %).

[0379] 1H NMR (500 MHz, CDC13) δ 6.87 (d, J = 3.7 Hz, 1 H), 6.64 (dt, J = 3.6, 0.8 Hz, 1 H), 3.69 (s, 3H), 3.66 (d, J = 0.6 Hz, 2H), 2.74 (t, J = 7.2 Hz, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.26 (s, 3H).

[0380] 13C NMR (126 MHz, CDC13) δ 172.9, 144.6, 129.3, 125.9, 111.5, 56.8, 52.3, 51.8, 41.8, 32.9.

[0381] HRMS (ESI) calculated for C10H14BrNO2S (M (79Br) + H): 292.0007, found: 291.9998; calculated for C10H14BrNO2S (M (81Br) + H+): 293.9986, found: 293.9977. TLC: Rf= 0.32 (PE I EtOAc 1 : 1).

[0382] 3-(((5-Bromothiophen-2-y l)methy l)(methy l)amino)propanoic acid (17)

[0383] The compound 16 (137 mg, 0.46 mmol, 1 eq) was dissolved in MeOH (5 mL). THF (6 mL) was added and the solution was cooled to 0 °C. An aqueous solution of KOH (6 ml_, 4 M) was added and the reaction mixture was stirred for 22 h at r.t. The solution was acidified with cone. HCI (2 mL) to pH = 1 and concentrated under reduced pressure. The crude product was purified by RP flash chromatography to yield compound 17 as a white solid (182 mg, 0.65 mmol, quant.).

[0384] 1H NMR (500 MHz, DMSO-d6) δ 7.26 (d, J = 3.8 Hz, 1 H), 7.23 (d, J = 3.8 Hz, 1 H), 4.50 (s, 2H), 3.21 (s, br, 2H), 2.83 (t, J = 7.6 Hz, 2H), 2.65 (s, 3H).

[0385] 13C NMR (126 MHz, DMSO-d6) δ 171.5, 133.4, 132.8, 130.6, 114.3, 52.2, 49.6, 38.4, 28.5.

[0386] HRMS (ESI) calculated for CgHi2BrNO2S (M (79Br) + H): 277.9850, found: 277.9848; calculated for CgHi2BrNO2S (M (81Br) + H+): 279.9830, found: 279.9827.

[0387] Af-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-(((5-bromothiophen-2- yl)methyl)(methyl)amino)propanamide (SW-C228)

[0388] To a stirring solution of compound 17 (90 mg, 0.32 mmol, 1 eq) in dry DMF (6 mL). DIPEA (168 μL, 0.96 mmol, 3 eq) and HATU (147 mg, 0.38 mmol, 1.2 eq) were added followed by piperonylamine (48 μL, 0.38 mmol, 1.2 eq) after 10 minutes. The yellow- oranigsh solution was stirred for 15 h at r. t. under nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3x30 mL). Phases were separated and combined organic phases were washed with brine (20 mL), dried over sodium sulfate, filtered, washed with DCM and concentrated under reduced pressure. The residue was purified by RP flash chromatography and HPLC afterwards to obtain compound SW-C228 (41 mg, 0.10 mmol, 32 %).

[0389] 1H NMR (700 MHz, MeOH-d4) δ 8.20 (s, 1H), 7.01 (d, J = 3.7 Hz, 1H), 6.89 (d, J = 3.7 Hz, 1 H), 6.80 (d, J = 1.2 Hz, 1 H), 6.77 (dd, J = 8.0, 1.4 Hz, 1 H), 6.75 (d, J = 7.9 Hz, 1 H), 5.92 (s, 2H), 4.28 (s, 2H), 4.03 (s, 2H), 3.01 (t, J = 6.7 Hz, 2H), 2.55 (t, J = 6.7 Hz, 2H), 2.49 (s, 3H).13C NMR (176 MHz, MeOH-d4) δ 173.3, 149.3, 148.3, 140.5, 133.6, 131.1 , 130.5, 122.1 , 114.2, 109.2, 109.0, 102.3, 56.2, 53.5, 44.0, 41.0, 32.8.

[0390] HRMS (ESI) calculated for Ci7Hi9BrN2O3S (M (79Br) + H+): 411.0378, found: 411.0374; calculated for CiyHwBrlWsS (M (81Br) + H+): 413.0358, found: 413.0367.

[0391] 2-Benzamido-3-methoxy-3-oxopropyl benzoate (18)

[0392] Compound 18 was prepared according to the procedure described in the literature (J. G. Varnes, G. Scott Lehr, G. L. Moore, J. M. Hulsizer, J. S. Albert, Tetrahedron Letters 2010, 51, 3756-3758).

[0393] A stirring solution of serine (1.5 g, 14.2 mmol, 1 eq) in MeOH (25 mL) was cooled to 0°C and thionylchloride (4.1 mL, 6.8 g, 57 mmol, 4 eq) was added. The solution was stirred for 16h at r.t.. All volatile components were removed under reduced pressure to obtain the methyl ester (2.5g, 19.7mmol, quant.) as a white solid which was used for the next step without purification.

[0394] To a solution of the serine methyl ester (2.3 g, 19.7 mmol, 1 eq) in DCM (65 mL) was added TEA (9.3 mL, 6.7 g, 66.9 mmol, 3.4 eq) and benzoylchloride (5.2 mL, 6.3 g, 45.3 mmol, 2.3 eq) at 5 °C. The reaction mixture allowed to warm to r.t. and was stirred for 4 h at r.t.. Then the solution was washed with NaHCO3(60mL) and with 0.5N HCI to remove excess TEA and layers were separated. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (10 - 50 % DCM in PE) to afford compound 18 (1 .7 g, 5.23 mmol, 27 %). The obtained NMR spectra are in accordance with published ones.

[0395] 1H NMR (500 MHz, CDC13) δ 8.01 - 7.99 (m, 2H), 7.83 - 7.82 (m, 2H), 7.59 - 7.57 (m, 1 H), 7.54 - 7.51 (m, 1 H), 7.46 - 7.43 (m, 4H), 7.07 (d, J = 7.2 Hz, 1 H), 5.19 (dt, J = 7.5, 3.7 Hz, 1 H), 4.80 - 4.76 (m, 2H), 3.84 (s, 3H).

[0396] LCMS (ESI): m / z 328 (M + H+). TLC: Rf= 0.35 (PE / DCM 1 : 1).

[0397] Methyl 2-(N-allylbenzamido)acrylate (19)

[0398] Compound 19 was prepared according to the procedure described in the literature by Varnes et al.

[0399] To a stirring solution of the benzoate 18 (1.7 g, 5.23 mmol, 1 eq) in DMF (25 mL) was added allyl bromide (5.4 mL, 7.5 g, 62.7 mmol, 12 eq) and sodium hydride (252 mg, 10.5 mmol, 2 eq) as a dispersion in mineral oil. The reaction mixture was stirred for 2 h at r.t.. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3x40 mL). combined organic phases were dried over sodium sulfate, filtered, washed with DCM and concentrated under reduced pressure. The crude product was purified by normal phase flash chromatography (0 - 65 % DCM in PE) and reversed phase flash chromatography afterwards to afford compound 19 (664 mg, 2.70 mmol, 52 %). The obtained NMR spectra are in accordance with published ones.

[0400] 1H NMR (500 MHz, CDC13) δ 7.48 - 7.47 (m, 2H), 7.40 - 7.37 (m, 1 H), 7.35 - 7.31 (m, 2H), 6.08 (s, 1 H), 5.95 - 5.87 (m, 1 H), 5.51 (s, 1 H), 5.26 - 5.20 (m, 2H), 4.31 (d, J = 5.5 Hz, 2H), 3.63 (s, 3H).

[0401] LCMS (ESI): m / z 246 (M + H+).

[0402] TLC: Rf= 0.20 (PE / DCM 1 : 2).

[0403] Methyl 2-benzoyl-2-azabicyclo[2.1.1]hexane-1 -carboxylate (20) Compound 20 was prepared according to the procedure described in the literature (P. Hughes, J. Clardy, J. Org. Chem. 1988, 53, 4793-4796).

[0404] A quartz glass test tube was charged with the acylate 19 (220 mg, 0.90 mmol, 1 eq) in MeCN (10 mL) and acetophenone (40 μL, 41.2 mg, 0.30 mmol, 0.33 eq). The reaction mixture was stirred for 8 h at r.t. under nitrogen atmosphere and was constantly irradiated with an UV lamp of the photoreactor. The reaction mixture was concentrated under reduced pressure. This procedure was done three times and the combined crude product was purified by normal phase flash chromatography (0 - 15 % MeOH in DCM) to yield compound 20 (546 mg, 2.22 mmol, 81 %). The obtained NMR spectra are in accordance with published ones.

[0405] 1H NMR (500 MHz, CDC13) δ 7.76 (d, J = 7.2 Hz, 2H), 7.49 - 7.47 (m, 1H), 7.43 - 7.40 (m, 2H), 3.81 (s, 3H), 3.57 (s, 2H), 2.82 - 2.81 (m, 1H), 2.24 - 2.19 (m, 2H), 1.83 - 1.79 (m, 2H).

[0406] LCMS (ESI): m / z 246 (M + H+).

[0407] TLC: Rf= 0.29 (DCM I MeOH 10 : 1).

[0408] 2-((5-Bromothiophen-2-yl)methyl)-2-azabicyclo[2.1.1]hexane-1 -carboxylic acid

[0409] To a stirring solution of compound 20 (199 mg, 1.56 mmol, 2 eq) in dry MeOH (7 mL) was added TEA (219 μL, 158 mg, 1.56 mmol, 2 eq) and 5-bromothiophene-2- carboxaldehyde (85 μL, 149 mg, 0.78 mmol, 1 eq) were added and the black solution was stirred for 16 h at r. t. under nitrogen atmosphere. Then sodium borohydride (118 mg, 3.12 mmol, 4 eq) was added and the mixture was stirred for another 16 h at r. t. under the same conditions. The solution was concentrated under reduced pressure and purified by RP flash chromatography. Product containing fractions were lyophilised to obtain compound 21 (39 mg, 0.13 mmol, 17 %).1H NMR (500 MHz, D2O) δ 7.04 (d, J = 3.7 Hz, 1 H), 6.87 (d, J = 3.7 Hz, 1 H), 3.93 - 3.91 (s, 2H), 2.79 (s, 2H), 2.62 (d, J = 3.0 Hz, 1H), 1.91 - 1.87 (m, 2H), 1.79 (dd, J = 4.8, 1.9 Hz, 2H)

[0410] 13C NMR (500 MHz, D2O) δ 177.8, 143.0, 129.8, 127.4, 110.7, 76.1, 55.7, 51.1 , 40.6, 39.2, 35.3.

[0411] HRMS (ESI) calculated for CiiHi2BrNO2S (M (79Br) + H+): 301.9850, found: 301.9848; calculated for CiiHi2BrNO2S (M (81Br) + H+): 303.9830, found: 398.9828.

[0412] N-(Benzo[d][1,3]dioxol-5-ylmethyl)-2-((5-bromothiophen-2-yl)methyl)-2- azabicyclo[2.1.1]hexane-1 -carboxamide (SW-C241)

[0413] To a stirring solution of compound 21 (30 mg, 99μmol, 1 eq) in dry DMF (1 mL) was added HATU (75 mg, 198μmol, 2 eq) and DIPEA (52 μL, 38 mg, 297μmol, 3 eq). After 10 minutes, piperonylamine (19 μL, 22 mg, 148 μmol, 1.5 eq) was added and the solution was stirred for 3 h at r. t. under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and purified by reversed phase flash chromatography and HPLC. Product containing fractions were lyophilised to yield compound SW-C241 (8 mg, 14 μmol, 18%) as a yellow oil.

[0414] 1H NMR (500 MHz, MeOH-d4) δ 7.40 (s, 1 H), 6.94 (d, J = 3.7 Hz, 1 H), 6.79 - 6.75 (m, 3H), 6.72 (d, J = 7.9 Hz, 1 H), 5.90 (s, 2H), 4.29 (s, 2H), 3.85 (s, 2H), 2.90 (s, 2H), 2.71 (d, J = 3.1 Hz, 1 H), 2.02 - 2.01 (m, 2H), 1.83 (d, J = 4.9, 2.0 Hz, 2H).

[0415] 13C NMR (126 MHz, MeOH-d4) δ 171.2, 149.2, 148.3, 144.8, 133.8, 130.7, 127.6, 122.0, 112.6, 109.1 , 109.0, 102.3, 76.3, 58.0, 52.9, 43.6, 40.3, 37.5.

[0416] HRMS (ESI) calculated for C19H19BrN2O3S (M (79Br) + H+): 435.0378, found: 435.0355; calculated for C19H19BrN2O3S (M (81Br) + H+): 437.0358, found: 437.0336.

[0417] A / -(Benzo[d][1,3]dioxol-5-yl)-2-(((5-bromothiophen-2-yl)methyl)(methyl)amino) acetamide (SW-C129)

[0418] To the compound 4 (0.020 g, 0.076 mmol, 1.0 eq.) in THF (1 mL) was added TEA (0.052 mL, 0.378 mmol, 5.0 eq.) under nitrogen atmosphere at 0 °C. Isobutylchloroformate (0.016 mL, 0.113 mmol, 1.50 eq.) was added dropwise at O °C. Stirred for 2 h at room temperature and 3,4-(methylenedioxy)aniline (0.010 g, 0.076 mmol, 1.0 eq.) was added at room temperature in a single portion and stirred at room temp for an additional 2 h. The reaction mixture was quenched with saturated NaHCOa solution (20 mL) and extracted with Et2O (2 x 20 mL). Combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified using column chromatography (1 :2, EtOAcPE) to obtain compound SW-C129 (0.014 g, 49%) as black oil.

[0419] TLC analysis: 1 :1. EtOAc: PE, Rf: 0.40 (Stain: KMnCU / UV).

[0420] 1H NMR (400 MHz, CDC13): δ= 7.32 (d, J = 1.9 Hz, 1 H), 6.87-6.95 (m, 2H), 6.72-6.83 (m, 2H), 5.95 (s, 2H), 3.90 (bs, 2H), 3.30 (bs, 2H), 2.49 (s, 3H).

[0421] 13C NMR (101 MHz, CDC13): δ= 167.5, 148.0, 144.4, 132.0, 129.9, 112.8, 108.3, 102.4, 101.4, 31.1 , 30.5, 29.8.

[0422] ESI-HRMS: Ci5Hi5BrN2O3S [M+H]+ calc. 383.0072, found 383.0072. tert-Butyl (2-((Benzo[d][1 ,3]dioxol-5-ylmethyl)amino)-2-oxoethyl)carbamate (22)

[0423] Piperonyl amine (48 mg, 0.318 mmol) was added to a solution of N-Boc-glycine succinimide ester (78 mg, 0.287 mmol) in acetonitrile (2 mL), and the mixture was stirred for 18 h at r. t. Volatiles were removed under reduced pressure. Flash chromatography of the residue (EtOAc : cyclohexane) provided the title compound as a pale yellow oil (60 mg, 0.195 mmol, 68%) which was carried through without further purification or characterization.

[0424] A / -(Benzo[d][1,3]dioxol-5-ylmethyl)-2-(((5-bromothiophen-2- yl)methyl)amino)acetamide (SW-C288)

[0425] Trifluoroacetic acid (0.25 mL) and deionized water (0.1 mL) were added to a solution of 22 (60 mg, 0.195 mmol) in acetonitrile (2.5 mL), and the resulting mixture was stirred at r. t. for 18 h and then concentrated to dryness. The residue was taken up in methanol (5 mL), 5-bromothiophene 2-carbaldehyde (90 mg, 0.471 mmol) and sodium cyanoborohydride (29 mg, 0.461 mmol) were added, and the mixture was stirred (RT, 72 h). The resulting mixture was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. Phases were separated and combined organic phases were washed with brine and dried over sodium sulfate then concentrated under reduced pressure. The residue was purified by C18 Flash (MeCN:H2O) and then by preparative HPLC on C18 silica (MeCN:H2O+0.1% HCOOH) providing SW-C288 as a colorless solid (10 mg, 0.026 mmol, 13%).

[0426] 1H NMR (500 MHz, CD3OD) δ =6.95 (d, 1 H, J = 3.70 Hz), 6.79-6.77 (m, 2H), 6.76-6.75 (m, 2H), 5.92 (s, 2H), 4.30 (s, 2H), 3.95 (br d, 2H, J = 0.8 Hz), 3.33 (s, 2H).

[0427] 13C NMR (126 MHz, CD3OD) δ =171.0, 147.4, 146.4, 143.3, 131.7, 129.0, 126.1, 120.1 , 110.5, 107.3, 107.2, 100.5, 49.3, 46.5, 41.8.

[0428] MS (ESI) calculated for C15H16BrN2O3S (M + H): 383, found: 383 tert-Buty I methy l(2-((naphthalen-1 -ylmethy l)amino)-2-oxoethy l)carbamate (23)

[0429] To the compound 1 (0.500 g, 2.64 mmol, 1.0 eq.) in THF (5 mL) was added TEA (1.10 mL, 7.92 mmol, 3.0 eq.) under nitrogen atmosphere at 0 °C. Isobutylchloroformate (0.45 mL, 3.34 mmol, 1.10 eq.) was added drop wise at 0 °C. Stirred for 2 h at room temperature and 1-napthylamine (0.039 mL, 2.64 mmol, 1.0 eq.) was added at r. t. in a single portion and stirred at r. t. for additional 2 h. Reaction mixture was quenched with saturated NaHCO3solution (30 mL) and extracted with diethylether (2 x 30 mL). Combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (2% MeOH in dichloromethane) to obtain the compound 23 (0.54 g, 63%) as an off-white solid.

[0430] TLC analysis: 20:1 , CH2CI2: MeOH, Rt : 0,35 (Stain: Ninhydrin / UV).

[0431] 1H NMR (400 MHz, CDCI3): δ = 7.90 (d, J = 8.1 Hz, 1 H), 7.84-7.90 (m, 1 H), 7.76-7.84 (m, 1 H), 7.46-7.57 (m, 2H), 7.38-7.45 (m, 2H), 4.92 (d, J = 5.7 Hz, 2H), 3.89 (s, 2H), 2.88 (s, 3H), 1.26 (bs, 9H).

[0432] 13C NMR (101 MHz, CDCI3): δ = 134.0, 133.4, 131.4, 128.9, 126.8, 126.6, 126.1 , 125.5, 123.5, 80.9, 53.5, 41.6, 35.9, 28.2.

[0433] ESI-HRMS: C19H24N2O3 [M+H]+ calc. 351.1685, found 351.1685.

[0434] 2-(Methylamino)-N-(naphthalen-1-ylmethyl)acetamide (24)

[0435] To the compound 23 (0.100 g, 0.304 mmol, 1.0 eq) in dichloromethane (2 mL) was added TFA (0.5 mL) at room temperature and stirred for 16 h. The reaction mixture was quenched into saturated NaHCO3solution (25 mL), extracted with CH2CI2 (2 x 30mL). Combined organic layers were dried over anhydrous NaaSCU, filtered and concentrated under reduced pressure. The compound 24 (54 mg, 78%) was obtained as a colorless liquid that was used in next step without any further purification.

[0436] TLC analysis: 10:1 , CH2CI2: MeOH, Rf : 0,15 (Stain: Ninhydrin / UV).

[0437] 2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)-N-(naphthalen-1-ylmethyl) acetamide (SW-C112)

[0438] To the compound 23 (0.054 g, 0.236 mmol, 1.0 eq.) in THF (2 mL) was added 1- naphthaldehyde (0.042 g, 0.236 mmol, 1.0 eq.) and acetic acid (0.028 mL, 0.473 mmol, 2.0 eq.) at r. t. under nitrogen. The reaction mixture was stirred for 5 min and NaBH(OAc)3 (0.075 g, 0.355 mmol, 1.5 eq.) was added in one portion, stirred overnight at r. t., quenched by the saturated NaHCO3solution (25 mL) and extracted with dichloromethane (2 x 25 mL). Combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The crude compound was purified by column chromatography (PE: EtOAc, 3:2) to obtain the compound 23 (76 mg, 64%) as a colorless liquid.

[0439] TLC analysis: 2:3, EtOAc: PE Rf: 0,35 (Stain: UV / KMnO4).

[0440] 1H NMR (400 MHz, CDCI3): δ = 8.01 (d, J = 8.1 Hz, 1 H), 7.86-7.91 (m, 1 H), 7.79-7.86 (m, 1 H), 7.48-7.59 (m, 2H), 7.41-7.48 (m, 2H), 7.37 (bs, 1 H), 6.79 (d, J = 3.6 Hz, 1 H), 6.53 (d, J = 3.6 Hz, 1 H), 4.83 (d, J = 5.8 Hz, 2H), 3.61 (s, 2H), 3.18 (s, 2H), 2.25 (s, 3H).

[0441] 13C NMR (101 MHz, CDCI3): δ =170.0, 143.3, 134.0, 133.6, 131.5, 129.4, 128.9, 128.7, 126.8, 126.7, 126.6, 126.1 , 125.5, 123.5, 111.9, 60.1 , 56.8, 43.2, 41.4. ESI-HRMS: C19H19BrN2OS [M+H]+ calc. 403.0480, found 403.0478.

[0442] / V-Benzyl-N-(tert-butoxycarbonyl)glycine (25)

[0443] To a cold (-20°C) suspension of NaH 60% in oil (1.60 g, 30.825 mmol, 3.0 eq.) in THF (30 mL) was added a solution of Boc-glycine (1.80 g, 10.275 mmol, 1.0 eq.) in THF (20 mL) over a period of 30 min. Thereafter, benzyl bromide (14.06 g, 82.199 mmol, 8.0 eq.) was added drop wise and the cooling bath was removed after 15 min. The reaction mixture was stirred at r. t. for 1 h and then heated at reflux for 16 h. The resulting mixture was cooled to 0°. H2O (~10 mL) was added dropwise over a 30 min period. After another 30 min, H2O (50 mL) was added. The mixture was washed with hexane (3 x 50 mL). 1 N Aqueous HCI (14 mL) was slowly added, followed by the addition of 4N aqueous HCI (300 mL). The resulting solution was extracted with EtOAc (25 mL) and then CH2CI2 (3 x 25 mL). The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered through diatomaceous earth and concentrated under reduced pressure to give the compound 25 (2.30 g, 84%) as a yellow solid.

[0444] TLC analysis: 10:1 , CH2CI2: MeOH, Rt : 0,2 (Stain: Ninhydrin / UV). tert-Butyl benzyl(2-(benzylamino)-2-oxoethyl)carbamate (26)

[0445] To the compound 25 (0.500 g, 1.879 mmol, 1.0 eq.) in THF (5 mL) was added TEA (0.79 mL, 5.639 mmol, 3.0 eq.) under nitrogen atmosphere at 0 °C. Isobutylchloroformate (0.293 mL, 2.255 mmol, 1.20 eq.) was added drop wise at 0 °C. The reaction mixture was stirred for 2 h at r. t. and benzyl amine (0.205 mL, 1.879 mmol, 1.0 eq.) was added at r. t. in a single portion and stirred at r. t. for additional 2 h. The reaction was quenched with saturated NaHCO3 solution (30 mL). The mixture was extracted with CH2CI2 (2 x 30 mL). Combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (1 :99, MeOH: DCM) to obtain compound 26 (0.625 g, 93%) as a colorless solid.

[0446] TLC analysis: 20:1 , CH2CI2: MeOH, Rf: 0,60 (Stain: Ninhydrin / UV).

[0447] 1H NMR (400 MHz, CDC13): δ = 7.10-7.40 (m, 10H), 4.50 (s, 2H), 4.37 (bs, 2H), 3.87 (bs, 2H), 1.43 (bs, 9H).

[0448] 13C NMR (101 MHz, CDC13): δ = 137.3, 128.9, 128.8, 127.8, 81.4, 51.2, 43.5, 28.4.

[0449] ESI-HRMS: C21H26N2O3 [M+Na]+ calc. 377.1841 , found 377.1841.

[0450] N-Benzyl-2-(benzylamino)acetamide (27)

[0451] To the compound 26 (0.120 g, 0.338 mmol, 1.0 eq) in dichloromethane (4 mL) was added TFA (0.8 mL) at r. t. and the reaction mixture was stirred for 16 h. The reaction was quenched with saturated NaHCO3solution (50 mL), extracted with CH2CI2 (2 x 50mL). Combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The compound 27 (85 mg, quant.) was obtained as a colorless liquid which was used in next step without any further purification.

[0452] TLC analysis: 50:1. CH2CI2: MeOH, Rf: 0.25 (Stain: Ninhydrin / UV).

[0453] 1H NMR (400 MHz, CDC13): δ = 7.55 (bs, 1 H), 7.18-7.40 (m, 10H), 4.46 (d, J = 6.0 Hz, 2H), 3.76 (s, 2H), 3.36 (s, 2H).

[0454] 13C NMR (101 MHz, CDC13): δ = 171.4, 139.3, 138.5, 128.8, 128.7, 128.2, 127.8, 127.6, 127.5, 54.1 , 52.0, 43.1.

[0455] ESI-HRMS: C16H18N2O [M+H]+ calc. 255.1497, found 255.1499.

[0456] A / -Benzy l-2-(benzy l(2,6-dibromobenzy l)amino)acetamide (SW-C183)

[0457] SW-C183 To the compound 27 (0.025 g, 0.098 mmol, 1.0 eq.) in THF (1 mL) was added 2,6- dibromobenzaldehyde (0.026 mL, 0.098 mmol, 1.0 eq.) and acetic acid (0.012 mL, 0.196 mmol, 2.0 eq.) at r. t. under nitrogen. The mixture was stirred for 5 min and NaBH(OAc)s (0.031 g, 0.147 mmol, 1.5 eq.) was added in one portion. The reaction mixture was stirred overnight at r. t.. The reaction was quenched into saturated NaHCOa solution (20 mL), extracted with diethylether (2 x 25 mL). Combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified using column chromatography (PE: EtOAc, 3:1) to obtain compound SW-C183 (25 mg, 51 %) as a white solid.

[0458] TLC analysis: 1 :3. EtOAc: PE Rf: 0,35 (Stain: UV / KMnO4).

[0459] 1H NMR (400 MHz, CDC13): δ = 7.40-7.59 (m, 2H), 7.17-7.39 (m, 8H), 7.06-7.17 (m, 2H), 6.89-7.00 (m, 1 H), 4.18 (d, J = 5.9 Hz, 2H), 4.02 (s, 2H), 3.73 (s, 2H), 3.23 (s, 2H).

[0460] 13C NMR (101 MHz, CDC13): δ = 171.0, 138.2, 137.2, 136.1 , 133.8, 132.9, 132.6, 130.4, 129.9, 128.7, 128.5, 128.0, 127.8, 127.4, 127.1 , 60.8, 59.1 , 56.5, 43.1. ESI-HRMS: C23H22Br2N2O [M+H]+ calc. 501.0177, found 501.0176.

[0461] 2-(((5-Bromothiophen-2-yl)methyl)(methyl)amino)-N-(4- (trifluoromethyl)benzyl)acetamide (SW-C247)

[0462] To a stirring solution of the compound 4 (94 mg, 0.356 mmol, 1 eq) in dry DMF (2 mL) was added DIPEA (186 μL, 138 mg, 1.068 mmol, 3 eq) and HATU (162 mg, 0.427 mmol, 1.2 eq). After 10 minutes, 4-(trifluoromethyl)benzylamine (61 μL, 75mg, 0.427 mmol, 1.2 eq) was added and the solution was stirred for 20 h at r. t. under argon atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3x30 mL). Combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, washed with DCM and concentrated under reduced pressure. The residue was purified by RP-flash chromatography and product containing fractions were lyophilised to yield the product as a yellow oil.1H NMR (500 MHz, CD3OD) δ 7.62 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 3.7 Hz, 1 H), 6.78 (dt, J = 3.7, 0.9 Hz, 1 H), 4.49 (s, 2H), 3.79 (s, 2H), 3.11 (s, 2H), 2.36 (s, 3H).

[0463] 13C NMR (125 MHz, CD3OD) δ 173.54, 145.11 , 144.84, 130.87, 129.17, 128.42, 126.53 (m), 112.72, 60.39, 57.45, 43.49, 43.42.

[0464] MS (ESI) calculated for Ci6Hi7BrF3N2OS (M + H+): 421 / 423, found: 421 / 423.

[0465] N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-chloroacetamide

[0466] Piperonylamine (120 mg, 0.79 mmol) was dissolved in DCM (2 ml), a solution of chloroacetic anhydride (171 mg) in DCM (1 ml) was added, and the solution was stirred (r. t., 17h). The solution was diluted with DCM (28 ml), washed with saturated aqueous

[0467] NaHCO3(3 x 20 ml) then brine (20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (131 mg) was carried through without further purification or characterisation.

[0468] 2-chloro-N-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)acetamide

[0469] (2,2-difluorobenzo[d][1 ,3]dioxol-5-yl)methanamine (59 mg, 0.31 mmol) was dissolved in DCM (2 ml), a solution of chloroacetic anhydride (68 mg, 0.4 mmol) in DCM (0.4 ml) was added, and the solution was stirred (r. t, 17h). The solution was diluted with DCM (28 ml), washed with saturated aqueous NaHCO3(3 x 20 ml) then brine (20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (72 mg) was carried through without further purification or characterisation. 2-chloro-N-(4-chlorobenzyl)acetamide

[0470] 4-Chlorobenzylamine (85 mg, 0.6 mmol) was dissolved in DCM (2 ml), a solution of chloroacetic anhydride (128 mg, 0.75 mmol) in DCM (0.75 ml) was added, and the solution was stirred (r. t., 17h). The solution was diluted with DCM (28 ml), washed with saturated aqueous NaHCOa (3 x 20 ml) then brine (20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (108 mg) was carried through without further purification or characterisation.

[0471] N-(4-bromobenzyl)-2-chloroacetamide

[0472] 4-Bromobenzylamine (73 mg, 0.39 mmol) was dissolved in DCM (2 ml), a solution of chloroacetic anhydride (119 mg, 0.7 mmol) in DCM (0.7 ml) was added, and the solution was stirred (r. t., 17h). The solution was diluted with DCM (28 ml), washed with saturated aqueous NaHCO3 (3 x 20 ml) then brine (20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (64 mg) was carried through without further purification or characterisation.

[0473] 2-chloro-N-(4-fluorobenzyl)acetamide

[0474] 4-Fluorobenzylamine (40 mg, 0.32 mmol) was dissolved in DCM (2 ml), a solution of chloroacetic anhydride (68 mg, 0.4 mmol) in DCM (0.4 ml) was added, and the solution was stirred (r. t, 17h). The solution was diluted with DCM (28 ml), washed with saturated aqueous NaHCO3 (3 x 20 ml) then brine (20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (59 mg) was carried through without further purification or characterisation.

[0475] 2-chloro-N-(3,5-dichlorobenzyl)acetamide

[0476] 3,5-Dichlorobenzylamine (99 mg, 0.56 mmol) was dissolved in DCM (2 ml), a solution of chloroacetic anhydride (102 mg, 0.6 mmol) in DCM (0.6 ml) was added, and the solution was stirred (r. t., 17h). The solution was diluted with DCM (28 ml), washed with saturated aqueous NaHCO3(3 x 20 ml) then brine (20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (127 mg) was carried through without further purification or characterisation.

[0477] 2-chloro-N-(4-(trifluoromethyl)benzyl)acetamide

[0478] 4-Trifluoromethylbenzylamine (150 mg, 0.86 mmol) was dissolved in DCM (2 ml), a solution of chloroacetic anhydride (153 mg, 0.9 mmol) in DCM (0.9 ml) was added, and the solution was stirred (r. t., 17h). The solution was diluted with DCM (28 ml), washed with saturated aqueous NaHCO3(3 x 20 ml) then brine (20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (190 mg) was carried through without further purification or characterisation.

[0479] 2-chloro-N-(3,4-dichlorobenzyl)acetamide

[0480] 3,4-Dichlorobenzylamine (121 mg, 0.69 mmol) was dissolved in DCM (2 ml), a solution of chloroacetic anhydride (120 mg, 0.7 mmol) in DCM (0.7 ml) was added, and the solution was stirred (r. t., 17h). The solution was diluted with DCM (28 ml), washed with saturated aqueous NaHCO3 (3 x 20 ml) then brine (20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (158 mg) was carried through without further purification or characterisation.

[0481] 2-chloro-N-(4-iodobenzyl)acetamide

[0482] 4-lodobenzylamine (81 mg, 0.35 mmoll) was dissolved in DCM (2 ml), a solution of chloroacetic anhydride (85 mg, 0.5 mmol) in DCM (0.5 ml) was added, and the solution was stirred (r. t, 17h). The solution was diluted with DCM (28 ml), washed with saturated aqueous NaHCO3(3 x 20 ml) then brine (20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (85 mg) was carried through without further purification or characterisation.

[0483] 2-chloro-N-(4-(trifluoromethoxy)benzyl)acetamide

[0484] 4-Trifluoromethoxybenzylamine (59 mg, 0.31 mmol) was dissolved in DCM (2 ml), a solution of chloroacetic anhydride (68 mg, 0.4 mmol) in DCM (0.4 ml) was added, and the solution was stirred (r. t., 17h). The solution was diluted with DCM (28 ml), washed with saturated aqueous NaHCO3(3 x 20 ml) then brine (20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (61 mg) was carried through without further purification or characterisation.

[0485] 2-chloro-N-(2-methoxybenzyl)acetamide 2-Methoxybenzylamine (70 mg,) was dissolved in DCM (2 ml), a solution of chloroacetic anhydride (120 mg, 0.7 mmol) in DCM (0.7 ml) was added, and the solution was stirred (r. t, 17h). The solution was diluted with DCM (28 ml), washed with saturated aqueous NaHCO3(3 x 20 ml) then brine (20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (83 mg) was carried through without further purification or characterisation.

[0486] 2-chloro-N-(3-fluorobenzyl)acetamide

[0487] 3-fluorobenzylamine (57 mg, 0.46) was dissolved in DCM (2 ml), a solution of chloroacetic anhydride (120 mg, 0.7 mmol) in DCM (0.7 ml) was added, and the solution was stirred (r. t, 17h). The solution was diluted with DCM (28 ml), washed with saturated aqueous NaHCO3(3 x 20 ml) then brine (20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (80 mg) was carried through without further purification or characterisation.

[0488] 2-bromo-N-(4-chlorobenzyl)acetamide

[0489] 4-Chlorobenzylamine (250 mg, 1.34 mmol) was dissolved in DCM (20 ml), a solution of bromoacetyl bromide (0.12 ml, 1.38 mmol) in DCM (10 ml) was added, and the solution was stirred (r. t, 17h). The solution was diluted with DCM (28 ml), washed with saturated aqueous NaHCOa (3 x 30 ml) then brine (20 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (289 mg) was carried through without further purification or characterisation.

[0490] 2-amino-N-(4-chlorobenzyl)acetamide

[0491] 4-Chlorobenzylamine (0.135 ml, 1.11 mmol) was added to a solution of Boc-Gly-OSu (252 mg, 0.92 mmol) in DCM (10 ml) and the resulting mixture was stirred (r. t., 16 h). The reaction mixture was then diluted with DCM (30 ml), washed with sat. aq. NaHCOs (3 x 20 ml), brine (10 ml), dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography (EtOAc / cHex 1 :1) and carried through without characterisation. The resulting solid was dissolved in DCM (0.5 ml), cooled in an ice bath, TFA (1 ml) was added, and the solution was stirred (0 °C, 4 h). Concentration of the reaction mixture under reduced pressure and repeated coevaporation from methanol provided the title compound as a low melting solid (153 mg, 84 %).

[0492] MS (ESI) calculated for C9H11CIN2O (M + H+): 199, found: 199.

[0493] General procedure 1

[0494] A mixture of (5-bromothiophen-2-yl)methanamine hydrochloride (15 mg, 0.066 mmol), triethylamine (10 pl, 0.072 mmol), toluene (0.5 ml) and the corresponding chloroacetamide (0.08 mmol) in dry acetonitrile (2.5 ml) was placed in an oven-dried microwave vial (5 ml) with a stirrer bar under an argon atmosphere and the vial was sealed. This reaction mixture was subjected to microwave irradiation (Biotage Initiator) to achieve 160 °C for 90 min. The resulting mixture was concentrated under reduced pressure, the residue was purified by preparative HPLC, and the fractions containing pure product were lyophilised.

[0495] 2-(((5-bromothiophen-2-yl)methyl)amino)-N-(4-chlorobenzyl)acetamide (SW- C298)

[0496] SW-C298

[0497] Following general procedure 1 provided the title compound (8 mg, 32%).

[0498] 1H NMR (700 MHz, CD3OD) δ 7.33 - 7.30 (m, 2H), 7.28 - 7.24 (m, 2H), 6.93 (d, J = 3.7 Hz, 1 H), 6.77 (d, J = 3.7 Hz, 1 H), 4.38 (s, 2H), 3.92 (s, 2H), 3.31 (s, 2H).

[0499] 13C NMR (176 MHz, CD3OD) δ 167.99, 138.48, 137.63, 134.38, 132.03, 131.81 , 130.48, 129.82, 115.37, 49.67, 46.58, 43.58.

[0500] MS (ESI) calculated for Ci4Hi5BrCIN2OS (M + H+): 373 / 375, found: 373 / 375

[0501] 2-(((5-bromothiophen-2-yl)methyl)amino)-N-((2,2-difluorobenzo[d][1,3]dioxol-5- yl)methyl)acetamide (SW-C293)

[0502] SW-C293

[0503] Following general procedure 1 provided the title compound (7 mg, 25%).

[0504] 1H NMR (700 MHz, CD3OD) δ 7.15 - 7.12 (m, 2H), 7.10 - 7.07 (m, 1 H), 6.92 (d, J = 3.7 Hz, 1H), 6.76 (d, J = 4.1 Hz, 1 H), 4.39 (s, 2H), 3.92 (s, 2H), 3.31 - 3.29 (m, 2H).

[0505] MS (ESI) calculated for C15H14BrF2N2O3S (M + H+): 419 / 421 , found: 419 / 421.

[0506] N-(4-bromobenzyl)-2-(((5-bromothiophen-2-yl)methyl)amino)acetamide (SW-

[0507] C294)

[0508] SW-C294

[0509] Following general procedure 1 provided the title compound (9 mg, 33%).

[0510] 1H NMR (700 MHz, CD3OD) δ 7.47 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 3.7 Hz, 1 H), 6.88 (d, J = 3.7 Hz, 1 H), 4.37 (s, 2H), 4.10 (s, 2H), 3.49 (s, 2H).

[0511] 13C NMR (176 MHz, CD3OD) δ 171.05, 142.11 , 139.16, 132.81 , 131.39, 130.73, 129.82, 122.19, 113.75, 50.28, 47.76, 43.49.

[0512] MS (ESI) calculated for CuHi5Br2N2OS (M + H+): 417 / 419 / 421 , found: 417 / 419 / 421.

[0513] 2-(((5-bromothiophen-2-yl)methyl)amino)-N-(4-fluorobenzyl)acetamide (SW- C295)

[0514] SW-C295

[0515] Following general procedure 1 provided the title compound (6 mg, 26%).

[0516] 1H NMR (700 MHz, CD3OD) δ 7.32 - 7.25 (m, 2H), 7.06 - 7.01 (m, 2H), 6.92 (d, J =

[0517] 3.7 Hz, 1 H), 6.75 (d, J = 3.7 Hz, 1 H), 4.37 (s, 2H), 3.90 (s, 2H), 3.29 (s, 2H).

[0518] MS (ESI) calculated for CuHuBrFNsOS (M + H+): 357 / 359, found: 357 / 359.

[0519] 2-(((5-bromothiophen-2-yl)methyl)amino)-N-(3,5-dichlorobenzyl)acetamide (SW- C297)

[0520]

[0521] SW-C297

[0522] Following general procedure 1 provided the title compound (13 mg, 48 %).

[0523] 1H NMR (700 MHz, CD3OD) δ 7.34 - 7.31 (m, 1H), 7.28 - 7.25 (m, 2H), 6.95 (d, J = 3.7 Hz, 1 H), 6.81 (d, J = 3.7 Hz, 1 H), 4.37 (s, 2H), 3.99 (s, 2H), 3.38 (s, 2H).

[0524] 13C NMR (176 MHz, CD3OD) δ 173.20, 144.94, 144.26, 136.32, 131.12, 128.38, 128.33, 127.34, 112.75, 51.16, 48.48, 43.05.

[0525] MS (ESI) calculated for CuHuBrCbtoOS (M + H+): 407 / 409 / 411 , found: 407 / 409 / 411.

[0526] 2-(((5-bromothiophen-2-yl)methyl)amino)-N-(4- (trifluoromethyl)benzyl)acetamide (SW-C299)

[0527] SW-C299

[0528] Following general procedure 1 provided the title compound (13 mg, 48%).

[0529] 1H NMR (700 MHz, CD3OD) δ 7.62 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 3.7 Hz, 1 H), 6.80 (d, J = 3.7 Hz, 1 H), 4.48 (s, 2H), 3.98 (s, 2H), 3.38 (s, 2H).

[0530] MS (ESI) calculated for C15H15BrF3N2OS (M + H+): 407 / 409, found: 407 / 409.

[0531] 2-(((5-bromothiophen-2-yl)methyl)amino)-N-(3,4-dichlorobenzyl)acetamide (SW- C300)

[0532] SW-C300

[0533] Following general procedure 1 provided the title compound (11 mg, 41 %)

[0534] 1H NMR (700 MHz, CD3OD) δ 7.48 - 7.45 (m, 2H), 7.21 (dd, J = 8.2, 1.9 Hz, 1 H), 6.96 (d, J = 3.7 Hz, 1 H), 6.82 (d, J = 3.7 Hz, 1 H), 4.37 (s, 2H), 4.00 (s, 2H), 3.39 (s, 2H).

[0535] 13C NMR (176 MHz, CD3OD) δ 172.83, 144.53, 141.02, 133.49, 132.19, 131.79, 131.17, 130.79, 128.63, 112.91 , 51.05, 48.40, 42.94.

[0536] MS (ESI) calculated for Ci4Hi4BrCI2N2OS (M + H+): 407 / 409 / 411 , found: 407 / 409 / 411

[0537] 2-(((5-bromothiophen-2-yl)methyl)amino)-N-(4-iodobenzyl)acetamide (SW-C302)

[0538] SW-C302

[0539] Following general procedure 1 provided the title compound (8.3 mg, 27%).

[0540] H NMR: 7.70-7.65 (m, 2H), 7.10-7.04 (m, 3H), 6.97-6.94 (m, 1 H), 4.36 (s, 2H), 4.24 (s, 2H), 3.63 (s, 2H).

[0541] 13C NMR (126 MHz, CD3OD) δ 169.13, 139.60, 139.31 , 138.95, 131.65, 131.21 , 130.92, 114.78, 93.42, 47.01 , 43.67.

[0542] MS (ESI) calculated for CuHi5BrlN2OS (M + H+): 465 / 467, found: 465 / 467. 2-(((5-bromothiophen-2-yl)methyl)amino)-N-(4-

[0543] (trifluoromethoxy)benzyl)acetamide (SW-C303)

[0544] SW-C303

[0545] Following general procedure 1 provided the title compound (15 mg, 54%).

[0546] 1H NMR (500 MHz, CD3OD) δ 7.39 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.05 (d, J = 3.7 Hz, 1 H), 6.96 (d, J = 3.7 Hz, 1 H), 4.43 (s, 2H), 4.24 (s, 2H), 3.64 (s, 2H).

[0547] MS (ESI) calculated for C15H15BrF3N2O2S (M + H+): 423 / 425, found: 423 / 425.

[0548] 2-(((5-bromothiophen-2-yl)methyl)amino)-N-(2-methoxybenzyl)acetamide (SW- C305)

[0549] SW-C305

[0550] Following general procedure 1 provided the title compound (7 mg, 29 %).

[0551] 1H NMR (500 MHz, CD3OD) δ 7.30 - 7.20 (m, 2H), 7.11 (d, J = 3.8 Hz, 1 H), 7.05 (d, J = 3.8 Hz, 1 H), 6.97 (d, J = 8.2 Hz, 1H), 6.90 (td, J= 7.4, 1.0 Hz, 1H), 4.41 (s, 4H), 3.85 (s, 3H), 3.79 (s, 2H).

[0552] 13C NMR (126 MHz, CD3OD) δ 166.16, 159.02, 135.25, 133.18, 132.01 , 130.36, 130.29, 126.86, 121.58, 116.19, 111.61 , 55.98, 48.01 , 45.87, 39.96.

[0553] MS (ESI) calculated for Ci5Hi8BrN2O2S (M + H+): 369 / 371 , found: 369 / 371. 2-(((5-bromothiophen-2-yl)methyl)amino)-N-(3-fluorobenzyl)acetamide (SW- C312)

[0554] SW-C312

[0555] Following general procedure 1 provided the title compound (9.5 mg, 40%).

[0556] 1H NMR (500 MHz, CD3OD) δ 7.34 (td, J = 7.9, 6.0 Hz, 1 H), 7.15 - 7.09 (m, 2H), 7.09 - 7.03 (m, 2H), 7.00 (td, J = 8.4, 2.3 Hz, 1 H), 4.43 (s, 4H), 3.84 (s, 2H).

[0557] MS (ESI) calculated for Ci4Hi5BrFN2OS (M + H+): 357 / 359, found: 357 / 359.

[0558] N-(4-chlorobenzyl)-2-(((5-methoxythiophen-2-yl)methyl)amino)acetamide (SW- C323)

[0559] SW-C323

[0560] 5-Methoxythiophene-2-carbaldehyde (29 mg, 0.20 mmol) was added to a solution of 2-amino-N-(4-chlorobenzyl)acetamide (30 mg, 0.151 mmol) in THF (0.5 ml) and the solution was stirred (r. t., 18 h). The mixture was cooled in an ice bath, sodium borohydride (20 mg, 5.3 mmol) was added, and the mixture was stirred (r. t, 3 h). Acetone (0.5 ml), DI water (0.5 ml), and acetic acid (0.5 ml) were sequentially added, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to provide the title compound (14 mg, 28%).1H NMR (500 MHz, CD3OD) δ 7.36 - 7.21 (m, 4H), 6.54 (d, J = 3.8 Hz, 1H), 6.03 (d, J = 3.8 Hz, 1 H), 4.37 (s, 2H), 3.82 (s, 3H), 3.78 (d, J = 0.8 Hz, 2H), 3.28 (s, 2H).

[0561] 13C NMR (126 MHz, CD3OD) δ 174.19, 167.50, 138.92, 134.13, 130.33, 130.29, 129.73, 124.87, 103.82, 60.66, 51.47, 43.28.

[0562] MS (ESI) calculated for Ci5Hi7CIN2NaO2S (M + Na+): 347, found: 347.

[0563] N-(4-chlorobenzyl)-2-((4-iodobenzyl)amino)acetamide (SW-C308)

[0564] SW-C308

[0565] Caesium carbonate (30 mg, 0.09 mmol) was added to a solution of 2-bromo-N-(4- chlorobenzyl)acetamide (20 mg, 0.08 mmol) and 4-iodobenzylamine (37 mg, 0.159 mmol) in DMF (1 ml), and this mixture was stirred (r. t., 16 h). The mixture was filtered, purified by preparative HPLC, and the fractions containing pure product were lyophilised to provide the title compound (14 mg, 44 %).

[0566] 1H NMR (500 MHz, CD3OD) δ 7.83 (d, J = 8.1 Hz, 2H), 7.36 - 7.19 (m, 6H), 4.40 (s, 2H), 4.20 (s, 2H), 3.82 (s, 2H).

[0567] 13C NMR (126 MHz, CD3OD) δ 166.27, 139.75, 138.35, 134.42, 133.23, 131.96, 130.51 , 129.84, 96.75, 51.58, 48.42, 43.63.

[0568] MS (ESI) calculated for Ci6Hi7CIIN2O (M + H+): 415, found: 415.

[0569] N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-((4-iodobenzyl)amino)acetamide (SW- C309)

[0570]

[0571] SW-C309

[0572] Caesium carbonate (30 mg, 0.09 mmol) was added to a solution of N- (benzo[d][1 ,3]dioxol-5-ylmethyl)-2-chloroacetamide (22 mg, 0.1 mmol) and 4- iodobenzylamine (37 mg, 0.159 mmol) in DMF (1 ml), and this mixture was stirred (r. t., 16 h). The mixture was filtered, directly purified by preparative HPLC, and the fractions containing pure product were lyophilised to provide the title compound (11 mg, 27 %).

[0573] 1H NMR (500 MHz, CD3OD) δ 7.69 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 6.82 - 6.77 (m, 1H), 6.77 - 6.72 (m, 2H), 5.92 (s, 2H), 4.29 (s, 2H), 3.82 (s, 2H), 3.38 (s, 2H).

[0574] 13C NMR (126 MHz, CD3OD) δ 171.88, 149.45, 148.49, 139.07, 138.44, 133.74, 132.14, 122.20, 109.32, 109.23, 102.53, 94.17, 53.16, 51.17, 43.93.

[0575] MS (ESI) calculated for C17H18IN2O3 (M + H+): 425, found: 425.

[0576] 2-((4-bromobenzyl)amino)-N-(4-chlorobenzyl)acetamide (SW-C314)

[0577] SW-C314

[0578] A mixture of 4-Bromobenzylamine (40 mg, 0.21 mmol) and 2-bromo-N-(4- chlorobenzyl)acetamide (26 mg, 0.1 mmol) in THF (4 ml) was placed in an oven-dried microwave vial (5 ml) with a stirrer bar under an argon atmosphere and the vial was sealed. This reaction mixture was subjected to microwave irradiation (Biotage Initiator) to achieve 150 °C for 90 min. The resulting mixture was concentrated under reduced pressure, the residue was purified by preparative HPLC, and the fractions containing pure product were lyophilised to provide the title compound (19 mg, 52%).

[0579] 1H NMR (500 MHz, CD3OD) δ 7.47 - 7.43 (m, 2H), 7.33 - 7.29 (m, 2H), 7.27 - 7.23 (m, 4H), 4.36 (s, 2H), 3.71 (s, 2H), 3.26 (s, 2H).

[0580] 13C NMR (126 MHz, CD3OD) δ 174.12, 140.12, 138.95, 134.13, 132.69, 131.59, 130.32, 129.73, 122.08, 53.67, 52.11 , 43.27.

[0581] MS (ESI) calculated for Ci6Hi7BrCIN2O (M + H+): 367 / 369, found: 367 / 369.

[0582] N-(4-bromobenzyl)-2-((4-bromobenzyl)amino)acetamide (SW-C316)

[0583] SW-C316

[0584] Caesium carbonate (100 mg, 0.3 mmol) was added to a solution of 2-bromo-N-(4- bromobenzyl)acetamide (50 mg, 0.19 mmol) and 4-bromo benzylamine (93 mg, 0.5 mmol) in DMF (1 ml), and this mixture was stirred (r. t., 16 h). The mixture was filtered, directly purified by preparative HPLC, and the fractions containing pure product were lyophilised to provide the title compound (16 mg, 20 %).

[0585] 1H NMR (500 MHz, CD3OD) δ 7.49 - 7.44 (m, 4H), 7.28 - 7.24 (m, 2H), 7.22 - 7.18 (m, 2H), 4.36 (s, 2H), 3.72 (s, 2H), 3.28 (s, 2H).

[0586] 13C NMR (126 MHz, CD3OD) δ 174.10, 140.09, 139.44, 132.76, 132.70, 131.60, 130.65, 122.09, 122.06, 53.66, 52.10, 43.32.

[0587] MS (ESI) calculated for Ci6Hi7Br2N2O (M + H+): 411 / 413 / 415, found: 411 / 413 / 415.

[0588] 2-((4-bromo-3-fluorobenzyl)amino)-N-(4-chlorobenzyl)acetamide (SW-C317)

[0589] SW-C317

[0590] Caesium carbonate (130 mg, 0.4 mmol) was added to a solution of 2-bromo-N-(4- chlorobenzyl)acetamide (60 mg, 0.23 mmol) and 3-Bromo-4-fluorobenzylamine hydrochloride (72 mg, 0.3 mmol) in DMF (1 ml), and this mixture was stirred (r. t, 16 h). The mixture was filtered, directly purified by preparative HPLC, and the fractions containing pure product were lyophilised to provide the title compound (15 mg, 17 %).

[0591] 1H NMR (700 MHz, CD3OD) δ 7.54 - 7.50 (m, 1H), 7.32 - 7.28 (m, 2H), 7.26 - 7.21 (m, 3H), 7.09 - 7.05 (m, 1H), 4.37 (s, 2H), 3.74 (s, 2H), 3.27 (s, 2H).

[0592] MS (ESI) calculated for Ci6Hi6BrCIFN2O (M + H+): 385 / 387, found: 385 / 387.

[0593] 2-((4-bromobenzyl)(ethyl)amino)-N-(4-chlorobenzyl)acetamide (SW-C324)

[0594] SW-C324

[0595] 2-bromo-N-(4-chlorobenzyl)acetamide (35 mg, 0.133 mmol) was added to ethylamine in THF (2 M, 1 ml, 2 mmol), the solution was stirred (36 h, r. t.) and then concentrated to dryness and coevaporated with toluene (3 x 2 ml). The residue was taken up in MeOH (2 ml), 4-bromobenzaldehyde (67 mg 0.36 mmol) and sodium cyanoborohydride (33 mg, 0.52 mmol) were added, and the mixture was stirred (60 h, r. t.). The reaction mixture was then diluted with sat. aq. NaHCO3(20 ml), extracted with EtOAc (3 x 20 ml), the organic layers were combined and washed with brine (20 ml), dried over sodium sulfate, filtered, and concentrated to dryness. Flash chromatography of the residue on silica gel (EtOAc / cHex + 0.1% EtsN 1 :9-1 :1) provided the title compound (23 mg, 44%).

[0596] 1H NMR (500 MHz, CD3OD) δ 7.40 (d, J = 8.4 Hz, 2H), 7.27 (dd, J = 10.8, 8.4 Hz, 4H), 7.16 (d, J = 8.6 Hz, 2H), 4.33 (s, 2H), 3.59 (s, 2H), 3.08 (s, 2H), 2.59 (q, J = 7.2 Hz, 2H), 1.08 (t, J = 7.2 Hz, 3H).

[0597] 13C NMR (126 MHz, CD3OD) δ 174.36, 139.21 , 139.01 , 134.07, 132.65, 132.33, 130.21 , 129.70, 122.19, 59.47, 57.96, 50.64, 43.09, 12.51.

[0598] MS (ESI) calculated for C18H21BrCIN2O (M + H+): 395 / 397, found: 395 / 397.

[0599] N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-((5-bromothiophen-2- yl)methoxy)acetamide (SW-C292)

[0600] SW-C292

[0601] Sodium borohydride (20 mg, 0.53 mmol) was added to a solution of 5-bromothiophene- 2-carbaldehyde (45 mg, 0.235 mmol) in THF (5 ml), and the mixture was stirred (r. t., 2h). Acetone (0.5 ml) and then DI H2O (20 ml) were added and the mixture was extracted with EtOAc (3 x 20 ml). The combined organic phases were washed with brine (10 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (40 mg) was dissolved in THF (1 ml) and cooled in an ice bath. Potassium t-butoxide (27 mg, 0.22 mmol) was added and the mixture was stirred (10 min), then N-(benzo[d][1 ,3]dioxol-5-ylmethyl)-2-chloroacetamide (68 mg 0.3 mmol) was added and the mixture was stirred (4 h, r. t.). The reaction mixture was diluted with EtOAc (30 ml), washed with DI H2O (3 x 20 ml) and brine (10 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by column chromatography (EtOAc / cHex 15:85 to 3:2) provided the title compound (33 mg, 37%).1H NMR (700 MHz, CDCI3) δ 6.93 (d, J = 3.7 Hz, 1 H), 6.80 - 6.70 (m, 5H), 5.96 (s, 1H), 4.64 (s, 2H), 4.38 (d, J = 6.0 Hz, 2H), 4.02 (s, 2H).

[0602] 13C NMR (126 MHz, CDCI3) δ 168.82, 147.91, 147.03, 140.84, 131.66, 129.61, 127.77, 121.12, 113.39, 108.40, 108.31, 101.08, 68.98, 67.70, 42.69.

[0603] MS (ESI) calculated for CisHisBrNCUS (M + H+): 384 / 386, found: 384 / 386.

[0604] N-(4-chlorobenzyl)-2-((1-(5-iodothiophen-2-yl)ethyl)amino)acetamide (SW-C318)

[0605] SW-C318

[0606] 2-Amino-N-(4-chlorobenzyl)acetamide (44 mg, 0.22 mmol) was added to a solution of 1-(5-iodothiophen-2-yl)ethenone (103 mg, 0.41 mmol) in MeOH (5 ml), and stirred (11 days, r. t.). Pyrrolidine (20 pl) was added and the solution was stirred (r. t., 2 days). The solution was cooled (0 °C), sodium borohydride (20 mg, 0.53 mmol) was added, and the solution was allowed to reach room temperature while stirred (18 h). Acetone (0.5 ml), DI water (0.5 ml), and acetic acid (0.5 ml) were sequentially added, and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (5 ml), basified by the addition of triethylamine, concentrated under reduced pressure, and the residue purified by column chromatography (iPrOH / EtOAc / cHex + 0.1% EtsN 1:1:8 to 1:3:6) to provide the title compound (13 mg, 14%).

[0607] 1H NMR (500 MHz, CD3OD) δ 7.35-7.30 (m, 2H), 7.27-7.23 (m, 2H), 7.08 (d, J = 3.6 Hz, 1 H), 6.65 (dd, J = 3.6, 0.6 Hz, 1H), 4.41 - 4.35 (m, 2H), 4.08 (q, J = 6.5 Hz, 1H), 3.22 (q, J = 16.6 Hz, 2H), 1.42 (d, J = 6.6 Hz, 3H).

[0608] MS (ESI) calculated for C15H17CIIN2OS (M + H+): 435, found: 435. (R)-2-(( 1 -(4-bromophenyl)ethyl)amino)-N-(4-chlorobenzyl)acetamide (SW-C321 )

[0609] SW-C321

[0610] 2-bromo-N-(4-chlorobenzyl)acetamide (40 mg, 0.152 mmol) was added to (R)-(+)-1- (4-bromophenyl)ethylamine (0.1 ml) and the solution was stirred (70 °C, 34 h). Dilution of the reaction mixture with DMSO (0.7 ml) and acetic acid (0.2 ml), filtration, direct purification by preparative HPLC, and lyophilisation of the fractions containing pure product provided the title compound (32 mg, 55 %)

[0611] 1H NMR (500 MHz, CD3OD) δ 7.46 - 7.40 (m, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.27 - 7.20 (m, 4H), 4.34 (q, J = 15.0 Hz, 2H), 3.73 (q, J = 6.6 Hz, 1 H), 3.18 - 3.03 (m, 2H), 1.33 (d, J = 6.6 Hz, 3H).

[0612] 13C NMR (126 MHz, CD3OD) δ 174.31 , 145.31 , 138.94, 134.11 , 132.79, 130.31 , 130.08, 129.71 , 121.93, 58.93, 50.99, 43.23, 24.16.

[0613] MS (ESI) calculated for Ci7Hi9BrCIN2O (M + H+): 381 / 383, found: 381 / 383.

[0614] Further, the following compounds have been tested in the assays below:

[0615] Biology

[0616] Strains, plasmids, and growth conditions All Salmonella strains were derived from Salmonella enterica subsp. enterica serovar Typhimurium SL1344 (Hoiseth, S, Stocker, B. 1981 “Aromatic-dependent Salmonella Typhimurium are non-virulent and effective as live vaccines” Nature 291 , 238-239). See table 1.

[0617] S. Typhimurium strains were cultured with low aeration at 37 °C in Luria Bertani (LB) medium with tetracycline (12.5 mg / ml) when required.

[0618] Escherichia coli pir116 was cultured at 37 °C in LB medium.

[0619] Plasmids pMIB5779 and pMIB7640 (table 2) were generated by Gibson cloning (Gibson, D., Young, L., Chuang, RY. et al. Enzymatic assembly of DNA molecules up to several hundred kilobases. Nat Methods 6, 343-345 (2009). https: / / doi.org / 10.1038 / nmeth.1318) using Q5 polymerase (New England Biolabs, USA) according to manufacturer’s instructions.

[0620] Plasmid pMIB7644 (table 2) was generated by QuickChange protocol (Agilent, USA) using KOD polymerase (Novagen®, Merck, Germany) according to manufacturer’s instructions.

[0621] Plasmid pMIB7640 was used to generate plasmid pMIB7644 which was then used to insert the gene coding for sfGFP downstream of hilA promoter by allelic exchange as previously described (Kaniga, Bossio, & Galan, Molecular Microbiology, Volume 13, Issue 4, 1994, Pages 555-568. https: / / onlinelibrary.wiley.eom / doi / 10.1111 / j.1365- 2958.1994.tb00450.x), resulting in the strain MIB5600.

[0622] Plasmid pMIB5779 was used to generate a hilD knockout mutant in MIB5600 strain background by allelic exchange as previously described (Kaniga, Bossio, & Galan, 1994. https: / / onlinelibrary.wiley.com / doi / 10.1111 / j.1365-2958.1994.tb00450.x), resulting in strain MIB5633.

[0623] Synthetic primers (table 3) were designed from the available complete sequence of S. Typhimurium SL1344 (https: / / doi.orq / 10.1073 / pnas.1201061109) (NCBI Reference Sequence: NC_016810.1) for primers 3, 4, 5, 6, 9, 10, 11 , 12, 13 and 14; from the sequence of pSB890 (Kaniga, 1994) (GenBank: GU321683.1 ) for primers 1 and 2; and from the sequence of sfGFP from pUC18T-mini-Tn7T-Apr-sfGFP (Ducas-Mowchun, K., De Silva, P. M., Crisostomo, L, Fernando, D. M., Chao, T.-C., Pelka, P., Schweizer, H. P., & Kumar, A. (2019). Next Generation of Tn 7 -Based Single-Copy Insertion Elements for Use in Multi- and Pan-Drug-Resistant Strains of Acinetobacter baumannii. Applied and Environmental Microbiology, 85(11)) (GenBank: MH976505.1) for primers 7 and 8.

[0624] Table 1. Strains

[0625] Table 2. Plasmids

[0626] Table 3. Primers.

[0627] HilD activity assay

[0628] A cell-based reporter gene assay was used to quantify HilD transcriptional activity. Reporter gene assays have been used in several studies to monitor HilD activity through the activation of hilA promoter (https: / / doi.org / 10.1038 / s41589-022-01122-3, https: / / journals.asm.Org / doi / 10.1128 / mbio.00012-23, https: / / doi.org / 10.1128%2FIAI.02506-14, https: / / doi.org / 10.1128 / IAI.71.9.5432- 5435.2003, https: / / doi.Org / 10.1111 / j.1574-695X.2000.tb01453.x).

[0629] Strain MIB5600 (P / j / w-sfGFP) and strain MIB5633 (khilD, Pww-sfGFP) were used for this purpose.

[0630] Cultures were performed in 1 ml LB supplemented with 0.3 M NaCL Inoculation was performed with 1 % from an overnight culture. Compounds at different concentrations or 1 % (v / v) DMSO were added to the corresponding tubes. Cultures were incubated at 37 °C, 180 rpm, for 5 h. Cells were then pelleted then resuspended in 100 pl PBS and transferred into a 96-well black, clear bottom plate (Thermo scientific, USA). Fluorescence intensity was measured with TECAN Spark® microplate reader with an excitation wavelength of 485 nm and emission wavelength of 510 nm. Dose-response curves and IC50 values were calculated using CDD Vault®.

[0631] Toxicity assay

[0632] Toxicity was assessed in HeLa cells (ATCC® CCL-2) using the ApoTox-Glo™ Triplex Assay (Promega, USA) according to manufacturer’s instructions. HeLa cells (104cells per well) were seeded into a 96-well plate and incubated 24 h at 37 °C, 5 % (v / v) CO2. HeLa cells were then treated with a compound at 100 pM or 1 % (v / v) DMSO in DMEM without phenol red for 14 h. Fluorescence intensity was measured with TECAN Spark® microplate reader. Cytotoxicity (%) and viability (%) values were determined relative to the control condition (1 % (v / v) DMSO) and were calculated using CDD Vault®.

[0633] Abbreviations

[0634] LB. Luria Bertani

[0635] PBS. Phosphate buffered saline nm. Nanometers

[0636] DMEM. Dulbecco's Modified Eagle Medium Results

[0637] Table 4 (HilD activity)

[0638] Table 5 (Toxicity)

Claims

Claims1 . A compound of formula (la):whereinAr is an optionally substituted arylene group; or an optionally substituted heteroarylene group;X is CHR4; NH; O; or a bond;R4is hydrogen; an alkyl group; or a heteroalkyl group;Y is NR3; O; or S;R1is an optionally substituted aryl group; or an optionally substituted heteroaryl group;R2is a halogen; or a C1-4 heteroalkyl group;R5is hydrogen or a methyl group;L is CH2; CHR6; CH2CH2; or a bond; andR3is hydrogen; an alkyl group; or a benzyl group; orL and R3together are part of a monocyclic or bicyclic cycloalkyl group; andR6is a C1-4 alkyl group or a C1-4 heteroalkyl group; or a salt thereof; for use in the treatment or prophylaxis of Salmonella infections (salmonellosis).

2. A compound for use according to claim 1, wherein R4is hydrogen or an alkyl group.

3. A compound for use according to claim 1 or 2, wherein Y is NR3.

4. A compound for use according to any one of the preceding claims, wherein R2is Br; Cl; I; or a C1-4 heteroalkyl group.

5. A compound for use according to any one of the preceding claims, wherein R6is methyl; CH2OH; CH2SH; or CH2CH2NH2.

6. A compound for use according to any one of the preceding claims, wherein L is CH2; CHMe; or CH2CH2.

7. A compound for use according to any one of the preceding claims, wherein R5is hydrogen.

8. A compound of formula (I):whereinAr is an optionally substituted arylene group; or an optionally substituted heteroarylene group;X is CHR4; NH; O; or a bond;R4is hydrogen; or an alkyl group;R1is an optionally substituted aryl group; or an optionally substituted heteroaryl group;R2is Br; Cl; or a C1-4 heteroalkyl group;L is CH2; CHMe; or CH2CH2; andR3is hydrogen; an alkyl group; or a benzyl group; orL and R3together are part of a monocyclic or bicyclic cycloalkyl group; or a salt thereof; for use in the treatment or prophylaxis of Salmonella infections (salmonellosis).

9. A compound for use according to any one of the preceding claims, wherein Ar is an optionally substituted phenylene group; or an optionally substituted heteroarylene group comprising 5 or 6 ring atoms that are independently selected from C, O, S and N.

10. A compound for use according to any one of the preceding claims, wherein Ar is the following group:

11. A compound for use according to any one of the preceding claims, wherein R4is hydrogen; methyl; or CH2OH; preferably hydrogen or methyl.

12. A compound for use according to any one of the preceding claims, wherein X is CH2.

13. A compound for use according to any one of the preceding claims, wherein R2is Br.

14. A compound for use according to any one of the preceding claims, wherein L is CH2.

15. A compound for use according to any one of the preceding claims, wherein R3is hydrogen or a C1-4 alkyl group.

16. A compound for use according to any one of the preceding claims, wherein R3is hydrogen; methyl; or ethyl; preferably a methyl group.

17. A compound for use according to claim 1 , 2, 8, 11 , 15 or 16, having the following formula (II):or a salt thereof.

18. A compound for use according to any one of the preceding claims, wherein R1is an optionally substituted phenyl group; an optionally substituted naphthyl group; or an optionally substituted heteroaryl group comprising 5 to 10 ring atoms that are independently selected from C, O, S and N.

19. A compound for use according to any one of the preceding claims, wherein R1is an optionally substituted phenyl group; or an optionally substituted heteroaryl group comprising 5 or 6 ring atoms that are independently selected from C, O, S and N.

20. A compound for use according to any one of the preceding claims, wherein R1is an optionally substituted phenyl group; or an optionally substituted naphthyl group; preferably an optionally substituted phenyl group.

21. A pharmaceutical composition for use in the treatment or prophylaxis of Salmonella infections (salmonellosis) comprising a compound for use according to anyone of the preceding claims and optionally one or more carrier substances and / or one or more adjuvants and / or one or more further antibacterial compounds.

22. Use of a compound of formula (la):whereinAr is an optionally substituted arylene group; or an optionally substituted heteroarylene group;X is CHR4; NH; O; or a bond;R4is hydrogen; an alkyl group; or a heteroalkyl group;Y is NR3; O; or S;R1is an optionally substituted aryl group; or an optionally substituted heteroaryl group;R2is a halogen; or a C1-4 heteroalkyl group;R5is hydrogen or a methyl group;L is CH2; CHR6; CH2CH2; or a bond; andR3is hydrogen; an alkyl group; or a benzyl group; orL and R3together are part of a monocyclic or bicyclic cycloalkyl group; andR6is a C1-4 alkyl group or a C1-4 heteroalkyl group; or a salt thereof; for the preparation of a medicament for the treatment or prophylaxis of Salmonella infections (salmonellosis).

23. The use according to claim 22, wherein R4is hydrogen or an alkyl group.

24. The use according to claim 22 or 23, wherein Y is NR3.

25. The use according to any one of the preceding claims 22 to 24, wherein R2isBr; Cl; I; or a C1-4 heteroalkyl group.

26. The use according to any one of the preceding claims 22 to 25, wherein R6is methyl; CH2OH; CH2SH; or CH2CH2NH2.

27. The use according to any one of the preceding claims 22 to 26, wherein L is CH2; CHMe; or CH2CH2.

28. The use according to any one of the preceding claims 22 to 27, wherein R5is hydrogen.

29. Use of a compound of formula (I):whereinAr is an optionally substituted arylene group; or an optionally substituted heteroarylene group;X is CHR4; NH; O; or a bond;R4is hydrogen; or an alkyl group;R1is an optionally substituted aryl group; or an optionally substituted heteroaryl group;R2is Br; Cl; or a C1-4 heteroalkyl group;L is CH2; CHMe; or CH2CH2; andR3is hydrogen; an alkyl group; or a benzyl group; orL and R3together are part of a monocyclic or bicyclic cycloalkyl group; or a salt thereof; for the preparation of a medicament for the treatment or prophylaxis of Salmonella infections (salmonellosis).

30. The use according to any one of the preceding claims 22 to 29, wherein Ar is an optionally substituted phenylene group; or an optionally substituted heteroarylene group comprising 5 or 6 ring atoms that are independently selected from C, O, S and N.

31. The use according to any one of the preceding claims 22 to 30, wherein Ar is the following group:

32. The use according to any one of the preceding claims 22 to 31 , wherein R4is hydrogen; methyl; or CH2OH; preferably hydrogen or methyl.

33. The use according to any one of the preceding claims 22 to 32, wherein X is CH2.

34. The use according to any one of the preceding claims 22 to 33, wherein R2is Br.

35. The use according to any one of the preceding claims 22 to 34, wherein L is CH2.

36. The use according to any one of the preceding claims 22 to 35, wherein R3is hydrogen or a C1-4 alkyl group.

37. The use according to any one of the preceding claims 22 to 36, wherein R3is hydrogen; methyl; or ethyl; preferably a methyl group.

38. The use according to claim 22, 23, 29, 32, 36 or 37, wherein the compound has the following formula (II):or a salt thereof.

39. The use according to any one of the preceding claims 22 to 38, wherein R1is an optionally substituted phenyl group; an optionally substituted naphthyl group; or an optionally substituted heteroaryl group comprising 5 to 10 ring atoms that are independently selected from C, O, S and N.

40. The use according to any one of the preceding claims 22 to 39, wherein R1is an optionally substituted phenyl group; or an optionally substituted heteroaryl group comprising 5 or 6 ring atoms that are independently selected from C, O, S and N.

41. The use according to any one of the preceding claims 22 to 40, wherein R1is an optionally substituted phenyl group; or an optionally substituted naphthyl group; preferably an optionally substituted phenyl group.

42. A method for the treatment or prophylaxis of Salmonella infections (salmonellosis) in a subject which comprises administering to the subject an effective amount of a compound of formula (la):whereinAr is an optionally substituted arylene group; or an optionally substituted heteroarylene group;X is CHR4; NH; O; or a bond;R4is hydrogen; an alkyl group; or a heteroalkyl group;Y is NR3; O; or S;R1is an optionally substituted aryl group; or an optionally substituted heteroaryl group;R2is a halogen; or a C1-4 heteroalkyl group;R5is hydrogen or a methyl group;L is CH2; CHR6; CH2CH2; or a bond; andR3is hydrogen; an alkyl group; or a benzyl group; orL and R3together are part of a monocyclic or bicyclic cycloalkyl group; andR6is a C1-4 alkyl group or a C1-4 heteroalkyl group; or a salt thereof.

43. The method according to claim 42, wherein R4is hydrogen or an alkyl group.

44. The method according to claim 42 or 43, wherein Y is NR3.

45. The method according to any one of the preceding claims 42 to 44, wherein R2is Br; Cl; I; or a C1-4 heteroalkyl group.

46. The method according to any one of the preceding claims 42 to 45, wherein R6is methyl; CH2OH; CH2SH; or CH2CH2NH2.

47. The method according to any one of the preceding claims 42 to 46, wherein L is CH2; CHMe; or CH2CH2.

48. The method according to any one of the preceding claims 42 to 47, wherein R5is hydrogen.

49. A method for the treatment or prophylaxis of Salmonella infections (salmonellosis) in a subject which comprises administering to the subject an effective amount of a compound of formula (I):(I) whereinAr is an optionally substituted arylene group; or an optionally substituted heteroarylene group;X is CHR4; NH; O; or a bond;R4is hydrogen; or an alkyl group;R1is an optionally substituted aryl group; or an optionally substituted heteroaryl group;R2is Br; Cl; or a C1-4 heteroalkyl group;L is CH2; CHMe; or CH2CH2; andR3is hydrogen; an alkyl group; or a benzyl group; orL and R3together are part of a monocyclic or bicyclic cycloalkyl group; or a salt thereof.

50. The method according to any one of the preceding claims 42 to 49, wherein Ar is an optionally substituted phenylene group; or an optionally substituted heteroarylene group comprising 5 or 6 ring atoms that are independently selected from C, O, S and N.

51. The method according to any one of the preceding claims 42 to 50, wherein Ar is the following group:

52. The method according to any one of the preceding claims 42 to 51 , wherein R4is hydrogen; methyl; or CH2OH; preferably hydrogen or methyl.

53. The method according to any one of the preceding claims 42 to 52, wherein X is CH2.

54. The method according to any one of the preceding claims 42 to 53, wherein R2is Br.

55. The method according to any one of the preceding claims 42 to 54, wherein L is CH2.

56. The method according to any one of the preceding claims 42 to 55, wherein R3is hydrogen or a C1-4 alkyl group.

57. The method according to any one of the preceding claims 42 to 56, wherein R3is hydrogen; methyl; or ethyl; preferably a methyl group.

58. The method according to claim 42, 43, 49, 52, 56 or 57, wherein the compound has the following formula (II):or a salt thereof.

59. The method according to any one of the preceding claims 42 to 58, wherein R1is an optionally substituted phenyl group; an optionally substituted naphthyl group; or an optionally substituted heteroaryl group comprising 5 to 10 ring atoms that are independently selected from C, O, S and N.

60. The method according to any one of the preceding claims 42 to 59, wherein R1is an optionally substituted phenyl group; or an optionally substituted heteroaryl group comprising 5 or 6 ring atoms that are independently selected from C, O, S and N.

61. The method according to any one of the preceding claims 42 to 60, wherein R1is an optionally substituted phenyl group; or an optionally substituted naphthyl group; preferably an optionally substituted phenyl group.

62. A compound selected from the following compounds:SW-C112 SW-C18363. A compound selected from the following compounds:

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