WO2014125075A1 - Albicidin derivatives, their use and synthesis - Google Patents

Albicidin derivatives, their use and synthesis Download PDF

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Publication number
WO2014125075A1
WO2014125075A1 PCT/EP2014/052922 EP2014052922W WO2014125075A1 WO 2014125075 A1 WO2014125075 A1 WO 2014125075A1 EP 2014052922 W EP2014052922 W EP 2014052922W WO 2014125075 A1 WO2014125075 A1 WO 2014125075A1
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WIPO (PCT)
Prior art keywords
unsubstituted
substituted
och
independently
alkyl
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PCT/EP2014/052922
Other languages
French (fr)
Inventor
Roderich SÜßMUTH
Julian KRETZ
Vivien SCHUBERT
Alexander PESIC
Manuela HÜGELLAND
Monique Royer
Stéphane COCIANCICH
Phillipe ROTT
Dennis KERWAT
Stefan GRÄTZ
Original Assignee
Technische Universität Berlin
Centre De Cooperation Internationale En Recherche Agronomique Pour Le Developpement (Cirad)
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Application filed by Technische Universität Berlin, Centre De Cooperation Internationale En Recherche Agronomique Pour Le Developpement (Cirad) filed Critical Technische Universität Berlin
Priority to CA2901576A priority Critical patent/CA2901576C/en
Priority to CN201480019427.4A priority patent/CN105143176B/en
Priority to EP14712606.4A priority patent/EP2956437B1/en
Priority to JP2015557442A priority patent/JP6474736B2/en
Priority to US14/768,323 priority patent/US10308595B2/en
Publication of WO2014125075A1 publication Critical patent/WO2014125075A1/en

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    • C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
    • C07C255/44—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms at least one of the singly-bound nitrogen atoms being acylated
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    • C07C2601/00—Systems containing only non-condensed rings
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    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • Albicidin derivatives their use and synthesis
  • Albicidin has been initially described as an antibiotic substance derived from Xanthomonas albilineans, a protobacterial sugarcane pathogen (US patent 4,525,354 to Birch and Patil, incorporated by reference herein).
  • ⁇ -albicidin Since its first description in 1985, ⁇ -albicidin has eluded structural determination in spite of its interesting properties, namely its antibiotic activity against gram-negative bacteria, a group which encompasses many medically important pathogens such as, for example, Escherichia coli, Salmonella, Shigella, Pseudomonas, Moraxella, Helicobacter, Stenotrophomonas, Neisseria, Hemophilus and Legionella.
  • pathogens such as, for example, Escherichia coli, Salmonella, Shigella, Pseudomonas, Moraxella, Helicobacter, Stenotrophomonas, Neisseria, Hemophilus and Legionella.
  • the problem underlying the present invention is the provision of new compounds, which comprise antibiotic properties, a method of their synthesis and their use. This problem is attained by the subject-matter of the independent claims.
  • purity refers to the content of said compound relative to the sum of all compounds contained in the preparation.
  • compound in this context is to be understood as a compound according to the general formula 1 (or any specific embodiments thereof) as well as any salts, hydrates or solvates thereof. Thus, the respective salts, hydrates or solvents are not considered as impurities according to the previous definition.
  • the "purity" of a compound may be determined using elemental analysis, HPLC analysis using UV diode array detection also in combination with mass spectrometry detection, or quantitative NMR analysis.
  • DIPEA is ⁇ , ⁇ -Diisopropylethylamine (CAS No. 7087-68-5).
  • HATU is (Dimethylamino)-/V,/V- dimethyl(3H-[1 ,2,3]triazolo[4,5-ib]pyridin-3-yloxy)methaniminium hexafluorophosphate (CAS No. 148893-10-1 ).
  • TEA is Triethylamine (CAS No. 121 -44-8).
  • BTC is Bis(trichloromethyl) carbonate (CAS No. 32315-10-9).
  • PFP is Pentafluorophenole (CAS No. 771 -61 -9).
  • PNP is para-nitrophenol (CAS No. 100-02-7).
  • HONB N-Hydroxy-5-norbornene-2,3-dicarboximide (CAS No. 21715-90-2).
  • NHS is N-hydroxysuccinimidyl (CAS No
  • Benzotriazolyloxytris-(dimethylamino)-phosphonium hexafluorophosphate (CAS No. 56602- 33-6).
  • pyBOP is Benzotriazol-1 -yl-oxy-tripyrrolidinophosphonium hexafluorophosphate (CAS No. 128625-52-5).
  • HBTU is N,N,N',N'-Tetramethyl-0-(1 H-benzotriazol-1 -yl)uronium hexafluorophosphate (CAS No. 94790-37-1 ).
  • DCC is ⁇ /,/V-Dicyclohexylcarbodiimide (CAS No. 538-75-0).
  • DIC is ⁇ /,/V-Dicyclopropylcarbodiimide (CAS No. 693-13-0)
  • EDC is 1 -Ethyl-3- (3-dimethylaminopropyl)carbodiimide (CAS No. 25952-53-8, 22572-40-3, 1892-57-5).
  • TFFH Fluoro- ⁇ , ⁇ , ⁇ ,N -tetramethylformamidinium hexafluorophosphate (CAS. No. 164298-23-1 ).
  • DEPT is 3-(Diethoxyphosphoryloxy)-1 ,2,3-benzotriazin-4(3H9-one (CAS No. 165534-43-0).
  • a protecting group in the context of the present specification is a group employed to reduce the reactivity of a particular moiety.
  • Protecting groups are well known to the person skilled in the art of organic chemistry. P. G. M. Wuts, "Greene's Protective Groups in Organic
  • PGH is a suitable protection group for hydroxyl groups known in the art.
  • PGA is a suitable protection group for carboxylic acid groups known in the art.
  • PGN is a suitable protection group for a NH 2 moiety of for example amino or amide groups known in the art.
  • a NH 2 moiety will be described as an amino moiety irrespective of the further parts of the compound.
  • M is a so called masked functional group such as - without being limited to - a -N0 2 group or a -N 3 group.
  • a masked functional group can be reduced under certain conditions to an -NH 2 functional group but does not interfere with the coupling reactions of an acid partner with an amino partner, as discussed further below.
  • Protecting groups for use as PGN, PGH or PGA groups herein include, but are not limited to: (i) ethers such as methyl, substituted methyl (methoxymethyl, methylthiomethyl,
  • An activated carboxylic acid moiety in the context of the present specification relates to a carboxylic acid (COOH) derivative that undergoes amidation (condensation with an amine moiety) with primary or secondary under conditions that allow for the preservation of other chemical functionalities present in either reaction partner.
  • Preferred reaction conditions are pH 4-9 and temperatures in the range of about -30° C to of about
  • activated carboxylic acid moieties examples include pentafluorophenol (PFP) esters, para- nitrophenol (PNP) esters, 2,4,5-trichlorophenol esters, N-Hydroxy-5-norbornene-2,3- dicarboximide (HONB) esters, N-hydroxy-succinimidyl (NHS) ester, carboxylic acid chloride
  • PFP pentafluorophenol
  • PNP para- nitrophenol
  • HONB 2,4,5-trichlorophenol esters
  • N-Hydroxy-5-norbornene-2,3- dicarboximide (HONB) esters N-hydroxy-succinimidyl (NHS) ester
  • carboxylic acid chloride examples include pentafluorophenol (PFP) esters, para- nitrophenol (PNP) esters, 2,4,5-trichlorophenol esters, N-Hydroxy-5-norbornene-2,3- dicarboximi
  • acyl chloride carboxylic acid fluoride
  • carboxylic acid bromide acyl bromide
  • triphenylphosphine and tetrachloromethane Fluoro- ⁇ , ⁇ , ⁇ ,N -tetramethylformamidinium hexafluorophosphate (TFFH) or cyanuric fluoride, benzotriazole esters or carbodiimide esters, generated by use of the carboxylic acid and coupling agents such as
  • HBTU Tetramethyl-0-(1 H-benzotriazol-1 -yl)uronium hexafluorophosphate
  • HATU Tetramethyl-0-(1 H-benzotriazol-1 -yl)uronium hexafluorophosphate
  • HATU Tetramethyl-0-(1 H-benzotriazol-1 -yl)uronium hexafluorophosphate
  • HATU Tetramethyl-0-(1 H-benzotriazol-1 -yl)uronium hexafluorophosphate
  • DCC Dicyclohexylmethandiimin
  • DIC ⁇ , ⁇ '-Diisopropylcarbodiimide
  • EDC 1 -Ethyl-3-(3- dimethylaminopropyl)carbodiimide
  • Carbonic anhydrides may be synthesized by use of coupling reagents, such as - without being limited to - 1 ,1 '-Carbonyldiimidazol (CDI), 1 ,1 ' -carbonylbis(3- methylimidazoliumtriflate) (CBMIT) and the before mentioned coupling agents or from carboxylic acid and acid chloride (e.g. pivaloylchloride), or from carboxylic acid and chloroformates (e.g. ethyl chloroformate).
  • anhydrides may be synthesized from carboxylic acid and 2-ethoxy-1 -ethoxycarbonyl-1 ,2-dihydroquinoline (EDDQ)
  • Coupling agents to achieve activated carboxylic moieties may further be - without being limited to - AOP (7-Azabenzotriazol-1 -yloxytris(dimethylamino)phosphonium
  • imidazolium agents may be employed to achieve activated carboxylic moieties, whereby examples of imidazolium agents are - without being limited to - BOI (2- (benzotriazol-1 -yl)oxy-1 ,3-dimethylimidazolidinium hexafluorophosphate - CAS 123377-20-8) or CMBI (2-chloro-1 ,3-dimethyl 1 H-benzimidazoliumhexafluorophosphate).
  • the coupling reactions may be supported by addition of bases or acylation catalysts such as - without being limited to - (/V,/V-Diisopropylethylamine) (DIEA), N-Methylmorpholine (NMM), 4-Dimethylaminopyridine (DMAP), 2,4,6-Trimethylpyridine (sym-collidine) or 2,6-di- tert-butyl-4-dimethylaminopyridine (DBDMAP).
  • bases or acylation catalysts such as - without being limited to - (/V,/V-Diisopropylethylamine) (DIEA), N-Methylmorpholine (NMM), 4-Dimethylaminopyridine (DMAP), 2,4,6-Trimethylpyridine (sym-collidine) or 2,6-di- tert-butyl-4-dimethylaminopyridine (DBDMAP).
  • DIEA N-Methylmorpholine
  • bases may be added, in particular the above mentioned bases, in order to prevent a removal of the protecting group due to acidic by products.
  • the coupling reaction may be catalyzed by addition of acylation catalysts as DMAP.
  • the carboxylic acid moiety may be activated by using a catalytic amount of a proton acid or a Lewis acid such as - without being limited to - boronic acid catalyst.
  • the coupling reactions may also be achieved by the azide coupling method using diphenyl phosphorazidate (DPPA) or alternative azides.
  • DPPA diphenyl phosphorazidate
  • substituted refers to the addition of a substituent group to a parent moiety.
  • Substituent groups can be protected or unprotected and can be added to one available site or to many available sites in a parent moiety. Substituent groups may also be further substituted with other substituent groups and may be attached directly or by a linking group such as an alkyl, an amide or hydrocarbyl group to a parent moiety.
  • sulfinyl (-S(0)R b ), sulfonyl (-S(0) 2 R b ), sulfonamidyl (-S(0) 2 N(R b )(R c )or -N(R b )S(0) 2 R b ) and fluorinated compounds -CH 2 CF 3 , -CHFCF 3 , -CF 2 CF 3 , -CHF 2 , -CH 2 F, -CF 3 , -OCF 3 , -SCF 3 , -SOCF 3 or -S0 2 CF 3 .
  • each R a , R b and R c is, independently, H or a further substituent group with a preferred list including without limitation, H, alkyl, alkenyl, alkynyl, aliphatic, alkoxy, acyl, aryl, heteroaryl, alicyclic, heterocyclic and heteroarylalkyl.
  • alkyl refers to a saturated straight or branched hydrocarbon moiety containing up to 8, particularly up to 4 carbon atoms.
  • alkyl groups include, without limitation, methyl, ethyl, propyl, butyl, isopropyl, n-hexyl, octyl, and the like.
  • Alkyl groups typically include from 1 to about 8 carbon atoms (CrC 8 alkyl), particularly with from 1 to about 4 carbon atoms (Ci-C 4 alkyl).
  • cycloalkyi refers to an interconnected alkyl group forming a saturated or unsaturated ring or polyring structure containing 3 to 10, particularly 5 to 10 carbon atoms.
  • examples of cycloalkyi groups include, without limitation, cyclopropane, cyclopentane, cyclohexane, norbornane, decaline or adamantan (Tricyclo[3.3.1 .1 ]decan), and the like.
  • Cycloalkyi groups typically include from 5 to 10 carbon atoms (C5-C10 cycloalkyi).
  • Alkyl or cycloalkyi groups as used herein may optionally include further substituent groups.
  • a substitution on the cycloalkyi group also encompasses an aryl, a hetreocylce or a heteroaryl substituent, which can be connected to the cycloalkyi group via one atom or two atoms of the cycloalkyi group (like tetraline).
  • haloalkyi refers to a saturated straight or branched hydrocarbon moiety containing 1 to 8, particularly 1 to 4, carbon atoms and at least one halogen atom, in particular CI or F, connected to a carbon atom.
  • haloalkyi groups include, without limitation, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CHFCF 3 , CHFCHF 2 , CHFCH 2 F, CF 2 CF 3 , CF 2 CHF 2 , CF 2 CH 2 F and the like.
  • Haloalkyi groups typically include 1 to 4 carbon atoms (C1 -C4 haloalkyi). More particularly haloalkyi groups comprise only F as halogen atoms.
  • halo cycloalkyi refers to an interconnected alkyl group forming a saturated or unsaturated ring or polyring structure containing 3 to 10, particularly 5 to 10 carbon atoms and at least one halogen atom, in particular CI or F, connected to a carbon atom.
  • halo cycloalkyi groups include, without limitation, fluorocyclopropane, chlorocyclohexane, dichlorocyclohexane, chloroadamantan, and the like.
  • Halo cycloalkyi groups typically include from 5 to 10 carbon atoms (C5-C10 cycloalkyi). More particularly cyclohaloalkyl groups comprise only F as halogen atoms.
  • Halo alkyl or halo cycloalkyi groups as used herein may optionally include further substituent groups.
  • a substitution on the halo cycloalkyi group also encompasses an aryl, a hetreocylce or a heteroaryl substituent, which can be connected to the halo cycloalkyi group via one atom or two atoms of the halo cycloalkyi group (like tetraline).
  • alkenyl refers to a straight or branched hydrocarbon chain moiety containing up to 8 carbon atoms and having at least one carbon-carbon double bond.
  • alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, 1 -methyl-2- buten-1 -yl, dienes such as 1 ,3-butadiene and the like.
  • Alkenyl groups typically include from 2 to about 8 carbon atoms, more typically from 2 to about 4 carbon atoms. Alkenyl groups as used herein may optionally include further substituent groups.
  • alkynyl refers to a straight or branched hydrocarbon moiety containing up to 8 carbon atoms and having at least one carbon-carbon triple bond.
  • alkynyl groups include, without limitation, ethynyl, 1 -propynyl, 1 -butynyl, and the like.
  • Alkynyl groups typically include from 2 to about 8 carbon atoms, more typically from 2 to about 4 carbon atoms.
  • Alkynyl groups as used herein may optionally include further substituent groups.
  • carboxy groups include without limitation, formate, acetate, lactate, citrate, oxalate and the like.
  • Carboxy groups as used herein may optionally include further substituent groups.
  • Non limiting examples are polyehtylester or polyacrylate.
  • alkoxy refers to an oxygen alkyl moiety containing 1 to 8, particularly 1 to 4 carbon atoms comprising at least one oxygen moiety, wherein the oxygen atom is used to attach the alkoxy group to a parent molecule.
  • alkoxy groups include without limitation, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert- butoxy, n-pentoxy, neopentoxy, n-hexoxy and the like.
  • Alkoxy groups as used herein may optionally include further substituent groups.
  • alkoxy” groups include straight or branched polyalkoxy groups (polyether), which comprise several interconnected momomere alkoxy groups (e. g. -0-CH 2 -CH 2 -).
  • Non limiting examples are polyehtyleneglycol (PEG) or polypropylenglycol (PPG).
  • heterocycle refers to an interconnected alkyl group forming a saturated or unsaturated ring or polyring structure containing 3 to 10, particularly 5 to 10 carbon atoms in which at least one carbon atom is replaced with an oxygen, a nitrogen or a sulphur atom forming a non aromatic structure.
  • heterocycle groups include, without limitation, oxalane, pyrrolidine or piperidine.
  • Heterocyclic groups as used herein may optionally include further substituent groups.
  • a substitution on the heterocyclic group also encompasses an aryl, a cycloalkyl or a heteroaryl substituent, which can be connected to the heterocyclic group via one atom or two atoms of the heterocyclic group (comparable to indole).
  • aryl refers to a hydrocarbon with alternating double and single bonds between the carbon atoms forming an aromatic ring structure, in particular a six (Ce to ten (Cio) membered ring or polyring structure.
  • heteroaryl refers to aromatic structures comprising a five to ten membered ring or polyring structure, comparable to aryl compounds, in which at least one member is an oxygen or a nitrogen or a sulphur atom. Due to simplicity reasons they are denominated C 5 to Cio heteroaryl, wherein at least one carbon atom is replaced with an oxygen, a nitrogen or a sulphur atom forming an aromatic structure.
  • a C 5 heteroaryl comprises a five membered ring structure with at least one carbon atom being replaced with an oxygen, a nitrogen or a sulphur atom.
  • Examples for such a C 5 heteroaryl are triazole, pyrazole, imidazole, thiophen, furan or oxazole.
  • a C 6 heteroaryl can be pyridine, pyrimidine or triazine.
  • a C 9 heteroaryl can be indole and a Cio heteroaryl can be quinoline.
  • Aryl or hetero aryl groups as used herein may optionally include further substituent groups.
  • a substitution on the hetero aryl group also encompasses an aryl, a cycloalkyl or a heterocycle substituent, which can be connected to the hetero aryl via one atom or two atoms of the hetero aryl group (comparable to indole). The same apllies to an aryl group.
  • linker refers to a covalently connected straight chain or a ring structure of carbon, sulphur, nitrogen and/or oxygen atoms connecting a moiety comprising E or R 4 (as defined below) to the parent moiety (termed PM) providing a distance between these moieties.
  • the distance may comprise between 1 up to 5 atoms, in particular 2 or 3 atoms, along the longitudinal extension direction of the parent moiety.
  • the straight chain or the ring structure of the linker atoms may comprise further substituents.
  • the linker may comprise a straight C 4 -chain (butyl) providing a distance of 4 atoms or a methyl group providing a distance of 1 atom.
  • a -N(H)S(0 2 )- group also provides a distance of 2 atoms.
  • the linker may further comprise a ring structure like a triazole providing a distance of 3 atoms along the longitudinal extension direction of the parent moiety.
  • linking function refers to a first linking function and a second linking function capable of selectively forming a covalent bond between each other (linking reaction or coupling reaction).
  • linking reactions may be an organometallic coupling reaction, a Wittig reaction, an addition reaction, a condensation reaction a "click chemistry” reaction or an amide coupling reaction.
  • * indicates a stereo center of a L- or D- enantiomer, which is located on the tertiary carbon atom below the asterisk * , and wherein the compound of a general formula comprising " * " is an essentially pure L-enantiomer, an essentially pure D-enantiomer or a mixture of the L- and D-enantiomer of the same molecular formula, wherein in particular such a compound is an essentially pure L-enantiomer or an essentially pure D-enantiomer.
  • the invention relates to antibiotically active compounds having a molecular structure as defined by formula 1
  • R 4 -D 1 - with R 4 being selected from a substituent group S3, S4 or S5, or iii. BA-D - with BA-D -being selected from
  • E being selected from a substituent group S3, S4 or S5, and
  • BB being selected from a substituent group S3 or S4, and
  • p 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and
  • X 2 being i. selected from a substituent group S1 or S2, and wherein a linker D 5 may be optionally situated between BE and the substituent group S1 or S2, or
  • R aa being selected independently from each other from -R a or -OR a ,
  • R ba being selected independently from each other from -R b or -OR b ,
  • M being a substituted or unsubstituted CrC 8 alkyl, in particular an
  • n is selected from 0, 1 or 2, in particular 0 or 1 ,
  • each R a , R b or R c being selected, where applicable, independently from each other from hydrogen, -CN, a substituent group S3, a substituent group S4 or a substituent group S5,
  • R 2 and R 3 of BA being selected, where applicable, independently from each other from - H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH 3 ) 2 , a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl , in particular from -H, -F, - CN, -OH,
  • R a and R b being selected, where applicable, independently from each other from hydrogen, -CN, a substituent group S3, a substituent group S4 or a substituent group S5,
  • R 8 of -D 2 -BC- being selected from -H, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCF 3 , -CH 2 CF 3 , - CHFCF3, -CF 2 CF 3 , -CHF 2 , -CH 2 F or -CF 3 , in particular with R 8 being selected from H or CH 3 , more particularly R 8 is H.
  • D ,D 2 , D 3 , D 4 or D 5 being each, independently from each other, a linker which comprises carbon, sulphur, nitrogen, phosphor and/or oxygen atoms and which is covalently connecting the moiety, BA and BB (D ), BB and BC (D 2 ), BC and BD (D 3 ), BD and BE (D 4 ) and BE and BF (D 5 ).
  • the invention relates to compounds characterized by the general formula 1 , wherein these compounds comprise no deuterium atoms in their structure.
  • the compounds may comprise one, two or more deuterium atoms (any hydrogen of the structure may be "exchanged") instead of hydrogen atoms. It is also possible that the compounds comprise only deuterium atoms instead of hydrogen atoms (all the H are "exchanged” with deuterium).
  • the invention relates to essentially pure L- and D- enantiomers of the general formula 1 or mixtures of the L- and D-enantiomers of the same molecular formula, whereby the stereo center concerning the building block BC is indicated by an asterisk " * " and located on the tertiary carbon atom below the asterisk.
  • the general formula 1 with the stereo center marked with an asterisk encompasses the essentially pure L- and the D- enantiomers.
  • a second aspect of the invention relates to the synthesis of compounds according to the general formula 1 .
  • a further aspect of the invention relates to compounds according to the invention or obtained by a method according to the invention for use in a method of treatment of diseases, in particular for use in a method of treatment of bacterial infections.
  • the invention relates to antibiotically active compounds having a molecular structure as defined by formula 1
  • R 4 -D 1 - with R 4 being selected from a substituent group S3, S4 or S5, or iii. BA-D - with BA-D -being selected from
  • E being selected from a substituent group S3, S4 or S5, and
  • BB being selected from a substituent group S3 or S4, and
  • p 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and
  • R aa being selected independently from each other from -R a or -OR a ,
  • R ba being selected independently from each other from -R b or -OR b ,
  • M being a substituted or unsubstituted CrC 8 alkyl, in particular an unsubstituted CrC 8 alkyl
  • n is selected from 0, 1 or 2, in particular 0 or 1 ,
  • each R a , R b or R c being selected, where applicable, independently from each other from hydrogen, -CN, a substituent group S3, a substituent group S4 or a substituent group S5,
  • S3 being - a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C 3 - C10 halo cycloalkyl, or
  • R 2 and R 3 of BA being selected, where applicable, independently from each other from - H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH 3 ) 2 , a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl , in particular from -H, -F, - CN, -OH,
  • R a and R b being selected, where applicable, independently from each other from hydrogen, -CN, a substituent group S3, a substituent group S4 or a substituent group S5,
  • R 8 of -D 2 -BC- being selected from -H, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCF 3 , -CH 2 CF 3 , - CHFCF3, -CF 2 CF 3 , -CHF 2 , -CH 2 F or -CF 3 , in particular with R 8 being selected from H or CH 3 , more particularly R 8 is H.
  • D ,D 2 , D 3 , D 4 or D 5 being each, independently from each other, a linker which comprises carbon, sulphur, nitrogen, phosphor and/or oxygen atoms and which is covalently connecting the moiety, BA and BB (D ), BB and BC (D 2 ), BC and BD (D 3 ), BD and BE (D 4 ) and BE and BF (D 5 ).
  • the compound according to the general formula 1 does not include a compound of the general formula 2a
  • R is H or CO(NH 2 ), R 2 is CO(NH 2 ) or CN, R 3 is H or OCH 3 , FN is H 2 N or Ma, wherein Ma is a masked functional group, in particular a -N0 2 or -N 3 moiety, and wherein the -NH 2 , - NH-, -COOH or -OH moieties can comprise a removable protecting group (PGN, PGH or PGA), in particular an allyl moiety and/or an activated carboxylic acid moiety CO act in particular a - COCI moiety.
  • PPN removable protecting group
  • the invention relates to compounds having a molecular structure as defined by a general formula (3),
  • the invention relates to compounds having a molecular structure as defined by a general formula (4),
  • the invention relates to compounds having a molecular structure as defined by a general formula (5),
  • the invention relates to compounds having a molecular structure as defined by a general formula (6),
  • the invention relates to compounds having a molecular structure as defined by a general formula (7),
  • the invention relates to compounds having a molecular structure as defined by a general formula (8),
  • the invention relates to compounds having a molecular structure as defined by a general formula (9),
  • the invention relates to compounds having a molecular structure as defined by a general formula (10),
  • the invention relates to compounds having a molecular structure as defined by a general formula (1 1 ),
  • the invention relates to antibiotically active compounds having a molecular structure as defined by a general formula (12),
  • the invention relates to compounds having a molecular structure as defined by a general formula (13),
  • the invention relates to compounds having a molecular structure as defined by a general formula (14),
  • the invention relates to compounds having a molecular structure as defined by a general formula (15),
  • the invention relates to compounds having a molecular structure as defined by a general formula (16),
  • the invention relates to compounds having a molecular structure as defined by a general formula (17),
  • the invention relates to compounds having a molecular structure as defined by a general formula (18),
  • the invention relates to compounds having a molecular structure as defined by a general formula (19),
  • the invention relates to compounds having a molecular structure as defined by a general formula (20),
  • the invention relates to compounds having a molecular structure as defined by a general formula (21 ),
  • the invention relates to compounds having a molecular structure as defined by a general formula (22),
  • the invention relates to compounds having a molecular structure as defined by a general formula (23),
  • the invention relates to compounds having a molecular structure as defined by a general formula (24),
  • the invention relates to compounds having a molecular structure as defined by a general formula (25),
  • the invention relates to compounds having a molecular structure as defined by a general formula (26),
  • the invention relates to compounds having a molecular structure as defined by a general formula (27),
  • the invention relates to compounds having a molecular structure as defined by a general formula (28),
  • the invention relates to compounds having a molecular structure as defined by a general formula (29),
  • the invention relates to compounds having a molecular structure as defined by a general formula (30),
  • the invention relates to compounds having a molecular structure as defined by a general formula (31 ),
  • the invention relates to compounds having a molecular structure as defined by a general formula (32),
  • the invention relates to compounds having a molecular structure as defined by a general formula (33),
  • the invention relates to compounds having a molecular structure as defined by a general formula (34),
  • m being selected from 0, 1 or 2, in particular 0 or 1 ,
  • each R a , R b or R c being selected, where applicable, independently from each other from
  • a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
  • a substituted or unsubstituted C1 -C16 alkyl a substituted or unsubstituted Cr C16 alkoxy, a substituted or unsubstituted C1 -C16 carboxy, a substituted or unsubstituted C 2 -Ci 6 alkenyl, a substituted or unsubstituted C 2 -Ci 6 alkynyl, or a C1 -C16 haloalkyl, in particular a substituted or unsubstituted CrC 8 alkyl, a substituted or unsubstituted C 2 -C 8 alkenyl, a substituted or unsubstituted C 2 - C 8 alkynyl, or a substituted or unsubstituted CrC 8 haloalkyl.
  • R a being a substituted or unsubstituted C1 -C16 alkyl, a substituted or unsubstituted C1 -C16 alkoxy, a substituted or unsubstituted C1 -C16 carboxy, a substituted or unsubstituted C 2 -Ci 6 alkenyl, a substituted or unsubstituted C 2 -Ci 6 alkynyl, or a C1 -C16 haloalkyl, in particular a substituted or unsubstituted Ci -C 8 alkyl, a substituted or unsubstituted C 2 -C 8 alkenyl, a substituted or unsubstituted C 2 -C 8 alkynyl, or a substituted or unsubstituted CrC 8 haloalkyl, or
  • - R d being -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C 6 H 5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
  • - p1 being selected from 1 to 20, in particular from 1 to 8
  • X is -NR a 2 or -NHR a ,
  • R a being a substituted or unsubstituted CrC 8 alkyl, a substituted or unsubstituted C 2 -C 8 alkenyl, a substituted or unsubstituted C 2 -C 8 alkynyl, or a substituted or unsubstituted CrC 8 haloalkyl.
  • X 1 is R 4 -D 1 -, with D having the same meaning as defined above, and wherein
  • a substituted or unsubstituted C Ci 6 alkyl a substituted or unsubstituted C Ci 6 alkoxy, a substituted or unsubstituted C Ci 6 carboxy, a substituted or unsubstituted C 2 -Ci 6 alkenyl, a substituted or unsubstituted C 2 -Ci 6 alkynyl, or a C Ci 6 haloalkyl, in particular a substituted or unsubstituted Ci-C 8 alkyl, a substituted or unsubstituted Ci-C 8 alkoxy, a substituted or unsubstituted C 2 -C 8 alkenyl, a substituted or unsubstituted C 2 -C 8 alkynyl, a substituted or unsubstituted CrC 8 haloalkyl, a substituted or unsubstituted C 3 -Cio cycloalkyl, or a substituted or unsubstitute
  • a substituted or unsubstituted C 3 -Ci 0 heterocycle or a substituted or unsubstituted C 3 -Ci 0 halo heterocycle in particular a substituted or unsubstituted C 4 -Ci 0 heterocycle or a substituted or unsubstituted C 4 -Cio halo heterocycle, or
  • X 1 is R 4 -D 1 -, with D having the same meaning as defined above, and wherein
  • a substituted or unsubstituted C 5 -C 6 halo heterocycle in particular a C 5 -C 6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F, a substituted or unsubstituted C 5 -C 6 heteroaryl,
  • a substituted C 6 aryl in particular a bicyclic C 6 aryl such as tetraline or indane, a substituted or unsubstituted C 5 -C 6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F; or
  • R 4 is selected from the group of substituted or unsubstituted pyrrole, furan, thiophene, benzothiophene, chromene, thiazole, pyrazine, pyridazine, pyridine, 1 ,2,3-triazole, 1 ,2,4- triazole, imidazole, oxazol, thiazol, indole, isoindole, quinoline, isoquinoline,
  • X 1 is R 4 -D 1 -, with D having the same meaning as defined above, and wherein
  • R 4 is selected from
  • X 1 is R 4 -D 1 -, with D having the same meaning as defined above, and wherein
  • X 1 is BA-D -, with D having the same meaning as defined above, and BA is selected from
  • BA is selected from
  • R 2 and R 3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH 2 , -NO2, -NHCH3, -NH(CH 3 ) 2 , a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyi, in particular with R 2 and R 3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, - NH 2 , -NO2, -NHCH3, -NH(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -OCH3, -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , - OCH(CH 3 ) 2 , -OCF3, -CH 2 CF 3 , -CHFCF3, -CF 2 CF 3 ,
  • Ci -C 8 alkyl a substituted or unsubstituted Ci -C 8 alkyl, a substituted or unsubstituted Ci -C 8 alkoxy, a substituted or unsubstituted C 2 -C 8 alkenyl, a substituted or unsubstituted C 2 -C 8 alkynyl, or a substituted or unsubstituted Ci -C 8 haloalkyl, or
  • C 5 -C 6 halo heterocycle in particular a C 5 -C 6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
  • - selected from the group of substituted or unsubstituted pyrrole, furan, thiophene, benzothiophene, chromene, thiazole, pyrazine, pyridazine, pyridine, 1 ,2,3-triazole, 1 ,2,4-triazole, imidazole, oxazol, thiazol, indole, isoindole, quinoline, isoquinoline, naphatalene, coumarin, aminocoumarin, umbelliferon, benzotriazole, psoralen, benzofurane, benzothiophene, benzimidazol, benzthiazole, benzoxazole or benzpyridazin or hydroxylated, methylated or halogenated derivatives thereof, or is selected from .
  • n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n being 1 , and
  • R aa being selected independently from each other being -R a or -OR a
  • R ba being selected independently from each other being -R b or -OR b
  • M being a substituted or unsubstituted CrC 8 alkyl, in particular an unsubstituted CrC 8 alkyl with m being selected from 0, 1 or 2, in particular 0 or 1 , with q being selected from 0, 1 or 2, in particular 0 or 1 ,
  • each R a , R b or R c being selected, where applicable, independently from each other from
  • C Ci 6 alkoxy a substituted or unsubstituted C Ci 6 carboxy, a substituted or unsubstituted C 2 -Ci 6 alkenyl, a substituted or unsubstituted C 2 -Ci 6 alkynyl, or a C Ci 6 haloalkyl, in particular a substituted or unsubstituted CrC 8 alkyl, a substituted or unsubstituted CrC 8 alkoxy, a substituted or unsubstituted C 2 -C 8 alkenyl, a substituted or unsubstituted C 2 -C 8 alkynyl, a substituted or unsubstituted CrC 8 haloalkyl, a substituted or unsubstituted C 3 - Cio cycloalkyl, or a substituted or unsubstituted C 3 -Cio halo cycloalkyl,
  • each R independently from any other R being -OH, -F, -CI, I, -CN, -OCH 3 , - OCF 3 , -OCONH 2 or -CF 3 .
  • n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly 1 , and
  • each R independently from any other R is selected from - -OH, -F, -CI, -Br, I, -CCH, -CN, -N 3 , -OCH 3 , -OCF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , - CH 3 , -CH 2 -CH 3 , -CF 3 , -OCONH 2 or -N0 2 ,
  • R aa being selected independently from each other being -R a or -OR a
  • R ba being selected independently from each other being -R b or -OR b
  • M being a substituted or unsubstituted CrC 8 alkyl, in particular an unsubstituted CrC 8 alkyl
  • m being selected from 0, 1 or 2, in particular 0 or 1 ,
  • q being selected from 0, 1 or 2, in particular 0 or 1 ,
  • each R a , R b or R c being selected, where applicable, independently from each other from
  • n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n 1 , and
  • R aa being selected independently from each other being -R a or -OR a
  • R ba being selected independently from each other being -R b or -OR b
  • M being a substituted or unsubstituted CrC 8 alkyl, in particular an unsubstituted CrC 8 alkyl
  • m being selected from 0, 1 or 2, in particular 0 or 1 ,
  • q being selected from 0, 1 or 2, in particular 0 or 1 ,
  • each R a , R b or R c being selected, where applicable, independently from each other from hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH2CH2CH2CH3, - CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -C6H5— CH2C6H5.
  • n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly 1 , and
  • C 5 -C 6 halo heterocycle in particular a C 5 -C 6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
  • n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n beingl , and with each R independently from any other R being OH, -F, -CI, -I, -CN, -OCH3, -OCF3, -OCONH 2 or -CF 3 , or
  • n of R n being 5 and R is F, or
  • R n 5
  • R one to four of R being F and the other ones of R being selected independently from any other R from -H, -OH, -CI, -I, -CN, -OCH 3 , -OCF 3 , - OCONH2 or -CF 3 , in particular from -OH, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , or with n of R n being 1 , and R being selected from -OH, -OCH 3 , -OCF 3 , -OCONH2 or - CF 3 , or
  • R n 5
  • R 6
  • R 6
  • R 6
  • R 6
  • n of R n being 2, and each R being selected independently from any other R from -OH, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , or
  • R n 5
  • R 6
  • R 6
  • R 6
  • R 6
  • n of R n being 3, and each R being selected independently from any other R from -OH, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , or
  • n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n being 1 , and with each R independently from any other R being - OH, OCH 3 , -F or -CF 3 .
  • E is with n of R n being 1 , 2, 3, 4 or 5, in particular n of R n being 1 , 2 or 3,
  • R a being a substituted or unsubstituted C Ci 6 alkyl, in particular an unsubstituted C Ci 4 alkyl,
  • - R d being -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C 6 H 5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
  • - p1 being selected from 1 to 20, in particular from 1 to 8,
  • - R d being -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C 6 H 5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
  • - p1 being selected from 1 to 20, in particular from 1 to 8,
  • R aa and R ba being selected, where applicable, independently from each other from -R a or -OR a and
  • R a being hydrogen, -OCH 3 , -OCH 2 CH 3 , -CH 3 , -CH 2 CH 3 , -C 6 H 5 - CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 C 6 H 5 or para-methoxybenzyl,
  • n is selected from 0, 1 or 2, in particular 0 or 1 ,
  • substituent Q and, where applicable, the other ones of R being selected independently from any other R from -H, -OH, -CI, I, -CN, -OCH 3 , -OCF 3 , - OCONH2 or -CF 3 , in particular from -OH, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , or
  • R the substituent Q
  • the other ones of R being selected independently from any other R from -H,-OH, -CI, I, -CN, -OCH 3 , -OCF 3 , - OCONH2 or -CF 3 , in particular -OH, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , or
  • substituent Q and, where applicable, the other ones of R being selected independently from any other R from -H,-OH, -CI, I, -CN, -OCH 3 , -OCF 3 , - OCONH2 or -CF 3 , in particular -OH, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , or
  • R is selected independently from any other R from -H,-OH, -CI, I, -CN, -OCH 3 , -OCF 3 , - OCONH2 or -CF 3 , in particular -OH, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , or
  • R being selected independently from each other R from -OH, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , or
  • each T being selected independently from each other from -CH 2 , -NH, -S or -O, - CHCH 3 , -C(CH 3 ) 2 or -NR c ,
  • R c being -OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3! -CH(CH 3 ) 2 , and
  • T being selected from -CH 2 , -NH, -S or -O, -CHCH 3 , -C(CH 3 ) 2 or -NR C , and
  • R 5 and R 6 being selected independently from each other from -H, -F, -CH 3 , -
  • R 5 and R 6 being selected independently from each other from H, -F or -CH 3 , and
  • R 6 being selected from -CH 3 , -OH, -OCH 3 or -OCH 2 CH 3
  • R 9 m being selected from 0, 1 , 2 or 3, and each R 9 being selected
  • R b being a substituted or unsubstituted CrC 5 alkyl, a substituted or
  • each T being selected independently from each other from -CH 2 , -CHCH 3 , - C(CH 3 ) 2 , -NH, NR C , -S or -O, in particular form -C(CH 3 ) 2 , -NH, -S or -O,
  • R c being -CH 2 OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CF 3 , - CHFCF 3 , -CF 2 CF 3 , -CHF 2 , -CH 2 F, -CF 3
  • T being selected from -CH 2 , -NH, -S or -O, -CHCH 3 , -C(CH 3 ) 2 or -NR C , in particular from -O, -S or -NH, and
  • R 5 and R 6 being selected independently from each other from -H, -F -CH 3 , - CH 2 CH 3 , -OCH 3 , -CH 2 CF 3 , -CHFCF 3 , -CF 2 CF 3 , -CHF 2 , -CH 2 F or -CF 3 , in particular with R 5 and R 6 being selected independently from each other from H, -F or CH 3 , and
  • R 6 being selected from OH, -OCH 3 , -OCH 2 CH 3 or -CH 3 ,
  • E is
  • a substituted or unsubstituted C Ci 6 alkyl a substituted or unsubstituted C Ci 6 alkoxy, a substituted or unsubstituted C Ci 6 carboxy, a substituted or unsubstituted C 2 -Ci 6 alkenyl, a substituted or unsubstituted C 2 -Ci 6 alkynyl, or a C Ci 6 haloalkyl, in particular a substituted or unsubstituted CrC 8 alkyl, a substituted or unsubstituted CrC 8 alkoxy, a substituted or unsubstituted C 2 -C 8 alkenyl, a substituted or unsubstituted C 2 -C 8 alkynyl, a substituted or unsubstituted CrC 8 haloalkyl, a substituted or unsubstituted C 3 -Cio cycloalkyl, or a substituted or unsubstituted C
  • E is
  • a substituted or unsubstituted Ci-C 8 alkyl a substituted or unsubstituted CrC 8 alkoxy, a substituted or unsubstituted C 2 -C 8 alkenyl, a substituted or unsubstituted C 2 -C 8 alkynyl, or a substituted or unsubstituted CrC 8 haloalkyl.
  • E is
  • E is
  • a substituted or unsubstituted C 5 -C 6 halo heterocycle in particular a C 5 -C 6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
  • a substituted C 6 aryl in particular a bicyclic C 6 aryl such as tetraline or indane, a substituted or unsubstituted C 5 -C 6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
  • benzpyridazin or hydroxylated, methylated or halogenated derivatives thereof selected from .
  • n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n being 1 , and
  • R aa being selected independently from each other being -R a or -OR a
  • R ba being selected independently from each other being -R b or -OR b
  • M being a substituted or unsubstituted CrC 8 alkyl, in particular an unsubstituted CrC 8 alkyl
  • m being selected from 0, 1 or 2, in particular 0 or 1 ,
  • q being selected from 0, 1 or 2, in particular 0 or 1 ,
  • each R a , R b or R c being selected, where applicable, independently from each other from
  • C Ci 6 alkoxy a substituted or unsubstituted C Ci 6 carboxy, a substituted or unsubstituted C 2 -Ci 6 alkenyl, a substituted or unsubstituted C 2 -Ci 6 alkynyl, or a C Ci 6 haloalkyl, in particular a substituted or unsubstituted CrC 8 alkyl, a substituted or unsubstituted CrC 8 alkoxy, a substituted or unsubstituted C 2 -C 8 alkenyl, a substituted or unsubstituted C 2 -C 8 alkynyl, a substituted or unsubstituted CrC 8 haloalkyl, a substituted or unsubstituted C 3 - Cio cycloalkyl, or a substituted or unsubstituted C 3 -Cio halo cycloalkyl,
  • each R independently from any other R being -OH, -F, -CI, I, -CN, -OCH 3 , -OCF 3 , - OCONH 2 or -CF 3 .
  • E is
  • n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly 1 , and
  • R aa being selected independently from each other being -R a or -OR a
  • R ba being selected independently from each other being -R b or -OR b
  • M being a substituted or unsubstituted CrC 8 alkyl, in particular an unsubstituted CrC 8 alkyl
  • m being selected from 0, 1 or 2, in particular 0 or 1 ,
  • q being selected from 0, 1 or 2, in particular 0 or 1 ,
  • each R a , R b or R c being selected, where applicable, independently from each other from
  • a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle,
  • E is
  • n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, particularly n of R n 1 , and
  • each R independently from any other R being selected from - OH, -F, -CI, -Br, I, -CCH, -CN, -N 3 , -OCH 3 , -OCF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , - CH 3 , -CH 2 -CH 3 , -CF 3 , -OCONH 2 or -N0 2 ,
  • R aa being selected independently from each other being -R a or -OR a
  • R ba being selected independently from each other being -R b or -OR b
  • M being a substituted or unsubstituted CrC 8 alkyl, in particular an unsubstituted CrC 8 alkyl
  • m being selected from 0, 1 or 2, in particular 0 or 1 ,
  • q being selected from 0, 1 or 2, in particular 0 or 1 ,
  • each R a , R b or R c being selected, where applicable, independently from each other from
  • n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n 1 , and
  • R aa being selected independently from each other being -R a or -OR a
  • R ba being selected independently from each other being -R b or -OR b
  • M being a substituted or unsubstituted CrC 8 alkyl, in particular an unsubstituted CrC 8 alkyl
  • m being selected from 0, 1 or 2, in particular 0 or 1 ,
  • q being selected from 0, 1 or 2, in particular 0 or 1 , ,
  • each R a , R b or R c being selected, where applicable, independently from each other from hydrogen,-CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH2CH2CH2CH3, - CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -C6H5— CH2C6H5
  • E is
  • n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly
  • C 5 -C 6 halo heterocycle in particular a C 5 -C 6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
  • n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n beingl , and with each R independently from any other R being -OH, -F, -CI, I, -CN, -OCH3, -OCF3, -CONH 2 or -CF 3 .
  • E is
  • n of R n being 5 and R is F, or
  • R n 5
  • R 6
  • F 6
  • R 6
  • R being selected from -OH, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , or with n of R n being 5, and one to three of R being F and the other ones of R being selected independently from any other R from -H, -OH, -CI, I, -CN, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , in particular -OH, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , or
  • n of R n being 2, and each R being selected independently from any other R from -OH, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , or
  • R n 5
  • R 6
  • R 6
  • R 6
  • R 6
  • n of R n being 3, and each R being selected independently from any other R from -OH, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 .
  • E is
  • n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n being 1 , and with each R independently from any other R being -OH, OCH 3 , -F, - OCONH2 or -CF 3 .
  • E is
  • n of R n being 1 , 2, 3, 4 or 5, in particular n of R n being 1 , 2 or 3,
  • R a being a substituted or unsubstituted C Ci 6 alkyl, in particular an unsubstituted C Ci 4 alkyl,
  • - R d being -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C 6 H 5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
  • - p1 being selected from 1 to 20, in particular from 1 to 8,
  • - R d being -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C 6 H 5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
  • - p1 being selected from 1 to 20, in particular from 1 to 8,
  • R aa and R ba being selected, where applicable, independently from each other from -R a or -OR a and
  • R a being hydrogen, -OCH 3 , -OCH 2 CH 3 , -CH 3 , -CH 2 CH 3 , -C 6 H 5 - CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 C 6 H 5 or para-methoxybenzyl
  • E is
  • R n 5
  • R the substituent Q
  • the other ones of R being selected independently from any other R from -H, -OH, -CI, -I, -CN, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , in particular from - OH, -OCH 3 , -OCF 3 , -OCONH 2 or -CF 3 , or
  • R n 5
  • R the substituent Q
  • the other ones of R being selected independently from any other R from -H,-OH, -CI, -I, -CN, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , in particular -OH, - OCH 3 , -OCF 3 , -OCONH 2 or -CF 3 , or
  • R n 5
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • the other ones of R being selected independently from any other R from -H,-OH, -CI, -I, -CN, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , in particular -OH, - OCH 3 , -OCF 3 , -OCONH 2 or -CF 3 , or
  • R n 5
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R 6
  • R the substituent Q
  • other ones of R being selected independently from any other R from -H,-OH, -CI, -I, -CN, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3
  • -OH -OCH 3
  • OCF 3 -OCONH 2 or -CF 3
  • n of R n 3
  • one R being the substituent Q, and the other R being selected independently from each other R from -OH, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , or with n of R n being 2, one R being the substituent Q and the other R being -H,-OH, - OCH 3 , -OCF 3 , -OCONH 2 or -CF 3 , or
  • n of R n 1 with R being the substituent Q, with Q having the same meaning as defined previously, and wherein in particular Q is in para position with respect to the attachment position of the phenyl moiety of E to the parent moiety,
  • each T being selected independently from each other from -CH 2 , -NH, -S or -O, - CHCH3, -C(CH 3 ) 2 or -NR c ,
  • R c being -OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , and
  • T being selected from -CH 2 , -NH, -S or -O, -CHCH 3 , -C(CH 3 ) 2 or -NR C , and
  • R 5 and R 6 being selected independently from each other from -H, -F, -CH 3 , - CH 2 CH 3 , -OCH 3 , -CH 2 CF 3 , -CHFCF 3 , -CF 2 CF 3 , -CHF 2 , -CH 2 F or -CF 3 , in particular with R 5 and R 6 being selected independently from each other from H, -F or -CH 3 , and
  • R 6 being selected from -OH, -OCH 3 , -OCH 2 CH 3 or -CH 3 ,
  • R b being a substituted or unsubstituted CrC 5 alkyl, a substituted or unsubstituted C 2 -C 5 alkenyl, a substituted or unsubstituted C 2 -C 5 alkynyl, or a CrC 5 haloalkyl.
  • E is
  • each T being selected independently from each other from -CH 2 , -CHCH 3 , - C(CH 3 ) 2 , -NH, NR C , -S or -O, in particular form -C(CH 3 ) 2 , -NH, -S or -O,
  • R c being -CH 2 OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 ,
  • T being selected from -CH 2 , -NH, -S or -O, -CHCH 3 , -C(CH 3 ) 2 or -NR C , in particular from -O, -S or -NH, and
  • R 5 and R 6 being selected independently from each other from -H, -F -CH 3 , - CH 2 CH 3 , -OCH 3 , -CH 2 CF 3 , -CHFCF 3 , -CF 2 CF 3 , -CHF 2 , -CH 2 F or -CF 3 , in particular with R 5 and R 6 being selected independently from each other from H, -F or CH 3 , and
  • R 6 being selected from OH, -OCH 3 , -OCH 2 CH 3 or -CH 3 ,
  • n of R n is 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly 1 , and each R independently from any other R is selected from
  • R aa being selected independently from each other being -R a or -OR a ,
  • R ba being selected independently from each other being -R b or -OR b ,
  • M being a substituted or unsubstituted CrC 8 alkyl, in particular an unsubstituted Ci- C 8 alkyl
  • m being selected from 0, 1 or 2, in particular 0 or 1
  • q being selected from 0, 1 or 2, in particular 0 or 1 ,
  • each R a , R b or R c being selected, where applicable, independently from each other from
  • C Ci 6 alkoxy a substituted or unsubstituted C Ci 6 carboxy, a substituted or unsubstituted C 2 -Ci 6 alkenyl, a substituted or unsubstituted C 2 -Ci 6 alkynyl, or a C Ci 6 haloalkyl, in particular a substituted or unsubstituted CrC 8 alkyl, a substituted or unsubstituted CrC 8 alkoxy, a substituted or unsubstituted C 2 -C 8 alkenyl, a substituted or unsubstituted C 2 -C 8 alkynyl, a substituted or unsubstituted CrC 8 haloalkyl, a substituted or unsubstituted C 3 - Cio cycloalkyl, or a substituted or unsubstituted C 3 -Cio halo cycloalkyl,
  • n of R n of BA being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n 1 , and
  • each R independently from any other R being selected from - -OH, -F, -CI, -Br, -I, -CCH, -CN, -N 3 , -OCH 3 , -OCF 3 , -NH 2 , -NH CH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 -CH 3 , -CF 3 , -OCONH 2 or -N0 2 ,
  • R aa being selected independently from each other being -R a or -OR a
  • R ba being selected independently from each other being -R b or -OR b
  • M being a substituted or unsubstituted CrC 8 alkyl, in particular an unsubstituted CrC 8 alkyl
  • m being selected from 0, 1 or 2, in particular 0 or 1
  • q being selected from 0, 1 or 2, in particular 0 or 1 ,
  • n of R n is 0, 1 , 2, 3, 4 or 5, in particular n of R n is 0, 1 , 2 or 3, more particularly 1 , and with each R independently from any other R being
  • a substituted or unsubstituted C 5 -C 6 heterocycle - a substituted or unsubstituted C 5 -C 6 halo heterocycle, in particular a C 5 -C 6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
  • a substituted or unsubstituted C 5 -C 6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F, a substituted or unsubstituted C 6 aryl.
  • n of R n is 0, 1 , 2, 3, 4 or 5, in particular n of R n is 0, 1 , 2 or 3, more particularly 1 , and with each R independently from any other R being -OH, -F, -CI, -I, -CN, -OCH 3 , -OCF 3 - OCONH 2 or -CF 3 .
  • R n of R n is 5 and R is F, or
  • R n of R n is 5, and one to four of R being F and the other ones of R are selected independently from any other R from -H, -OH, -CI, -I, -CN, -OCH 3 , -OCF 3 , -OCONH 2 or - CF 3 , in particular from -OH, -OCH 3 , -OCF 3 , -OCONH 2 or -CF 3 , or
  • R - n of R n is 1 , and R are selected from -OH, -OCH 3 , -OCF 3 , -OCONH 2 or -CF 3 , or
  • R n of R n is 5, and one to three of R are F and the other ones of R are selected independently from any other R from -H, -OH, -CI, -I, -CN, -OCH 3 , -OCF 3 , -OCONH 2 or - CF 3 , in particular from -OH, -OCH 3 , -OCF 3 or -CF 3 , or
  • R n of R n is 2, and each R is selected independently from any other R from -OH, -OCH 3 , -OCF 3 , -OCONH 2 or -CF 3 , or
  • R n of R n is 5, and one or two of R are F and the other ones of R are selected independently from any other R from -H,-OH, -CI, I, -CN, -OCH 3 , -OCF 3 , -OCONH 2 or - CF 3 , in particular from -OH, -OCH 3 , -OCF 3 , -OCONH 2 or -CF 3 , or
  • R n of R n is 3, and each R is selected independently from any other R from -OH, -OCH 3 , -OCF 3 , -OCONH 2 or -CF 3 .
  • n of R n is 0, 1 , 2, 3, 4 or 5, in particular n of R n is 0, 1 , 2 or 3, more particularly n of R n is 1 , and with each R independently from any other R being -OH, OCH 3 , -F or -CF 3 .
  • n of R n is 1 , 2, 3, 4 or 5, in particular n of R n is 1 , 2 or 3,
  • R a being a substituted or unsubstituted C Ci 6 alkyl, in particular an unsubstituted C Ci 4 alkyl,
  • - R d being -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C 6 H 5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
  • - p1 being selected from 1 to 20, in particular from 1 to 8,
  • - R d being -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C 6 H 5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
  • - p1 being selected from 1 to 20, in particular from 1 to 8,
  • R aa and R ba being selected, where applicable, independently from each other from -R a or -OR a and
  • R a being hydrogen, -OCH 3 , -OCH 2 CH 3 , -CH 3 , -CH 2 CH 3 , -C 6 H 5 - CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 C 6 H 5 or para-methoxybenzyl
  • R being selected independently from each other R from -OH, -F, -CI, I, - CN, -OCH3, -OCF3, -OCONH2 or -CF 3 , in particular from -OH, -F, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 .
  • R n of R n is 5, and one to four of R are F, one R is the substituent Q, and, where applicable, the other ones of R are selected independently from any other R from -H, - OH, -CI, I, -CN, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , in particular from -OH, -OCH 3 , -OCF 3 , - OCONH2 or -CF 3 , or
  • R n of R n is 5, and one to three of R are F, one R is the substituent Q, and, where applicable, the other ones of R are selected independently from any other R from -H,- OH, -CI, I, -CN, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , in particular -OH, -OCH 3 , -OCF 3 , - OCONH2 or -CF 3 , or
  • R n of R n is 5, and one or two of R are F, one R is the substituent Q, and, where applicable, the other ones of R are selected independently from any other R from -H,- OH, -CI, I, -CN, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , in particular -OH, -OCH 3 , -OCF 3 , - OCONH2 or -CF 3 , or
  • R n of R n is 5, and one of R is F, one R is the substituent Q, and, where applicable, the other ones of R are selected independently from any other R from -H,-OH, -CI, I, -CN, - OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , in particular from -OH, -OCH 3 , -OCF 3 , -OCONH2 or - CF 3 , or
  • R n of R n is 3, one R is the substituent Q, and the other R are selected independently from each other R from -OH, -OCH 3 , -OCF 3 , -OCONH2 or -CF 3 , or
  • R n of R n is 2, one R is the substituent Q and the other R is -H,-OH, -OCH 3 , -OCF 3 , - OCONH2 or -CF 3 , or
  • n of R n is 1 , with R being the substituent Q,
  • R 2 and R 3 are selected, where applicable, independently from each other from -H, -F, - CN, -OH, -NH 2 , -NO2, -NHCH3, -NH(CH 3 ) 2 , a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl.
  • R 2 and R 3 are selected, where applicable, independently from each other from -H, -F, - CN, -OH, -NH 2 , -NO2, -NHCH3, -NH(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -OCH3, -OCH 2 CH 3 , - OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF3, -CH 2 CF 3 , -CHFCF 3 , -CF 2 CF 3 , -CHF 2 , -CH 2 F or -CF 3 .
  • R 2 and R 3 are selected independently from each other from -H, -F or -CH 3 .
  • X 1 is selected from
  • R 8 being selected from H or CH 3
  • in particluar R 8 is H and with V being selected from O, NH or S, in particular from O or NH.
  • X 1 is selected from
  • R 8 being selected from H or CH 3 , in particluar R 8 is H.
  • BB is
  • BB is
  • n of R 3 n being 1 , 2, 3 or 4 with each R 3 being F, in particular n is 4 and each R 3 is F.
  • BC is selected from
  • p 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and
  • R a and R b being selected, where applicable, independently from each other from
  • Ci-C 4 alkyl a substituted or unsubstituted Ci-C 4 alkyl, a substituted or
  • Ci-C 4 alkoxy a substituted or unsubstituted Ci-C 4 carboxy, a substituted or unsubstituted C 2 -C 4 alkenyl, a substituted or unsubstituted C 2 -C 4 alkynyl, or a Ci -C 4 haloalkyl, or
  • L 3 being selected from -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , a Ci -C 2 -fluoro alkyl
  • L , L 2 , L 3 , L 4 and L 5 comprise the structure elements of amino acids and their derivatives.
  • the respective amino acid is named in brackets.
  • BC is selected from
  • p 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and
  • R a and R b being selected, where applicable, independently from each other from CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , - CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -C 6 H 5 ,-CH 2 C 6 H 5 , mono methoxybenzyl, in particular para-methoxybenzyl, or dimethoxybenzyl or trimethoxybenzyl
  • L 3 being selected from -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , a Ci-C 2 -fluoro alkyl,
  • Z being -H, -OH, -CH 3 , -CH 2 CH 3 , -OCH 3 , -NH 2 NHCH 3 , N(CH 3 ) 2 or N(CH 3 ) 3 + .
  • BC is selected from
  • Ci -C 4 alkoxy a substituted or unsubstituted Ci -C 4 carboxy, a substituted or unsubstituted C 2 -C 4 alkenyl, a substituted or unsubstituted C 2 -C 4 alkynyl, or a Ci -C 4 haloalkyl, or
  • BC is selected from
  • R a and R b being selected, where applicable, independently from each other from CH 3 , - CH 2 CH3, -CH 2 CH 2 CH3, -CH 2 CH 2 CH 2 CH3, -CH(CH3) 2 , -CH 2 CH(CH3) 2 , -C(CH3)3, -C6H5 ,- CH 2 C 6 H 5 , mono methoxybenzyl, in particular para methoxybenzyl, or dimethoxybenzyl or trimethoxybenzyl.
  • BC is selected from
  • R a and R b being selected, where applicable, independently from each other from
  • Ci-C 4 alkyl a substituted or unsubstituted Ci-C 4 alkyl, a substituted or
  • Ci-C 4 alkoxy a substituted or unsubstituted Ci-C 4 carboxy, a substituted or unsubstituted C 2 -C 4 alkenyl, a substituted or unsubstituted C 2 -C 4 alkynyl, or a Ci -C 4 haloalkyl, or
  • BC is selected from
  • R a and R b being selected, where applicable, independently from each other from CH 3 , - CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -C6H5 ,- CH 2 C 6 H 5 , mono methoxybenzyl, in particular para methoxybenzyl, or dimethoxybenzyl or trimethoxybenzyl.
  • BC is selected from
  • R a and R b being selected, where applicable, independently from each other from
  • Ci-C 4 alkyl a substituted or unsubstituted Ci-C 4 alkyl, a substituted or
  • Ci-C 4 alkoxy a substituted or unsubstituted Ci-C 4 carboxy, a substituted or unsubstituted C 2 -C 4 alkenyl, a substituted or unsubstituted C 2 -C 4 alkynyl, or a Ci-C 4 haloalkyl, or
  • BC is selected from
  • R a and R b being selected, where applicable, independently from each other from CH 3 , - CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , -C6H5 ,- CH 2 C 6 H 5 , mono methoxybenzyl, in particular para methoxybenzyl, or dimethoxybenzyl or trimethoxybenzyl.
  • -D 2 -BC- is
  • each R 8 being selected independently from each other from -H, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCF 3 , -CH 2 CF 3 , - CHFCF 3 , -CF 2 CF 3 , -CHF 2 , -CH 2 F or -CF 3 , in particular with each R 8 being selected independently from each other from H or CH 3 , more particularly each R 8 being H.
  • p 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and with R 8 being H or CH 3 .
  • BD is
  • BD is
  • n of R 2 n being 1 , 2, 3 or 4 with each R 2 being F, in particular n is 4 and each R 3 is F.
  • BE is
  • n of R n being 0, 1 , 2, 3 or 4, in particular n of R n being 0, 1 , 2 or 3,
  • each R being selected independently from any other R from -OH, -F, -CI, -Br, -I, - CCH, -CN, -N 3 , -OCH3, -OCF3, -NH 2 , -NHCH3, -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 OCH 3 , - CHCH 2 , -CH 2 OH, -S0 2 NH 2 , -S0 2 N(CH 3 ) 2 , -S0 2 NHCH 3 , -CH 3 , -CF 3 or -N0 2 , in particular from -OH, -F, -OCH 3 , -OCF 3 or -CF 3 , or
  • each R being selected independently from any other R from -OH, -F, -CI, -Br, -I, - CCH, -CN, -N 3 , -OCH 3 , -OCF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 OCH 3 , - CHCH 2 , -CH 2 OH, -S0 2 NH 2 , -S0 2 N(CH 3 ) 2 , -S0 2 NHCH 3 , -CH 3 , -CF 3 or -N0 2 , in particular from -OH, -F, -OCH 3 , -OCF 3 or -CF 3 , wherein, each carbon atom of the cyclic system which comprises no substituent R comprises F instead of H.
  • BE is
  • n of R n being 2, and with each R independently from any other R being -OH, -OCH 3 or -OCF 3 , in particular -OCH 3 or -OCF 3 , more particularly with one R being -OH and the other R being -OCH 3 or -OCF 3 , in particular -OCH 3 , wherein more particularly OH is in ortho and OCH3 or -OCF 3 in meta position with respect to the attachment position of the phenyl moiety of BE to D 5 , or
  • n of R n being 1
  • R being -OH , wherein in particular OH is in ortho position with respect to the attachment position of the phenyl of BE to D 5 or
  • n of R n being 1
  • R being -OCH 3 or -OCF 3 , in particular or -OCH 3 , wherein more particularly -OCH 3 or -OCF 3 is in meta position with respect to the attachment position of the phenyl of BE to D 5 , or
  • n of R n being 4 and each R is F.
  • BE is
  • n of R n being 1 , 2, 3 or 4, in particular n of R n being 1 , 2 or 3,
  • R a being a substituted or unsubstituted C1 -C16 alkyl, in particular an unsubstituted C1 -C14 alkyl,
  • R d being -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
  • - p1 being selected from 1 to 20, in particular from 1 to 8, -(CH 2 ) m -[(CH 2 ) m1 -0-(CH 2 ) m2 ] p1 -OR d , in particular -[-0-(CH 2 ) 2 ] p1 -OR d , with
  • R d being -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3! -CH(CH 3 ) 2 , ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
  • - p1 being selected from 1 to 20, in particular from 1 to 8,
  • R aa and R ba being selected, where applicable, independently from each other from -R a or -OR a and
  • R a being hydrogen, -OCH 3 , -OCH 2 CH 3 , -CH 3 , -CH 2 CH 3 , -C 6 H 5 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 C 6 H 5 or para-methoxybenzyl
  • n is selected from 0, 1 or 2, in particular 0 or 1 ,
  • each carbon atom of the cyclic system which comprises no substituent R comprises F instead of H.
  • BE is
  • n of R n being 0 or 2
  • one R being Q and the other R being -OCH 3 or - OCF 3 more particularly Q is in ortho and OCH 3 or -OCF 3 is in meta position with respect to the attachment position of the phenyl moiety of BB to D 5 , with Q having the same meaning as defined above.
  • each T" being selected from -CH 2 , -NH, -S, -O, or -NR C , in particular T" is O,
  • R c being -OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 ,
  • n of R n being 0, 1 , 2 or 3, in particular n of R n being 0, 1 , or 2,
  • each R being selected independently from any other R from -OH, -F, -CI, - Br, -I, -CCH, -CN, -N 3 , -OCH 3 , -OCF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , - CH 2 OCH 3 , -CHCH 2 , -CH 2 OH, -S0 2 NH 2 , -S0 2 N(CH 3 ) 2 , -S0 2 NHCH 3 , -CH 3 , -CF 3 or -N0 2 , in particular from -OH, -F, -OCH 3 , -OCF 3 or -CF 3 , or
  • each R being selected independently from any other R from -OH, -F, -CI, - Br, -I, -CCH, -CN, -N 3 , -OCH 3 , -OCF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , - CH 2 OCH 3 , -CHCH 2 , -CH 2 OH, -S0 2 NH 2 , -S0 2 N(CH 3 ) 2 , -S0 2 NHCH 3 , -CH 3 , -CF 3 or -N0 2 , in particular from -OH, -F, -OCH 3 , -OCF 3 or -CF 3 , wherein, each carbon atom of the cyclic system which comprises no substituent R comprises F instead of H.
  • each T" being selected from -CH 2 , -NH, -S, -O, or -NR C , in particular T" is O,
  • R c being -OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 ,
  • n of R n being 2, and with each R independently from any other R being -OH, -OCH 3 or -OCF 3 , in particular -OCH 3 or -OCF 3 , more particularly with one R being -OH and the other R being -OCH 3 or - OCF 3 , in particular -OCH 3 , wherein more particularly OH is in ortho and OCH3 or -OCF3 in meta position with respect to the attachment position of the phenyl moiety of BE to D 5 , or
  • R being -OCH 3 or -OCF 3 , in particular or - OCH3, wherein more particularly -OCH 3 or -OCF 3 is in meta position with respect to the attachment position of the phenyl of BE to D 5 , or
  • each T" being selected from -CH 2 , -NH, -S, -O, or -NR C , in particular T" is O,
  • R c being -OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , with n of R n being 1 , 2 or 3, in particular n of R n being 1 or 2,
  • R a being a substituted or unsubstituted C1 -C16 alkyl, in particular an unsubstituted C1 -C14 alkyl,
  • - p1 being selected from 1 to 20, in particular from 1 to 8,
  • - R d being -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C 6 H 5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
  • - p1 being selected from 1 to 20, in particular from 1 to 8,
  • R aa and R ba being selected, where applicable, independently from each other from -R a or -OR a and
  • R a being hydrogen, -OCH 3 , -OCH 2 CH 3 , -CH 3 , -CH 2 CH 3 , -C 6 H 5 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 C 6 H 5 or para-methoxybenzyl with m being selected from 0, 1 or 2, in particular 0 or 1 ,
  • q being selected from 0, 1 or 2, in particular 0 or 1 , and
  • R being selected independently from any other R from -OH, -F, - CI, -Br, -I, -CCH, -CN, -N 3 , -OCH 3 , -OCF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , - CH 2 CH 3 , -CH 2 OCH 3 , -CHCH 2 , -CH 2 OH, -S0 2 NH 2 , -S0 2 N(CH 3 ) 2 , -S0 2 NHCH 3 , - CH 3 , -CF 3 or -N0 2 , in particular from -OH, -F, -OCH 3 , -OCF 3 or -CF 3 , or with the other R being selected independently from any other R from -OH, -F, - CI, -Br, -I, -CCH, -CN, -N 3 ,
  • each T" being selected from -CH 2 , -NH, -S, -O, or -NR C , in particular T" is O,
  • R c being -OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , with n of R n being 0 or 2, and with one R being Q and the other R being -OCH 3 or - OCF 3 , more particularly Q is in ortho and OCH 3 or -OCF 3 is in meta position with respect to the attachment position of the phenyl moiety of BB to D 5 , with Q having the same meaning as defined above.
  • R is a substituent Q, with Q being selected from
  • R a being a substituted or unsubstituted C Ci 6 alkyl, in particular an unsubstituted C Ci 4 alkyl,
  • - R d being -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C 6 H 5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
  • - p1 being selected from 1 to 20, in particular from 1 to 8,
  • - R d being -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C 6 H 5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
  • - p1 being selected from 1 to 20, in particular from 1 to 8,
  • R aa and R ba being selected, where applicable, independently from each other from -R a or -OR a and
  • R a being hydrogen, -OCH 3 , -OCH 2 CH 3 , -CH 3 , -CH 2 CH 3 , -C 6 H 5 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 C 6 H 5 or para-methoxybenzyl
  • n is selected from 0, 1 or 2, in particular 0 or 1 ,
  • q being selected from 0, 1 or 2, in particular 0 or 1 .
  • X 2 is
  • R aa being selected independently from each other from -R a or -OR a ,
  • R ba being selected independently from each other from -R b or -OR b ,
  • M being a substituted or unsubstituted CrC 8 alkyl, in particular an unsubstituted Ci-C 8 alkyl
  • n is selected from 0, 1 or 2, in particular 0 or 1 ,
  • each R a , R b or R c being selected independently from each other from - hydrogen, -CN,
  • - a substituted or unsubstituted C1-C16 alkyl, a substituted or unsubstituted C1-C16 alkoxy, a substituted or unsubstituted C1-C16 carboxy, a substituted or unsubstituted C 2 -Ci 6 alkenyl, a substituted or unsubstituted C 2 -Ci 6 alkynyl, or a C1-C16 haloalkyl, and
  • linker D 5 may be optionally situated between BE and X 2
  • X 2 is
  • R aa being selected independently from each other from -R a or -OR a ,
  • R ba being selected independently from each other from -R b or -OR b ,
  • M being a substituted or unsubstituted CrC 8 alkyl, in particular an unsubstituted CrC 8 alkyl
  • n is selected from 0, 1 or 2, in particular 0 or 1 ,
  • linker D 5 may be optionally situated between BE and X 2
  • BF is
  • a substituted or unsubstituted C 3 -Ci 0 heterocycle or a substituted or unsubstituted C 3 -Ci 0 halo heterocycle in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
  • BF is
  • T being selected from
  • R aa being selected independently from each other being -R a or -OR a
  • R ba being selected independently from each other being -R b or -OR b
  • M being a substituted or unsubstituted CrC 8 alkyl, in particular an unsubstituted CrC 8 alkyl
  • m being selected from 0, 1 or 2, in particular 0 or 1 ,
  • q being selected from 0, 1 or 2, in particular 0 or 1 ,
  • each R a , R b or R c being selected, where applicable, independently from each other from
  • C Ci 6 alkoxy a substituted or unsubstituted C Ci 6 carboxy, a substituted or unsubstituted C 2 -Ci 6 alkenyl, a substituted or unsubstituted C 2 -Ci 6 alkynyl, or a C Ci 6 haloalkyl, or
  • n of R 0 n being 0, 1 , 2, 3 or 4, in particular n of R 0 n being 0, 1 , 2 or 3, 4, and with each R 0 independently from any other R 0 being selected from
  • R aa being selected independently from each other being -R a or -OR a
  • R ba being selected independently from each other being -R b or -OR b
  • M being a substituted or unsubstituted CrC 8 alkyl, in particular an unsubstituted CrC 8 alkyl
  • m being selected from 0, 1 or 2, in particular 0 or 1 ,
  • q being selected from 0, 1 or 2, in particular 0 or 1 ,
  • each R a , R b or R c being selected, where applicable, independently from each other from
  • C Ci 6 alkoxy a substituted or unsubstituted C Ci 6 carboxy, a substituted or unsubstituted C 2 -Ci 6 alkenyl, a substituted or unsubstituted C 2 -Ci 6 alkynyl, or a C Ci 6 haloalkyl, in particular a substituted or unsubstituted CrC 8 alkyl, a substituted or unsubstituted CrC 8 alkoxy, a substituted or unsubstituted C 2 -C 8 alkenyl, a substituted or unsubstituted C 2 -C 8 alkynyl, a substituted or unsubstituted CrC 8 haloalkyl, a substituted or unsubstituted C 3 - Cio cycloalkyl, or a substituted or unsubstituted C 3 -Cio halo cycloalkyl,
  • BF is
  • n of R n being 0, 1 , 2, 3 or 4, in particular n of R n being 0, 1 , 2 or 3, and
  • R aa being selected independently from each other being -R a or -OR a
  • R ba being selected independently from each other being -R b or -OR b
  • M being a substituted or unsubstituted CrC 8 alkyl, in particular an unsubstituted CrC 8 alkyl, in particular Ci to C 2 alkyl
  • m being selected from 0, 1 or 2, in particular 0 or 1
  • q being selected from 0, 1 or 2, in particular 0 or 1 ,
  • each R a , R b or R c being selected, where applicable, independently from each other from
  • n of R 0 n being 0, 1 , 2, 3 or 4, in particular n of R 0 n being 0, 1 , 2 or 3, and
  • a substituted or unsubstituted C 5 -C 6 halo heterocycle in particular a C 5 -C 6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
  • a substituted or unsubstituted C 5 -C 6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F, a substituted or unsubstituted C 6 aryl.
  • CI of F particularly comprising one CI or one F, a substituted or unsubstituted C 6 aryl.
  • R 0 independently from any other R 0 being -OH, -F, -CI, -Br, -I, -CCH, -CN, -N 3 , -OCH 3 , -OCF 3 , -NH 2 , -NHCH3, -N(CH 3 ) 2 , -CH3, -CH 2 CH 3 , -CH 2 OCH 3 , -CHCH 2 , -CH 2 OH, -S0 2 NH 2 , - S0 2 N(CH 3 ) 2 , -S0 2 NHCH 3 , -CH 3 , -CF 3 or -N0 2 , in particular from -OH, -F, -OCH 3 , -OCF 3 or - CF 3 .
  • -OH, -OCH 3 or -OCF 3 in particular OH or -OCH 3 , more particularly with one R 0 being -OH and the other R 0 being -OCH 3 , wherein further in particular OH is in meta and OCH 3 or - OCF 3 in ortho position with respect to the attachment position of the phenyl moiety of BF to D 5 , or
  • n of R 0 n being 1
  • R 0 being -OH, wherein in particular OH is in meta position with respect to the attachment position of the phenyl of BF to D 5 or
  • R 0 being -OCH 3 or -OCF 3 ,in particular or -OCH 3 , wherein more particularly -OCH 3 or or -OCF 3 is in ortho position with respect to the attachment position of the phenyl of BF to D 5 , or
  • n of R 0 n 0, or with n of R 0 n being 4 and each R 0 is F.
  • n of R 0 n being 0, 1 , 2, 3 or 4, in particular n of R n being 0, 1 , 2 or 3, and with each R 0 independently from any other R 0 being -OH, OCH 3 , -F or -CF 3 .
  • n of R 0 n being 1 , 2, 3 or 4, in particular n of R 0 n being 1 , 2 or 3,
  • R 0 being a substituent Q, with Q being selected from
  • R a being a substituted or unsubstituted C Ci 6 alkyl, in particular an unsubstituted C Ci 4 alkyl,
  • - R d being -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C 6 H 5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
  • - p1 being selected from 1 to 20, in particular from 1 to 8,
  • R d being -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
  • - p1 being selected from 1 to 20, in particular from 1 to 8,
  • R aa and R ba being selected, where applicable, independently from each other from -R a or -OR a and
  • R a being hydrogen, -OCH 3 , -OCH 2 CH 3 , -CH 3 , -CH 2 CH 3 , -C 6 H 5 - CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 C 6 H 5 or para-methoxybenzyl
  • n is selected from 0, 1 or 2, in particular 0 or 1 ,
  • R 0 being selected independently from each other R 0 from - OH, -F, -CI, - Br, -I, -CCH, -CN, -N 3 , -OCH 3 , -OCF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 OCH 3 , - CHCH 2 , -CH 2 OH, -S0 2 NH 2 , -S0 2 N(CH 3 ) 2 , -S0 2 NHCH 3 , -CH 3 , -CF 3 or -N0 2 , in particular from -OH, -F, -OCH 3 , -OCF 3 or -CF 3 .
  • R 0 is 5, and one to four of R being F, one R 0 being the substituent Q, and, where applicable, the other ones of R 0 being selected independently from any other R from -H, -OH, -F, -CI, -Br, -I, -CCH, -CN, -N 3 , -OCH 3 , -OCF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 OCH 3 , -CHCH 2 , -CH 2 OH, -S0 2 NH 2 , -S0 2 N(CH 3 ) 2 , -S0 2 NHCH 3 , -CH 3 , -CF 3 or -N0 2 , in particular from -OH, -F, -OCH 3 , -OCF 3 or -CF 3 , or
  • R 0 with n of R 0 n being 5, and one to three of R 0 being F, one R 0 being the substituent Q, and, where applicable, the other ones of R 0 being selected independently from any other R 0 from - ⁇ ,- ⁇ , -F, -CI, -Br, -I, -CCH, -CN, -N 3 , -OCH 3 , -OCF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 OCH 3 , -CHCH 2 , -CH 2 OH, -S0 2 NH 2 , -S0 2 N(CH 3 ) 2 , -S0 2 NHCH 3 , -CH 3 , -CF 3 or -N0 2 , in particular from -OH, -F, -OCH 3 , -OCF 3 or -CF 3 ,
  • R 0 with n of R 0 n being 5, and one or two of R 0 being F, one R 0 being the substituent Q, and, where applicable, the other ones of R 0 being selected independently from any other R 0 from -H,-OH, -F, -CI, -Br, -I, -CCH, -CN, -N 3 , -OCH 3 , -OCF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 OCH 3 , -CHCH 2 , -CH 2 OH, -S0 2 NH 2 , -S0 2 N(CH 3 ) 2 , -S0 2 NHCH 3 , -CH 3 , -CF 3 or -N0 2 , in particular from -OH, -F, -OCH 3 , -OCF 3 or -CF 3 ,
  • R 0 with n of R 0 n being 5, and one of R 0 being F, one R 0 being the substituent Q, and, where applicable, the other ones of R 0 being selected independently from any other R 0 from -H,-OH, -F, -CI, -Br, -I, -CCH, -CN, -N 3 , -OCH 3 , -OCF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 OCH 3 , -CHCH 2 , -CH 2 OH, - S0 2 NH 2 , -S0 2 N(CH 3 ) 2 , -S0 2 NHCH 3 , -CH 3 , -CF 3 or -N0 2 , in particular from - OH, -F, -OCH 3 , -OCF 3 or -CF 3 , or
  • R 0 being 3, one R 0 being the substituent Q, and the other R 0 being selected independently from each other R 0 from -H,-OH, -F, -CI, -Br, -I, -CCH, -CN, -N 3 , -OCH 3 , -OCF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 OCH 3 , -CHCH 2 , -CH 2 OH, -S0 2 NH 2 , -S0 2 N(CH 3 ) 2 , -S0 2 NHCH 3 , -CH 3 , -CF 3 or -N0 2 , in particular from -OH, -F, -OCH 3 , -OCF 3 or -CF 3 , or
  • R 0 is 2, one R 0 being the substituent Q and the other R 0 being -H,-OH, -F, -CI, -Br, -I, -CCH, -CN, -N 3 , -OCH 3 , -OCF 3 , -NH 2 , -NHCH 3 , - N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 OCH 3 , -CHCH 2 , -CH 2 OH, -S0 2 NH 2 , - S0 2 N(CH 3 ) 2 , -S0 2 NHCH 3 , -CH 3 , -CF 3 or -N0 2 , in particular from -OH, -F, - OCH 3 , -OCF 3 or -CF 3 , or
  • any hydrogen of the phenyl group may be substituted with F.
  • any hydrogen of the phenyl group may be substituted with F.
  • each T" being selected from -CH 2 , -NH, -S, -O, or -NR C , in particular T" is O,
  • R c being -OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , with n of R 0 n being 0, 1 , 2 or 3, in particular n of R n being 0, 1 or 2,
  • each R 0 being selected independently from any other R 0 from -OH, -F, -CI, -Br, -I, - CCH, -CN, -N 3 , -OCH 3 , -OCF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 OCH 3 , - CHCH 2 , -CH 2 OH, -S0 2 NH 2 , -S0 2 N(CH 3 ) 2 , -S0 2 NHCH 3 , -CH 3 , -CF 3 or -N0 2 , in particular from -OH, -F, -OCH 3 , -OCF 3 or -CF 3 , or
  • each R 0 being selected independently from any other R 0 from -OH, -F, -CI, -Br, -I, - CCH, -CN, -N 3 , -OCH 3 , -OCF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 OCH 3 , - CHCH 2 , -CH 2 OH, -S0 2 NH 2 , -S0 2 N(CH 3 ) 2 , -S0 2 NHCH 3 , -CH 3 , -CF 3 or -N0 2 , in particular from -OH, -F, -OCH 3 , -OCF 3 or -CF 3 , wherein, each carbon atom of the cyclic system which comprises no substituent R 0 comprises F instead of H In some embodiments, in particular according to any one of the sub aspects 1 to 17, 19, 21
  • each T" being selected from -CH 2 , -NH, -S, -O, or -NR C , in particular T" is O,
  • R c being -OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 with n of R 0 n being 2, and with each R 0 independently from any other R 0 being -OH, -OCH 3 or -OCF 3 , in particular -OCH 3 or -OCF 3 , more particularly with one R 0 being -OH and the other R 0 being -OCH 3 or -OCF 3 , in particular -OCH 3 , wherein more particularly OH is in ortho and OCH 3 or -OCF 3 in meta position with respect to the attachment position of T, or with n of R 0 n being 1 , and with R 0 being -OH, wherein in particular OH is in ortho position with respect to the attachment position of T, or
  • R 0 being -OCH 3 or -OCF 3 , in particular or -OCH 3 , wherein more particularly -OCH 3 or -OCF 3 is in meta position with respect to the attachment position of T, or
  • n of R 0 n being 4 and each R 0 is F.
  • T having the same meaning as defined above, with each T" being selected from -CH 2 , -NH, -S, -O, or -NR C , in particular T" is O,
  • R c being -OH, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , with n of R 0 n being 1 , 2 or 3, in particular n of R 0 n being 1 or 2,
  • R 0 being a substituent Q, with Q being selected from
  • R a being a substituted or unsubstituted C Ci 6 alkyl, in particular an unsubstituted C Ci 4 alkyl,
  • - R d being -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C 6 H 5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and

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Abstract

The present invention relates to a antibiotically active compounds characterized by general formula (I), wherein X1, BB, BC, BD, BE and X2 are building blocks with D1, D2, D3, D4 or D5 being linkers which comprise carbon, sulphur, nitrogen, phosphor and/or oxygen atoms and which are covalently connecting the moities BA and BB, BB and BC, BC and BD, BD and BE and BE and BF, respectively, and wherein in particular the building block BC comprises an amino acid derivative. The invention relates further to said compounds for use in a method of treatment of diseases, in particular for use in a method of treatment of bacterial infections.

Description

Albicidin derivatives, their use and synthesis
DESCRIPTION
Albicidin has been initially described as an antibiotic substance derived from Xanthomonas albilineans, a protobacterial sugarcane pathogen (US patent 4,525,354 to Birch and Patil, incorporated by reference herein).
Since its first description in 1985, β-albicidin has eluded structural determination in spite of its interesting properties, namely its antibiotic activity against gram-negative bacteria, a group which encompasses many medically important pathogens such as, for example, Escherichia coli, Salmonella, Shigella, Pseudomonas, Moraxella, Helicobacter, Stenotrophomonas, Neisseria, Hemophilus and Legionella.
However, the molecular structure of albicidin was determined only recently
Figure imgf000002_0001
(Albicidin)
The inventors found out that a variation of one building block of albicidin provides
compounds, which comprise antibiotic properties, in particular an antibiotic activity against resistant pathogens.
The problem underlying the present invention is the provision of new compounds, which comprise antibiotic properties, a method of their synthesis and their use. This problem is attained by the subject-matter of the independent claims.
TERMS AND DEFINITIONS
The term "purity" as used in the context of the present specification with respect to a preparation of a certain compound refers to the content of said compound relative to the sum of all compounds contained in the preparation. The term "compound" in this context is to be understood as a compound according to the general formula 1 (or any specific embodiments thereof) as well as any salts, hydrates or solvates thereof. Thus, the respective salts, hydrates or solvents are not considered as impurities according to the previous definition. The "purity" of a compound may be determined using elemental analysis, HPLC analysis using UV diode array detection also in combination with mass spectrometry detection, or quantitative NMR analysis.
DIPEA is Ν,Ν-Diisopropylethylamine (CAS No. 7087-68-5). HATU is (Dimethylamino)-/V,/V- dimethyl(3H-[1 ,2,3]triazolo[4,5-ib]pyridin-3-yloxy)methaniminium hexafluorophosphate (CAS No. 148893-10-1 ).TEA is Triethylamine (CAS No. 121 -44-8). BTC is Bis(trichloromethyl) carbonate (CAS No. 32315-10-9). PFP is Pentafluorophenole (CAS No. 771 -61 -9). PNP is para-nitrophenol (CAS No. 100-02-7). HONB N-Hydroxy-5-norbornene-2,3-dicarboximide (CAS No. 21715-90-2). NHS is N-hydroxysuccinimidyl (CAS No. 6066-82-6). BOB is
Benzotriazolyloxytris-(dimethylamino)-phosphonium hexafluorophosphate (CAS No. 56602- 33-6). pyBOP is Benzotriazol-1 -yl-oxy-tripyrrolidinophosphonium hexafluorophosphate (CAS No. 128625-52-5). HBTU is N,N,N',N'-Tetramethyl-0-(1 H-benzotriazol-1 -yl)uronium hexafluorophosphate (CAS No. 94790-37-1 ). DCC is Λ/,/V-Dicyclohexylcarbodiimide (CAS No. 538-75-0). DIC is Λ/,/V-Dicyclopropylcarbodiimide (CAS No. 693-13-0), EDC is 1 -Ethyl-3- (3-dimethylaminopropyl)carbodiimide (CAS No. 25952-53-8, 22572-40-3, 1892-57-5). TFFH is Fluoro-Ν,Ν,Ν ,N -tetramethylformamidinium hexafluorophosphate (CAS. No. 164298-23-1 ). DEPT is 3-(Diethoxyphosphoryloxy)-1 ,2,3-benzotriazin-4(3H9-one (CAS No. 165534-43-0).
A protecting group in the context of the present specification is a group employed to reduce the reactivity of a particular moiety. Protecting groups are well known to the person skilled in the art of organic chemistry. P. G. M. Wuts, "Greene's Protective Groups in Organic
Synthesis, "4th ed. (2006, Wiley; ISBN 978-0-471 -69754-1 ; 5th edition June 2013 Wiley- Blackwell).
PGH is a suitable protection group for hydroxyl groups known in the art.
PGA is a suitable protection group for carboxylic acid groups known in the art.
PGN is a suitable protection group for a NH2 moiety of for example amino or amide groups known in the art. Hereinafter, due to simplicity reasons, a NH2 moiety will be described as an amino moiety irrespective of the further parts of the compound.
M is a so called masked functional group such as - without being limited to - a -N02 group or a -N3 group. A masked functional group can be reduced under certain conditions to an -NH2 functional group but does not interfere with the coupling reactions of an acid partner with an amino partner, as discussed further below.
Protecting groups for use as PGN, PGH or PGA groups herein include, but are not limited to: (i) ethers such as methyl, substituted methyl (methoxymethyl, methylthiomethyl,
(phenyidimethylsilyl) methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, p-nitrobenzyloxymethyl, o-nitrobenzyloxymethyl, (4-methoxyphenoxy) methyl, guaia- colmethyl, t-butoxymethyl, 4- pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2,-trichloroethoxymethyl, bis(2-chloroethoxymethyl), 2-(trimethylsilyl)ethoxymethyl, menthoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1 -methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl,
4-methoxytetrahydrothiopyranyl S,S-dioxide, 1 -[(2-chloro-4-methyl)phenyl]-4-methoxy- piperidin-4-yl, 1 -(2-fluorophenyl)-4-methoxypiperidin-4-yl, 1 ,4-dioxan- 2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro- 7,8, 8-trimethyl-4, 7-methano-benzofuran- 2-yl), substituted ethyl (1 -ethoxyethyl,1 -(2-chloroethoxy) ethyl, 1 -[2-(trimethyl-silyl) ethoxy] ethyl, 1 -methyl-1 -methoxyethyl, 1 -methyl-1 -benzyloxyethyl, 1 -methyl-1 -benzyloxy-2-fluoro- ethyl, 1 -methyl-1 -phenoxyethyl, 2,2,2-trichloroethyl, 1 ,1 -dianisyl-2,2,2-trichloroethyl,
1 ,1 ,1 ,3,3,3-hexafluoro-2-phenylisopropyl, 2-trimethylsilylethyl, 2-(benzylthio)ethyl, 2-(phenyl- selenyl)ethyl), t-butyl, allyl, propargyl, p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, 2, 4-dinitrophenyl, 2,3,5,6- tetrafluoro-4-(trifluoromethyl)phenyl, benzyl, substituted benzyl (p-methoxybenzyl, 3,4,-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,
2,6-dichlorobenzyl, p-phenylbenzyl, p-phenylenzyl, 2,6-difluorobenzyl, p-acylaminobenzyl, p-azidobenzyl, 4-azido-3-chlorobenzyl, 2- trifluoromethylbenzyl, p- (methylsulfinyl) benzyl), 2- and 4-picolyl, 3-methyl-2-picolyl-N-oxido, 2-quinolinylmethyl, 1 -pyrenylmethyl, diphenyl- methyl, ρ,ρ'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl) methyl, 4-(4-'-bromophenacyloxy)phenyldiphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimido- phenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)- methyl, 4,4'-dimethoxy-3"-[N-(imidazolylmethyl)]trityl, 4,4'-dimethoxy-3"-[N-(imidazolylethyl) carbamoyl]trityl, 1 ,1 -bis(4-methoxyphenyl-l'-pyrenylmethyl, 9-Anthryl, 9-(9- phenyl) xanthenyl, 4-(17-tetrabenzo[a,c,g.lgfluorenylmethyl)-4, 4"-dimethoxytrityl, 9-(9-phenyl-10-oxo)anthryl,
1 .3- benzodithiolan-2-yl, benzisothiazolyl, s,s-dioxido, silylethers (trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyl- dimethylsilyl, t-butyidiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenyl- methylsilyl, di-t-butylmethylsilyl, tris(trimethylsilyl)silyl(sisyl), (2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl, t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl); (ii) esters such as formate, benzoylformate, acetate, substituted acetate (chloroacetate,
dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, phenylacetate, p-P-phenylacetate, diphenyl- acetate), nicotinate, 3-phenylpropionate, 4-pentenoate, 4-oxopentanoate (levulinate),
4.4- (ethylenedithio)pentanoate, 5-[3-bis(4-methoxyphenyl)hydroxymethylphenoxy]levulinate, pivaloate, 1 -adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate(mesitoate), carbonates (methyl, methoxymethyl, 9- fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 1 ,1 ,-dimethyl-2, 2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenyl- sulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4,-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, 2-dansylethyl,
2-(4-nitrophenyl)ethyl, 2-(2,4-dinitrophenyl)ethyl, 2-cyano-1 -phenylethyl, S-benzylthio- carbonate, 4-ethoxy-1 -naphthyl, methyldithiocarbonate), 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate,
2-(methylthiomethoxy)ethylcarbonate, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxy- methyl)benzoate, 2-(chloroacetoxymethyl)benzoate, 2-[(2-chloroacetoxy)ethyl]benzoate, 2-[2-(benzyloxy)ethyl]benzoate, 2-[2-(4-methoxybenzyloxy)ethyl]benzoate, 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4-(1 ,1 ,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1 ,1 - dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccionoate, (E)-2- methyl-2-butenoate (tigloate), o-(methoxycarbonyl) benzoate, p-P-benzoate, a-naphthoate, nitrate, alkyl Ν,Ν,Ν',Ν'-tetramethylphosphorodiamidate, 2-chlorobenzoate, 4-bromobenzoate, 4-nitrobenzoate, 3'5'-dimethoxybenzoin, a wild and woolly photolabile fluorescent ester, N-phenylcarbamate, borate, dimethylphosphinothioyl, 2, 4-dinitrophenylsulfenate; and (iii) sulfonates (sulfate, allylsulfonate, methanesulfonate (mesylate), benzylsulfonate, tosylate, 2-[(4-nitrophenyl)ethyl]sulfonate).
An activated carboxylic acid moiety in the context of the present specification relates to a carboxylic acid (COOH) derivative that undergoes amidation (condensation with an amine moiety) with primary or secondary under conditions that allow for the preservation of other chemical functionalities present in either reaction partner. Preferred reaction conditions are pH 4-9 and temperatures in the range of about -30° C to of about
80 ° C, in particular at temperatures from 25 °C to 30 °C.
Examples for activated carboxylic acid moieties are pentafluorophenol (PFP) esters, para- nitrophenol (PNP) esters, 2,4,5-trichlorophenol esters, N-Hydroxy-5-norbornene-2,3- dicarboximide (HONB) esters, N-hydroxy-succinimidyl (NHS) ester, carboxylic acid chloride
(acyl chloride), carboxylic acid fluoride (acyl fluoride), carboxylic acid bromide (acyl bromide), which may be produced - without being limited to - by the reaction of the carboxylic acid and thionyl chloride phosphorus pentachloride, cyanuric chloride, S02CI2, SOCI2,
triphenylphosphine and tetrachloromethane, Fluoro-Ν,Ν,Ν ,N -tetramethylformamidinium hexafluorophosphate (TFFH) or cyanuric fluoride, benzotriazole esters or carbodiimide esters, generated by use of the carboxylic acid and coupling agents such as
Benzotriazolyloxytris-(dimethylamino)-phosphonium hexafluoro-phosphate (BOB),
Benzotriazol-1 -yl-oxy-tripyrrolidinophosphonium hexafluorophosphate (pyBOP), Ν,Ν,Ν',Ν'-
Tetramethyl-0-(1 H-benzotriazol-1 -yl)uronium hexafluorophosphate (HBTU), (0-(7- azabenzotriazol-1 -yl)-/V,/V,/V,/V-tetramethyluronium hexafluorophosphate) (HATU), Λ/,/V-
Dicyclohexylmethandiimin (DCC), Ν,Ν'-Diisopropylcarbodiimide (DIC), 1 -Ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), or 3-(Diethoxyphosphoryloxy)-1 ,2,3-benzotriazin-
4(3H)-one (DEPT) bromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBrop). Furthermore carboxylic acid moieties can be activated with chloroformates (e.g. ethyl chloroformate).
Further examples of activated carboxylic moieties are symmetric and mixed carbonic anhydrides. Carbonic anhydrides may be synthesized by use of coupling reagents, such as - without being limited to - 1 ,1 '-Carbonyldiimidazol (CDI), 1 ,1 '-carbonylbis(3- methylimidazoliumtriflate) (CBMIT) and the before mentioned coupling agents or from carboxylic acid and acid chloride (e.g. pivaloylchloride), or from carboxylic acid and chloroformates (e.g. ethyl chloroformate). Alternatively anhydrides may be synthesized from carboxylic acid and 2-ethoxy-1 -ethoxycarbonyl-1 ,2-dihydroquinoline (EDDQ)
Coupling agents to achieve activated carboxylic moieties may further be - without being limited to - AOP (7-Azabenzotriazol-1 -yloxytris(dimethylamino)phosphonium
hexafluorophosphate - CAS 15631 1 -85-2), PyAOP ([(7-azabenzotriazol-1 -yl)oxy]tris- (pyrrolidino) phosphonium hexafluorophosphate CAS - 15631 1 -83-0), Brop
(bromotris(dimethylamino)phosphonium hexafluorophosphate, CAS 50296-37-2), PyBrop (bromotri(pyrrolidino)phosphonium hexafluorophosphate, CAS 132705-51 -2), PyClop (chlorotri(pyrrolidino)phosphonium hexafluorophosphate, CAS 128625-52-5), BOP-CI (N,N0- bis(2-oxo-3-oxazolidinyl)-phosphinic chloride, CAS 68641 -49-6), TDBTU (2-(3,4-dihydro-4- oxo-1 ,2,3-benzotriazin-3-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate, CAS: 125700-69- 8), TNTU (2-(5-norbornene-2,3-dicarboximido)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate - CAS 125700-73-4), TSTU (2-succinimido-1 ,1 ,3,3-tetramethyluroniumtetrafluoroborate - CAS 105832-38-0), BTC (bis(trichloromethyl)carbonate - CAS 32315-10-9), BTFFH
(bis(tetramethylene)fluoroformamidinium hexafluorophosphate - CAS 164298-25-3 ), DFIH (1 ,3-dimethyl-2-fluoro-4,5-dihydro-1 H-imidazoliumhexafluorophosphate)
Furthermore, imidazolium agents may be employed to achieve activated carboxylic moieties, whereby examples of imidazolium agents are - without being limited to - BOI (2- (benzotriazol-1 -yl)oxy-1 ,3-dimethylimidazolidinium hexafluorophosphate - CAS 123377-20-8) or CMBI (2-chloro-1 ,3-dimethyl 1 H-benzimidazoliumhexafluorophosphate).
The coupling reactions may be supported by addition of bases or acylation catalysts such as - without being limited to - (/V,/V-Diisopropylethylamine) (DIEA), N-Methylmorpholine (NMM), 4-Dimethylaminopyridine (DMAP), 2,4,6-Trimethylpyridine (sym-collidine) or 2,6-di- tert-butyl-4-dimethylaminopyridine (DBDMAP). The addition of bases allows a deprotonation of the carboxylic acid and facilitates the reaction to the respective activated carboxylic acid.
Furthermore, bases may be added, in particular the above mentioned bases, in order to prevent a removal of the protecting group due to acidic by products. In certain cases the coupling reaction may be catalyzed by addition of acylation catalysts as DMAP. Alternatively, the carboxylic acid moiety may be activated by using a catalytic amount of a proton acid or a Lewis acid such as - without being limited to - boronic acid catalyst.
The coupling reactions may also be achieved by the azide coupling method using diphenyl phosphorazidate (DPPA) or alternative azides.
The term "substituted" refers to the addition of a substituent group to a parent moiety.
"Substituent groups" can be protected or unprotected and can be added to one available site or to many available sites in a parent moiety. Substituent groups may also be further substituted with other substituent groups and may be attached directly or by a linking group such as an alkyl, an amide or hydrocarbyl group to a parent moiety. "Substituent groups" amenable herein include, without limitation, halogen, oxygen, nitrogen, sulphur, hydroxyl, alkyl, alkenyl, alkynyl, acyl (-C(0)Ra), carboxyl (-C(0)ORa), aliphatic groups, alicyclic groups, alkoxy, substituted oxy (-ORa), aryl, aralkyl, heterocyclic radical, heteroaryl, heteroarylalkyl, amino (-N(Rb)(Rc)), imino(=NRb), amido (-C(0)N(Rb)(Rc) or -N(Rb)C(0)Ra), hydrazine derivates (-C(NH)NRaRb), tetrazole (CN4H2), azido (-N3), nitro (-N02), cyano (-CN), isocyano (-NC), cyanato (-OCN), isocyanato (-NCO), thiocyanato (-SCN); isothio- cyanato (-NCS); carbamido (-OC(0)N(Rb)(Rc) or -N(Rb)C(0)ORa), thiol (-SRb),
sulfinyl (-S(0)Rb), sulfonyl (-S(0)2Rb), sulfonamidyl (-S(0)2N(Rb)(Rc)or -N(Rb)S(0)2Rb) and fluorinated compounds -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F, -CF3, -OCF3, -SCF3, -SOCF3 or -S02CF3. Wherein each Ra, Rb and Rc is, independently, H or a further substituent group with a preferred list including without limitation, H, alkyl, alkenyl, alkynyl, aliphatic, alkoxy, acyl, aryl, heteroaryl, alicyclic, heterocyclic and heteroarylalkyl.
As used herein the term "alkyl," refers to a saturated straight or branched hydrocarbon moiety containing up to 8, particularly up to 4 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, butyl, isopropyl, n-hexyl, octyl, and the like. Alkyl groups typically include from 1 to about 8 carbon atoms (CrC8 alkyl), particularly with from 1 to about 4 carbon atoms (Ci-C4 alkyl).
As used herein the term "cycloalkyi" refers to an interconnected alkyl group forming a saturated or unsaturated ring or polyring structure containing 3 to 10, particularly 5 to 10 carbon atoms. Examples of cycloalkyi groups include, without limitation, cyclopropane, cyclopentane, cyclohexane, norbornane, decaline or adamantan (Tricyclo[3.3.1 .1 ]decan), and the like. Cycloalkyi groups typically include from 5 to 10 carbon atoms (C5-C10 cycloalkyi).
Alkyl or cycloalkyi groups as used herein may optionally include further substituent groups. A substitution on the cycloalkyi group also encompasses an aryl, a hetreocylce or a heteroaryl substituent, which can be connected to the cycloalkyi group via one atom or two atoms of the cycloalkyi group (like tetraline).
As used herein the term "haloalkyi," refers to a saturated straight or branched hydrocarbon moiety containing 1 to 8, particularly 1 to 4, carbon atoms and at least one halogen atom, in particular CI or F, connected to a carbon atom. Examples of haloalkyi groups include, without limitation, CF3, CHF2, CH2F, CH2CF3, CH2CHF2, CH2CH2F, CHFCF3, CHFCHF2, CHFCH2F, CF2CF3, CF2CHF2, CF2CH2F and the like. Haloalkyi groups typically include 1 to 4 carbon atoms (C1 -C4 haloalkyi). More particularly haloalkyi groups comprise only F as halogen atoms.
As used herein the term "halo cycloalkyi" refers to an interconnected alkyl group forming a saturated or unsaturated ring or polyring structure containing 3 to 10, particularly 5 to 10 carbon atoms and at least one halogen atom, in particular CI or F, connected to a carbon atom. Examples of halo cycloalkyi groups include, without limitation, fluorocyclopropane, chlorocyclohexane, dichlorocyclohexane, chloroadamantan, and the like. Halo cycloalkyi groups typically include from 5 to 10 carbon atoms (C5-C10 cycloalkyi). More particularly cyclohaloalkyl groups comprise only F as halogen atoms.
Halo alkyl or halo cycloalkyi groups as used herein may optionally include further substituent groups. A substitution on the halo cycloalkyi group also encompasses an aryl, a hetreocylce or a heteroaryl substituent, which can be connected to the halo cycloalkyi group via one atom or two atoms of the halo cycloalkyi group (like tetraline).
As used herein the term "alkenyl," refers to a straight or branched hydrocarbon chain moiety containing up to 8 carbon atoms and having at least one carbon-carbon double bond.
Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, 1 -methyl-2- buten-1 -yl, dienes such as 1 ,3-butadiene and the like. Alkenyl groups typically include from 2 to about 8 carbon atoms, more typically from 2 to about 4 carbon atoms. Alkenyl groups as used herein may optionally include further substituent groups.
As used herein the term "alkynyl," refers to a straight or branched hydrocarbon moiety containing up to 8 carbon atoms and having at least one carbon-carbon triple bond.
Examples of alkynyl groups include, without limitation, ethynyl, 1 -propynyl, 1 -butynyl, and the like. Alkynyl groups typically include from 2 to about 8 carbon atoms, more typically from 2 to about 4 carbon atoms. Alkynyl groups as used herein may optionally include further substituent groups.
As used herein the term "carboxy," refers to an carboxy (-C(=0)-0- or -0-C(=0)-) alkyl moiety containing 1 to 8, particularly 1 to 4 carbon atoms comprising at least one carboxy moiety, wherein the carboxy group is used to attach the carboxy group to a parent molecule. Examples of carboxy groups include without limitation, formate, acetate, lactate, citrate, oxalate and the like. Carboxy groups as used herein may optionally include further substituent groups. In particular "carboxy" groups include straight or branched polycarboxy groups (polyester), which comprise several interconnected momomere carboxy groups (e. g. -C(=0)-0-CH2-CH2-). Non limiting examples are polyehtylester or polyacrylate.
As used herein the term "alkoxy," refers to an oxygen alkyl moiety containing 1 to 8, particularly 1 to 4 carbon atoms comprising at least one oxygen moiety, wherein the oxygen atom is used to attach the alkoxy group to a parent molecule. Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert- butoxy, n-pentoxy, neopentoxy, n-hexoxy and the like. Alkoxy groups as used herein may optionally include further substituent groups. In particular "alkoxy" groups include straight or branched polyalkoxy groups (polyether), which comprise several interconnected momomere alkoxy groups (e. g. -0-CH2-CH2-). Non limiting examples are polyehtyleneglycol (PEG) or polypropylenglycol (PPG).
As used herein the term "heterocycle" refers to an interconnected alkyl group forming a saturated or unsaturated ring or polyring structure containing 3 to 10, particularly 5 to 10 carbon atoms in which at least one carbon atom is replaced with an oxygen, a nitrogen or a sulphur atom forming a non aromatic structure. Examples of heterocycle groups include, without limitation, oxalane, pyrrolidine or piperidine. Heterocyclic groups as used herein may optionally include further substituent groups. A substitution on the heterocyclic group also encompasses an aryl, a cycloalkyl or a heteroaryl substituent, which can be connected to the heterocyclic group via one atom or two atoms of the heterocyclic group (comparable to indole).
As used herein the term "aryl" refers to a hydrocarbon with alternating double and single bonds between the carbon atoms forming an aromatic ring structure, in particular a six (Ce to ten (Cio) membered ring or polyring structure. The term "heteroaryl" refers to aromatic structures comprising a five to ten membered ring or polyring structure, comparable to aryl compounds, in which at least one member is an oxygen or a nitrogen or a sulphur atom. Due to simplicity reasons they are denominated C5 to Cio heteroaryl, wherein at least one carbon atom is replaced with an oxygen, a nitrogen or a sulphur atom forming an aromatic structure. For example a C5 heteroaryl comprises a five membered ring structure with at least one carbon atom being replaced with an oxygen, a nitrogen or a sulphur atom. Examples for such a C5 heteroaryl are triazole, pyrazole, imidazole, thiophen, furan or oxazole. A C6 heteroaryl can be pyridine, pyrimidine or triazine. A C9 heteroaryl can be indole and a Cio heteroaryl can be quinoline. Aryl or hetero aryl groups as used herein may optionally include further substituent groups. A substitution on the hetero aryl group also encompasses an aryl, a cycloalkyl or a heterocycle substituent, which can be connected to the hetero aryl via one atom or two atoms of the hetero aryl group (comparable to indole). The same apllies to an aryl group.
As used herein the term "linker" refers to a covalently connected straight chain or a ring structure of carbon, sulphur, nitrogen and/or oxygen atoms connecting a moiety comprising E or R4 (as defined below) to the parent moiety (termed PM) providing a distance between these moieties. The distance may comprise between 1 up to 5 atoms, in particular 2 or 3 atoms, along the longitudinal extension direction of the parent moiety. The straight chain or the ring structure of the linker atoms may comprise further substituents. For example the linker may comprise a straight C4-chain (butyl) providing a distance of 4 atoms or a methyl group providing a distance of 1 atom. The linker may further comprises a -C(=0)N(CH3)- or -C(=0)N(H)- group a providing a distance of 2 atoms. A -N(H)S(02)- group also provides a distance of 2 atoms. A distance of three atoms may be provided by a -OC(=0)N(H)- or -N(H)C(=0)N(H)- group. The linker may further comprise a ring structure like a triazole providing a distance of 3 atoms along the longitudinal extension direction of the parent moiety.
As used herein the term "linking function" refers to a first linking function and a second linking function capable of selectively forming a covalent bond between each other (linking reaction or coupling reaction). Such linking reactions may be an organometallic coupling reaction, a Wittig reaction, an addition reaction, a condensation reaction a "click chemistry" reaction or an amide coupling reaction.
As used herein "*" indicates a stereo center of a L- or D- enantiomer, which is located on the tertiary carbon atom below the asterisk *, and wherein the compound of a general formula comprising "*" is an essentially pure L-enantiomer, an essentially pure D-enantiomer or a mixture of the L- and D-enantiomer of the same molecular formula, wherein in particular such a compound is an essentially pure L-enantiomer or an essentially pure D-enantiomer.
SUMMARY OF THE INVENTION
According to a first aspect, the invention relates to antibiotically active compounds having a molecular structure as defined by formula 1
X-BB— D— BC— D— BD— D— BE— X2
(1 ),
a. with X1 being
i. selected from a substituent group S1 or S2, or
ii. R4-D1-, with R4 being selected from a substituent group S3, S4 or S5, or iii. BA-D - with BA-D -being selected from
Figure imgf000011_0001
with E being selected from a substituent group S3, S4 or S5, and
with BB being selected from a substituent group S3 or S4, and
with BC
being selected from
Figure imgf000011_0002
with p being 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and with r being 2, 3, 4 or 5, in particular r being 2, or
with -D2-BC- being
Figure imgf000011_0003
with p being 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and
d. with BD being selected from a substituent group S3 or S4, and
e. with BE being selected from a substituent group S3, and
f. with X2 being i. selected from a substituent group S1 or S2, and wherein a linker D5 may be optionally situated between BE and the substituent group S1 or S2, or
ii. being -D5-BF, wherein BF is selected from a substituent group S2
with S1 being
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -N02, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2CH3 or -CF3,
with S2 being
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, - (CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, - (CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, -(CH2)m-OC(=S)NRaRb, - (CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, -(CH2)m-S(02)Ra, -(CH2)m- S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, -(CH2)m-NRaRb, -(CH2)m- NRcC(=0)Ra, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m-NRcC(=0)ORa, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m-NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m- P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)- (M)-C(=0)OH, -(CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0- (CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa
- with Raa being selected independently from each other from -Ra or -ORa,
- with Rba being selected independently from each other from -Rb or -ORb,
- with M being a substituted or unsubstituted CrC8 alkyl, in particular an
unsubstituted CrC8 alkyl,
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 ,
- with each Ra, Rb or Rc being selected, where applicable, independently from each other from hydrogen, -CN, a substituent group S3, a substituent group S4 or a substituent group S5,
with S3 being
- a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3- Cio halo cycloalkyl, or
a substituted or unsubstituted C6-Cio aryl, with S4 being
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3- C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
- a substituted or unsubstituted C5-C10 heteroaryl,
with S5 being
- a substituted or unsubstituted C1-C16 alkyl, a substituted or unsubstituted C1-C16 alkoxy, a substituted or unsubstituted C1-C16 carboxy, a substituted or unsubstituted C2-C16 alkenyl, a substituted or unsubstituted C2-Ci 6 alkynyl, or a C1-C16 haloalkyl, with R2 and R3 of BA being selected, where applicable, independently from each other from - H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl , in particular from -H, -F, - CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or - CF3,more particularly with R2 and R3 being selected independently from each other from -H, -F or -CH3,
with L , L2, L3, L4 or L5 being selected independently from each other from,-H, -CH3, - CH2CH2CH2NHC(NRc)N(Rb)(Ra), -CH2CON(Rb)(Ra), -CH2C(=0)ORa, -CH2SRa, - CH2CH2C(=0)N(Rb)(Ra), -CH2CH2C(=0)ORa, -CH2(C3H3N2), -CH2CH2CH2CH2, - CH2CH2SCH3, -CH2(C6H5), -CH2CH2CH2-, -CH2ORa, -CH(ORa)CH3, -CH2(C8H6N)ORa, - CH2(C6H4)ORa, -CH(CH3)2, -CCH, -CN, -OCH3 -CF3, -Ra, -CH(Rb)(Ra), -CH2C(=0)Ra, - C(=0)ORa, -OC(=0)NRbRa, -C(=0)NRbRa, -CH2C(=0)NRb (ORa), -CH2S(02)Ra, -S(02)ORa, - CH2S(02)ORa, -CH2NRbC(=0)Ra, -CH2NRbS(02)Ra, -CH2P(=0)(ORb)(ORa), - CH2P(=0)(ORb)(Ra), -CH2P(=0)(Rb)(Ra) or -CH2S(02)NRbRa,
- with Ra and Rb being selected, where applicable, independently from each other from hydrogen, -CN, a substituent group S3, a substituent group S4 or a substituent group S5,
- with R8 of -D2-BC- being selected from -H, -CH3, -CH2CH3, -OCH3, -OCF3, -CH2CF3, - CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with R8 being selected from H or CH3, more particularly R8 is H.
with Y being selected from -CN, -C(=0)OH, -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)NHCH3, - C(=0)NHCH2CH3, -C(=0)N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3), -CF3 or - C(=0)NH2, and with Z being selected from -H, -OH, -CH3, -CH2CH3, -OCH3 -NH2 -NHCH3, -N(CH3)2 or - N(CH3)3 +, in particular Z is -H and Y is -CN or -C(=0)NH2,
with D ,D2, D3, D4 or D5 being each, independently from each other, a linker which comprises carbon, sulphur, nitrogen, phosphor and/or oxygen atoms and which is covalently connecting the moiety, BA and BB (D ), BB and BC (D2), BC and BD (D3), BD and BE (D4) and BE and BF (D5).
It is understood that a general expert will identify - on basis of his basic knowledge - combinations of the above mentioned selection, which will not lead to stable compounds. For example, concerning X the substituents -NRa 2 and -NHRa are not possible with a C2 alkynyl. Furthermore, concerning E connected to a vinyl group a C3 heterocycle, like aziridine, is not a stable compound. The same applies for other combinations.
It is understood that the invention relates to compounds characterized by the general formula 1 , wherein these compounds comprise no deuterium atoms in their structure. Furthermore the compounds may comprise one, two or more deuterium atoms (any hydrogen of the structure may be "exchanged") instead of hydrogen atoms. It is also possible that the compounds comprise only deuterium atoms instead of hydrogen atoms (all the H are "exchanged" with deuterium).
It is understood that the invention relates to essentially pure L- and D- enantiomers of the general formula 1 or mixtures of the L- and D-enantiomers of the same molecular formula, whereby the stereo center concerning the building block BC is indicated by an asterisk "*" and located on the tertiary carbon atom below the asterisk. Thus, the general formula 1 with the stereo center marked with an asterisk encompasses the essentially pure L- and the D- enantiomers.
A second aspect of the invention relates to the synthesis of compounds according to the general formula 1 .
A further aspect of the invention relates to compounds according to the invention or obtained by a method according to the invention for use in a method of treatment of diseases, in particular for use in a method of treatment of bacterial infections.
DETAILED DESCRIPTION OF THE INVENTION
According to a first aspect, the invention relates to antibiotically active compounds having a molecular structure as defined by formula 1
X— BB— D— BC— D— BD— D— BE— X2
(1 ), a. with X1 being
i. selected from a substituent group S1 or S2, or
ii. R4-D1-, with R4 being selected from a substituent group S3, S4 or S5, or iii. BA-D - with BA-D -being selected from
Figure imgf000015_0001
with E being selected from a substituent group S3, S4 or S5, and
with BB being selected from a substituent group S3 or S4, and
with BC
being selected from
Figure imgf000015_0002
with p being 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and with r being 2, 3, 4 or 5, in particular r being 2, or
with -D2-BC- being
Figure imgf000015_0003
with p being 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and
d. with BD being selected from a substituent group S3 or S4, and e. with BE being selected from a substituent group S3, and
f. with X2 being
i. selected from a substituent group S1 or S2, and wherein a linker D5 may be
optionally situated between BE and the substituent group S1 or S2, or ii. being -D5-BF, wherein BF is selected from a substituent group S2
with S1 being
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -N02, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2CH3 or -CF3,
with S2 being
-B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, - (CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, - (CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, -(CH2)m- OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, -(CH2)m- S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, -(CH2)m- NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa , -(CH2)m-NRcC(=0)NRaRb, - (CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m-NRcC(=S)ORa, -(CH2)m- NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or -(CH2)m- S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, -(CH2)m-0-C(=0)-(M)-C(=0)ORa, - (CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0- (CH2)q-S(02)ORa„
- with Raa being selected independently from each other from -Ra or -ORa,
- with Rba being selected independently from each other from -Rb or -ORb,
- with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl,
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 ,
- with each Ra, Rb or Rc being selected, where applicable, independently from each other from hydrogen, -CN, a substituent group S3, a substituent group S4 or a substituent group S5,
with S3 being - a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3- C10 halo cycloalkyl, or
- a substituted or unsubstituted C6-Cio aryl,
with S4 being
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3- C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
- a substituted or unsubstituted C5-C10 heteroaryl,
with S5 being
- a substituted or unsubstituted C1-C16 alkyl, a substituted or unsubstituted C1-C16 alkoxy, a substituted or unsubstituted C1-C16 carboxy, a substituted or unsubstituted C2-C16 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C1-C16 haloalkyl, with R2 and R3 of BA being selected, where applicable, independently from each other from - H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl , in particular from -H, -F, - CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or - CF3,more particularly with R2 and R3 being selected independently from each other from -H, -F or -CH3,
with L , L2, L3, L4 or L5 being selected independently from each other from,-H, -CH3, - CH2CH2CH2NHC(NRc)N(Rb)(Ra), -CH2CON(Rb)(Ra), -CH2C(=0)ORa, -CH2SRa, - CH2CH2C(=0)N(Rb)(Ra), -CH2CH2C(=0)ORa, -CH2(C3H3N2), -CH2CH2CH2CH2, - CH2CH2SCH3, -CH2(C6H5), -CH2CH2CH2-, -CH2ORa, -CH(ORa)CH3, -CH2(C8H6N)ORa, - CH2(C6H4)ORa, -CH(CH3)2, -CCH, -CN, -OCH3 -CF3, -Ra, -CH(Rb)(Ra), -CH2C(=0)Ra, - C(=0)ORa, -OC(=0)NRbRa, -C(=0)NRbRa, -CH2C(=0)NRb (ORa), -CH2S(02)Ra, -S(02)ORa, - CH2S(02)ORa, -CH2NRbC(=0)Ra, -CH2NRbS(02)Ra, -CH2P(=0)(ORb)(ORa), - CH2P(=0)(ORb)(Ra), -CH2P(=0)(Rb)(Ra) or -CH2S(02)NRbRa,
- with Ra and Rb being selected, where applicable, independently from each other from hydrogen, -CN, a substituent group S3, a substituent group S4 or a substituent group S5,
- with R8 of -D2-BC- being selected from -H, -CH3, -CH2CH3, -OCH3, -OCF3, -CH2CF3, - CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with R8 being selected from H or CH3, more particularly R8 is H. with Y being selected from -CN, -C(=0)OH, -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)NHCH3, - C(=0)NHCH2CH3, -C(=0)N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3), -CF3 or - C(=0)NH2, and
with Z being selected from -H, -OH, -CH3, -CH2CH3 , -OCH3 ,-NH2 -NHCH3, -N(CH3)2 or - N(CH3)3 +, in particular Z is -H and Y is -CN or -C(=0)NH2,
with D ,D2, D3, D4 or D5 being each, independently from each other, a linker which comprises carbon, sulphur, nitrogen, phosphor and/or oxygen atoms and which is covalently connecting the moiety, BA and BB (D ), BB and BC (D2), BC and BD (D3), BD and BE (D4) and BE and BF (D5).
In an embodiment of the present invention the compound according to the general formula 1 does not include a compound of the general formula 2a
Figure imgf000018_0001
or the general formula 2b
Figure imgf000018_0002
wherein R is H or CO(NH2), R2 is CO(NH2) or CN, R3 is H or OCH3, FN is H2N or Ma, wherein Ma is a masked functional group, in particular a -N02 or -N3 moiety, and wherein the -NH2, - NH-, -COOH or -OH moieties can comprise a removable protecting group (PGN, PGH or PGA), in particular an allyl moiety and/or an activated carboxylic acid moiety COact in particular a - COCI moiety.
According to a first sub aspect (sub aspect 1 ) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (3),
Figure imgf000019_0001
(formula 3), with X1 , D2, BC, D3, BD, D4, BE, D5 and BF having the same meaning as defined previously.
According to another sub aspect (sub aspect 2) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (4),
Figure imgf000019_0002
(formula 4), with X1 , R8, BC, D3, BD, D4, BE, D5 and BF having the same meaning as defined previously.
According to another sub aspect (sub aspect 3) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (5),
Figure imgf000019_0003
(formula 5), with X1 , D2, BC, D3, D4, BE, D5 and BF having the same meaning as defined previously.
According to another sub aspect (sub aspect 4) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (6),
Figure imgf000019_0004
(formula 6), with X1 , R8, BC, BE, D5 and BF having the same meaning as defined previously. According to another sub aspect (sub aspect 5) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (7),
Figure imgf000020_0001
(formula 7), with X1 , D2, BC, D3, D4, R n, D5 and BF having the same meaning as defined previously or further below.
According to another sub aspect (sub aspect 6) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (8),
Figure imgf000020_0002
with X1 , R8, BC, R n, D5 and BF having the same meaning as defined previously or further below.
According to another sub aspect (sub aspect 7) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (9),
Figure imgf000020_0003
(formula 9), with X1 , D2, BC, D3, D4, R , D5 and BF having the same meaning as defined previously or further below. According to another sub aspect (sub aspect 8) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (10),
Figure imgf000021_0001
(formula 10), with X1 , R8, BC, R , D5 and BF having the same meaning as defined previously or further below.
According to another sub aspect (sub aspect 9) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (1 1 ),
Figure imgf000021_0002
(formula 1 1 ), with X1 , R8, BC, D5 and BF having the same meaning as defined previously.
According to another sub aspect (sub aspect 10) of the first aspect, the invention relates to antibiotically active compounds having a molecular structure as defined by a general formula (12),
Figure imgf000021_0003
(formula 12), with X1 , D2, BC, D3, D4, R , R 0 n, T and D5 having the same meaning as defined previously or further below. According to another sub aspect (sub aspect 1 1 ) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (13),
Figure imgf000022_0001
(formula 13), with E, R2, R3, D1 , D2, BC, D3, D4, R11 , R 0 n, T and D5 having the same meaning as defined previously or further below.
According to another sub aspect (sub aspect 12) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (14),
Figure imgf000022_0002
(formula 14), with R2, R3, D1 , D2, BC, D3, D4, R n, R11 , R 0 n, T and D5 having the same meaning as defined previously or further below.
According to another sub aspect (sub aspect 13) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (15),
Figure imgf000022_0003
(formula 15), with Y, Z, R2,R3, D1 , D2, D3, D4, R11 , R 0 n, R n, T and D5 having the same meaning as defined previously or further below.
According to another sub aspect (sub aspect 14) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (16),
Figure imgf000023_0001
(formula 16),
with X1 , R8, BC and BF having the same meaning as defined previously.
According to another sub aspect (sub aspect 15) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (17),
Figure imgf000023_0002
(formula 17),
with X1 , R8, D2, BC, D3, D5 and BF having the same meaning as defined previously.
According to another sub aspect (sub aspect 16) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (18),
Figure imgf000023_0003
(formula 18),
with X1 , R8, BC, D5 and BF having the same meaning as defined previously. According to another sub aspect (sub aspect 17) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (19),
Figure imgf000024_0001
(formula 19),
with X1 , R8, BC, R 0n, and T having the same meaning as defined previously or further below.
According to another sub aspect (sub aspect 18) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (20),
Figure imgf000024_0002
(formula 20),
with X1 , R8, BC, R 0 and T having the same meaning as defined previously or further below.
According to another sub aspect (sub aspect 19) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (21 ),
Figure imgf000024_0003
(formula 21 ),
with X1 , R8, BC, R n, R 0 n and T having the same meaning as defined previously or further below. According to another sub aspect (sub aspect 20) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (22),
Figure imgf000025_0001
(formula 22),
with X1 , R8, BC and T having the same meaning as defined previously or further below.
According to another sub aspect (sub aspect 21 ) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (23),
Figure imgf000025_0002
(formula 23),
with X1 , R8, BC, D4, D5, R n, R 0 n and T having the same meaning as defined previously or further below.
According to another sub aspect (sub aspect 22) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (24),
Figure imgf000025_0003
(formula 24),
with X1 , R8, BC, D4, D5, R , R 0 and T having the same meaning as defined previously or further below. According to another sub aspect (sub aspect 23) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (25),
Figure imgf000026_0001
(formula 25),
with X1 , R8, BC, R , R 0 and T having the same meaning as defined previously or further below.
According to another sub aspect (sub aspect 24) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (26),
Figure imgf000026_0002
(formula 26), with E, R2, R3, D , R8, BC, R n, R 0 n and T having the same meaning as defined previously or further below.
According to another sub aspect (sub aspect 25) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (27),
Figure imgf000026_0003
with E, R2, R3, D , R8, BC, R , R 0 and T having the same meaning as defined previously or further below. According to another sub aspect (sub aspect 26) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (28),
Figure imgf000027_0001
(formula 28), with E, R2, R3, D , R8, BC, R 0 and T having the same meaning as defined previously or further below.
According to another sub aspect (sub aspect 27) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (29),
Figure imgf000027_0002
(formula 29), with R n, R 0n, R n, R2, R3, D , R8, BC and T having the same meaning as defined previously or further below.
According to another sub aspect (sub aspect 28) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (30),
Figure imgf000027_0003
with R n, R , R 0, D , R2, R3, R8, BC and T having the same meaning as defined previously or further below. According to another sub aspect (sub aspect 29 of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (31 ),
Figure imgf000028_0001
(formula 31 ), with R n, R , R 0, R2, R3, R8, BC and T having the same meaning as defined previously or further below.
According to another sub aspect (sub aspect 30) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (32),
Figure imgf000028_0002
(formula 32), with R n, R2, R3, D , R8, BC and T having the same meaning as defined previously or further below.
According to another sub aspect (sub aspect 31 ) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (33),
Figure imgf000028_0003
(formula 33), with R n, R2, R3, R8, BC and T having the same meaning as defined previously or further below. According to another sub aspect (sub aspect 32) of the first aspect, the invention relates to compounds having a molecular structure as defined by a general formula (34),
Figure imgf000029_0001
(formula 34), with R , R n, R , R 0, Z, Y and T having the same meaning as defined previously or further below.
In some embodiments, in particular according to any one of the sub aspects 1 to 10 or 14 to
23, X1 is
- -OH-OH, -F, -CI, -Br, I, -CCH, -CN, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, - CH2CH3 or -CF3,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, -(CH2)m- OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m- OC(=S)Ra, -(CH2)m-OC(=S)ORa, -(CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m- SRa, -(CH2)m-S(=0)Ra, -(CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m- OS(02)ORa, -(CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa, -(CH2)m- NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m-NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or -(CH2)m- S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, -(CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m- 0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa, with Raa being selected independently from each other from -Ra or -ORa, with Rba being selected independently from each other from -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl,
with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 , with each Ra, Rb or Rc being selected, where applicable, independently from each other from
hydrogen, -CN,
a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
a substituted or unsubstituted C6-Ci o aryl,
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl,
a substituted or unsubstituted C1 -C16 alkyl, a substituted or unsubstituted Cr C16 alkoxy, a substituted or unsubstituted C1 -C16 carboxy, a substituted or unsubstituted C2-Ci 6 alkenyl, a substituted or unsubstituted C2-Ci 6 alkynyl, or a C1 -C16 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2- C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl.
In some embodiments, in particular according to any one of the sub aspects 1 to 10 or 14 to
23, X1 is
- -NRa 2, -NH Ra, -C(=0)ORa or -ORa,
with Ra being a substituted or unsubstituted C1 -C16 alkyl, a substituted or unsubstituted C1 -C16 alkoxy, a substituted or unsubstituted C1 -C16 carboxy, a substituted or unsubstituted C2-Ci 6 alkenyl, a substituted or unsubstituted C2-Ci 6 alkynyl, or a C1 -C16 haloalkyl, in particular a substituted or unsubstituted Ci -C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or a substituted or unsubstituted C5-C10 heteroaryl, in particular a substituted or unsubstituted 1 ,2,3-triazole, a substituted or unsubstituted 1 ,2,4-triazole, a substituted or unsubstituted indole, a substituted or unsubstituted isoindole, a substituted or unsubstituted quinoline or a substituted or unsubstituted isoquinoline, or -[(CH2)m1-0-C(=0)-(CH2)m2]p1-C(=0)ORd or -[(CH2)m1-0-(CH2)m2]p1-ORd with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8
In some embodiments, in particular according to any one of the sub aspects 1 to 10 or 14 to
23, X1 is
- -NRa 2, -NHRa or -C(=0)ORa, in particular X is -NRa 2 or -NHRa,
- with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl.
In some embodiments, in particular according to any one of the sub aspects 1 to 10 or 14 to 23, X1 is R4-D1-, with D having the same meaning as defined above, and wherein
R4 is
a substituted or unsubstituted C Ci6 alkyl, a substituted or unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C Ci6 haloalkyl, in particular a substituted or unsubstituted Ci-C8 alkyl, a substituted or unsubstituted Ci-C8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted CrC8 haloalkyl, a substituted or unsubstituted C3-Cio cycloalkyl, or a substituted or unsubstituted C3-Cio halo cycloalkyl.
a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Ci0 halo heterocycle, in particular a substituted or unsubstituted C4-Ci0 heterocycle or a substituted or unsubstituted C4-Cio halo heterocycle, or
a substituted or unsubstituted C5-Cio heteroaryl, or
a substituted or unsubstituted C6-Cio aryl.
In some embodiments, in particular according to any one of the sub aspects 1 to 10 or 14 to 23, X1 is R4-D1-, with D having the same meaning as defined above, and wherein
R4 is
a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F, a substituted or unsubstituted C5-C6 heteroaryl,
a substituted C6 aryl, in particular a bicyclic C6 aryl such as tetraline or indane, a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F; or
R4 is selected from the group of substituted or unsubstituted pyrrole, furan, thiophene, benzothiophene, chromene, thiazole, pyrazine, pyridazine, pyridine, 1 ,2,3-triazole, 1 ,2,4- triazole, imidazole, oxazol, thiazol, indole, isoindole, quinoline, isoquinoline,
naphatalene, coumarin, aminocoumarin, umbelliferon, benzotriazole, psoralen, benzofurane, benzothiophene, benzimidazol, benzthiazole, benzoxazole or
benzpyridazin or hydroxylated, methylated or halogenated derivatives thereof.
In some embodiments, in particular according to any one of the sub aspects 1 to 10 or 14 to 23, X1 is R4-D1-, with D having the same meaning as defined above, and wherein
R4 is
a substituted or unsubstituted CrC5 alkyl or a substituted or unsubstituted C6-Ci o cycloalkyl, a substituted or unsubstituted C5-C10 heteroaryl or a substituted or unsubstituted C6-Ci o aryl, in particular R4 is selected from
Figure imgf000032_0001
In some embodiments, in particular according to any one of the sub aspects 1 to 10 or 14 to 23, X1 is R4-D1-, with D having the same meaning as defined above, and wherein
R4 is
an unsubstituted C1 -C5 alkyl or an unsubstituted C6-Ci o cycloalkyl. In some embodiments, in particular according to any one of the sub aspects 1 to 10 or 14 to 23, X1 is BA-D -, with D having the same meaning as defined above, and BA is selected from
Figure imgf000033_0001
in particular BA is selected from
Figure imgf000033_0002
more particularly BA is
Figure imgf000033_0003
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyi, in particular with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, - NH2, -NO2, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 and R3 being selected independently from each other from -H, -F or -CH3, and a. E is
- a substituted or unsubstituted C1-C16 alkyl, a substituted or unsubstituted C1-C16 alkoxy, a substituted or unsubstituted C1-C16 carboxy, a substituted or
unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a Ci- C16 haloalkyi, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted CrC8 haloalkyl, a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C3-C10 halo cycloalkyl,
- a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl,
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle; in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle,
- a substituted or unsubstituted C5-C10 heteroaryl;
- a substituted or unsubstituted C6-Ci o aryl, or
E is
a substituted or unsubstituted Ci -C8 alkyl, a substituted or unsubstituted Ci -C8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted Ci -C8 haloalkyl, or
E is
a substituted or unsubstituted C1 -C5 alkyl, a substituted or unsubstituted C6-Ci o cycloalkyl, a substituted or unsubstituted C5-C10 heteroaryl or a substituted or unsubstituted C8-Ci o aryl, or
E is
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted C6 aryl, in particular a bicyclic C6 aryl such as tetraline or indane,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
- selected from the group of substituted or unsubstituted pyrrole, furan, thiophene, benzothiophene, chromene, thiazole, pyrazine, pyridazine, pyridine, 1 ,2,3-triazole, 1 ,2,4-triazole, imidazole, oxazol, thiazol, indole, isoindole, quinoline, isoquinoline, naphatalene, coumarin, aminocoumarin, umbelliferon, benzotriazole, psoralen, benzofurane, benzothiophene, benzimidazol, benzthiazole, benzoxazole or benzpyridazin or hydroxylated, methylated or halogenated derivatives thereof, or is selected from .
Figure imgf000035_0001
- with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n being 1 , and
- with each R independently from any other R being selected from
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2-CH3, -CF3, -OCONH2 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m- C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, - (CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, - (CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa, -(CH2)m- NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m- NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m- P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, - (CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), ), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl with m being selected from 0, 1 or 2, in particular 0 or 1 , with q being selected from 0, 1 or 2, in particular 0 or 1 ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen, -CN
- a substituted or unsubstituted C Ci6 alkyl, a substituted or
unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C Ci6 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted CrC8 haloalkyl, a substituted or unsubstituted C3- Cio cycloalkyl, or a substituted or unsubstituted C3-Cio halo cycloalkyl,
- a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl,
- a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Cio halo heterocycle, in particular a substituted or unsubstituted C4-Ci0 heterocycle or a substituted or unsubstituted C4-Cio halo heterocycle,
- a substituted or unsubstituted C5-Cio heteroaryl,
- a substituted or unsubstituted C6-Cio aryl, in particular
- with each R independently from any other R being -OH, -F, -CI, I, -CN, -OCH3, - OCF3, -OCONH2 or -CF3.
is
Figure imgf000036_0001
- with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly 1 , and
- each R independently from any other R is selected from - -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2-CH3, -CF3, -OCONH2 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m- C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, - (CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m- C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, - (CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, - (CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa, -(CH2)m- NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m- NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m- P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, - (CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl
with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen, -CN
- a substituted or unsubstituted C Ci6 alkyl, a substituted or
unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C Ci6 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted CrC8 haloalkyl, a substituted or unsubstituted C3- Cio cycloalkyl, or a substituted or unsubstituted C3-Cio halo cycloalkyl, - a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl,
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle,
- a substituted or unsubstituted C5-C10 heteroaryl,
- a substituted or unsubstituted C6-Ci o aryl, or
is
Figure imgf000038_0001
- with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n 1 , and
- with each R independently from any other R being selected from
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NH CH3, -N(CH3)2, - CH3, -CH2-CH3, -CF3, -OCONH2 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)ORa, -(CH2)m- OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m- C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, - (CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, - (CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m- NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m-NRcC(=S)ORa, -(CH2)m- NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or -(CH2)m- S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, -(CH2)m-0-C(=0)-(M)- C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), - (CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-S(02)OH or - (CH2)m-C(=0)0-(CH2)q-S(02)ORa,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl
with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, - CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -C6H5— CH2C6H5.
with E being
Figure imgf000039_0001
- with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly 1 , and
- with each R independently from any other R being
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, - OCONH2 or -N02,
- a substituted or unsubstituted C5-C6 heterocycle,
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
- a substituted or unsubstituted C6 aryl.
E is
Figure imgf000039_0002
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n beingl , and with each R independently from any other R being OH, -F, -CI, -I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, or
E is
Figure imgf000040_0001
with n of R n being 5 and R is F, or
with n of R n being 5, and one to four of R being F and the other ones of R being selected independently from any other R from -H, -OH, -CI, -I, -CN, -OCH3, -OCF3, - OCONH2 or -CF3, in particular from -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or with n of R n being 1 , and R being selected from -OH, -OCH3, -OCF3, -OCONH2 or - CF3, or
with n of R n being 5, and one to three of R being F and the other ones of R being selected independently from any other R from -H, -OH, -CI, I, -CN, -OCH3, -OCF3, - OCONH2 or -CF3, in particular -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
with n of R n being 2, and each R being selected independently from any other R from -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
with n of R n being 5, and one or two of R being F and the other ones of R being selected independently from any other R from -H,-OH, -CI, I, -CN, -OCH3, -OCF3 , - OCONH2 or -CF3, in particular -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
with n of R n being 3, and each R being selected independently from any other R from -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
E is
Figure imgf000040_0002
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n being 1 , and with each R independently from any other R being - OH, OCH3, -F or -CF3.
E is
Figure imgf000041_0001
with n of R n being 1 , 2, 3, 4 or 5, in particular n of R n being 1 , 2 or 3,
with one R being a substituent Q, with Q being selected from
- -(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa, -(CH2)m-0- S(02)OH, -(CH2)m-0-S(02)ORa, in particular -(CH2)m-0-S(02)OH, -(CH2)m-0- S(02)ORa, with m being selected from 0, 1 or 2, in particular from 0 or 1 , with Ra being -CH3, -CH2CH3, -C6H5, -CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
- -C(=0)-0-Ra, -0-C(=0)-Ra, in particular -0-C(=0)-Ra, with Ra being a substituted or unsubstituted C Ci6 alkyl, in particular an unsubstituted C Ci4 alkyl,
- -(ΟΗ2)η-[(ΟΗ2)η1-0-0(=0)-(ΟΗ2)η2]ρ1-0(=0)ΟΡ , in particular -(CH2)-[-0-C(=0)- (CH2)2]p1-C(=0)ORd with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
- -(CH2)m-[(CH2)m1-0-(CH2)m2]p1-ORd, in particular -[-0-(CH2)2]p1-ORd, with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
- -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), in particular from -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa),
- with Raa and Rba being selected, where applicable, independently from each other from -Ra or -ORa and
- with Ra being hydrogen, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -C6H5 - CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para-methoxybenzyl,
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 , , and with the other R being selected independently from each other R from -OH, -F, - CI, I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular from -OH, -F, -OCH3, -OCF3, - OCONH2 or -CF3, or
E is
Figure imgf000042_0001
- with n of R n being 5, and one to four of R being F, one R being the
substituent Q, and, where applicable, the other ones of R being selected independently from any other R from -H, -OH, -CI, I, -CN, -OCH3, -OCF3, - OCONH2 or -CF3, in particular from -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
- with n of R n being 5, and one to three of R being F, one R being the substituent Q, and, where applicable, the other ones of R being selected independently from any other R from -H,-OH, -CI, I, -CN, -OCH3, -OCF3, - OCONH2 or -CF3, in particular -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
- with n of R n being 5, and one or two of R being F, one R being the
substituent Q, and, where applicable, the other ones of R being selected independently from any other R from -H,-OH, -CI, I, -CN, -OCH3, -OCF3, - OCONH2 or -CF3, in particular -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
- with n of R n being 5, and one of R being F, one R being the substituent Q, and, where applicable, the other ones of R being selected independently from any other R from -H,-OH, -CI, I, -CN, -OCH3, -OCF3, - OCONH2 or -CF3, in particular -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
- with n of R n being 3, one R being the substituent Q, and the other R
being selected independently from each other R from -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
- with n of R n being 2, one R being the substituent Q and the other R
being -H,-OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
with n of R n being 1 with R being the substituent Q,
with Q having the same meaning as defined previously, and wherein in particular Q is in para position with respect to the attachment position of the phenyl moiety of E to the parent moiety, and wherein in particular any hydrogen of the phenyl group may be substituted with F, E is
Figure imgf000043_0001
- with each T being selected independently from each other from -CH2, -NH, -S or -O, - CHCH3, -C(CH3)2 or -NRc,
- with Rc being -OH, -CH3, -CH2CH3, -CH2CH2CH3! -CH(CH3)2, and
- with T being selected from -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2 or -NRC, and
- with T" being selected from -CH or =N, and
- with R5 and R6 being selected independently from each other from -H, -F, -CH3, -
CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with R5 and R6 being selected independently from each other from H, -F or -CH3, and
- with R6 being selected from -CH3, -OH, -OCH3 or -OCH2CH3
- with R7 being selected from =NH, =S or =0, and
- with m of R9m being selected from 0, 1 , 2 or 3, and each R9 being selected
independently from each other -CI, -F, Br, I, -OH, -CCH, -CN -CH3, -CH2CH3, - OCH3, -COOH, -COORb, -C(0)NH2, -C(0)NH(Rb); -C(0)N(Rb)2, -NHC(=0)ORb, - NRbC(=0)ORb, -NRbC(=0)OH, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3
- with Rb being a substituted or unsubstituted CrC5 alkyl, a substituted or
unsubstituted C2-C5 alkenyl, a substituted or unsubstituted C2-C5 alkynyl, or a C1-C5 haloalkyl, or E is
Figure imgf000044_0001
- with m of R being 0, and
- with each T being selected independently from each other from -CH2, -CHCH3, - C(CH3)2, -NH, NRC, -S or -O, in particular form -C(CH3)2, -NH, -S or -O,
- with Rc being -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CF3, - CHFCF3, -CF2CF3, -CHF2, -CH2F, -CF3
- with T being selected from -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2 or -NRC, in particular from -O, -S or -NH, and
- with T" being selected from -CH or =N, in particular T" is =N, and
- with R5 and R6 being selected independently from each other from -H, -F -CH3, - CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with R5 and R6 being selected independently from each other from H, -F or CH3, and
- with R6 being selected from OH, -OCH3, -OCH2CH3 or -CH3,
- with R7 being selected from =NH, =S or =0, in particular R7 is =0, or
E is selected from
Figure imgf000044_0002
Figure imgf000045_0001
In some embodiments, in particular according to any one of the sub aspects 1 1 or 24 to 26, E is
a substituted or unsubstituted C Ci6 alkyl, a substituted or unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C Ci6 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted CrC8 haloalkyl, a substituted or unsubstituted C3-Cio cycloalkyl, or a substituted or unsubstituted C3-Cio halo cycloalkyl,
a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl,
a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Ci0 halo heterocycle; in particular a substituted or unsubstituted C4-Cio heterocycle or a substituted or unsubstituted C4-Cio halo heterocycle,
a substituted or unsubstituted C5-Cio heteroaryl;
a substituted or unsubstituted C6-Cio aryl.
In some embodiments, in particular according to any one of the sub aspects 1 1 or 24 to 26, E is
a substituted or unsubstituted Ci-C8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl.
In some embodiments, in particular according to any one of the sub aspects 1 1 or 24 to 26, E is
a substituted or unsubstituted CrC5 alkyl, a substituted or unsubstituted C6-Cio cycloalkyl, a substituted or unsubstituted C5-Cio heteroaryl or a substituted or unsubstituted C8-Cio aryl. In some embodiments, in particular according to any one of the sub aspects 1 1 or 24 to 26, E is
a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
a substituted or unsubstituted C5-C6 heteroaryl,
a substituted C6 aryl, in particular a bicyclic C6 aryl such as tetraline or indane, a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
selected from the group of substituted or unsubstituted pyrrole, furan, thiophene, benzothiophene, chromene, thiazole, pyrazine, pyridazine, pyridine, 1 ,2,3-triazole, 1 ,2,4- triazole, imidazole, oxazol, thiazol, indole, isoindole, quinoline, isoquinoline,
naphatalene, coumarin, aminocoumarin, umbelliferon, benzotriazole, psoralen, benzofurane, benzothiophene, benzimidazol, benzthiazole, benzoxazole or
benzpyridazin or hydroxylated, methylated or halogenated derivatives thereof selected from .
Figure imgf000046_0001
- with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n being 1 , and
- with each R independently from any other R being selected from
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2-CH3, -CF3, -OCONH2 or -N02, -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m- C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, - (CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, - (CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa, -(CH2)m- NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m- NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m- P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, - (CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q-
Figure imgf000047_0001
(CH2)q-S(02)OH, -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl
with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen, -CN
- a substituted or unsubstituted C Ci6 alkyl, a substituted or
unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C Ci6 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted CrC8 haloalkyl, a substituted or unsubstituted C3- Cio cycloalkyl, or a substituted or unsubstituted C3-Cio halo cycloalkyl,
- a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl, - a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle,
- a substituted or unsubstituted C5-C10 heteroaryl,
- a substituted or unsubstituted C6-Ci o aryl, in particular
- with each R independently from any other R being -OH, -F, -CI, I, -CN, -OCH3, -OCF3, - OCONH2 or -CF3.
In some embodiments, in particular according to any one of the sub aspects 1 1 or 24 to 26, E is
Figure imgf000048_0001
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly 1 , and
with each R independently from any other R being selected from
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -
CH2-CH3, -CF3, -OCONH2 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, -
(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, - (CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, -(CH2)m- OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, -(CH2)m- S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, -(CH2)m- NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, - (CH2)m-NRcC(=S)NRaRb, -(CH2)m-NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m- P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0- C(=0)-(M)-C(=0)OH, -(CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, - (CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa-(CH2)m- C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl
with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
hydrogen, -CN
a substituted or unsubstituted C Ci 6 alkyl, a substituted or unsubstituted Ci - Ci 6 alkoxy, a substituted or unsubstituted C Ci 6 carboxy, a substituted or unsubstituted C2-Ci 6 alkenyl, a substituted or unsubstituted C2-Ci 6 alkynyl, or a C1 -C16 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2- C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted Ci -C8 haloalkyl, a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C3-C10 halo cycloalkyl, a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle,
a substituted or unsubstituted C5-C10 heteroaryl,
a substituted or unsubstituted C6-Ci o aryl.
In some embodiments, in particular according to any one of the sub aspects 1 1 or 24 to 26, E is
Figure imgf000049_0001
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, particularly n of R n 1 , and
with each R independently from any other R being selected from - OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2-CH3, -CF3, -OCONH2 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m- C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, - (CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m- C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, - (CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, - (CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa, -(CH2)m- NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m- NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m- P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, - (CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl
with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen, -CN
- a substituted or unsubstituted C Ci6 alkyl, a substituted or
unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C Ci6 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted CrC8 haloalkyl, a substituted or unsubstituted C3- Cio cycloalkyl, or a substituted or unsubstituted C3-Cio halo cycloalkyl, - a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl,
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle,
- a substituted or unsubstituted C5-C10 heteroaryl,
- a substituted or unsubstituted C6-Ci o aryl, or
is
Figure imgf000051_0001
- with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n 1 , and
- with each R independently from any other R being selected from
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NH CH3, -N(CH3)2, - CH3, -CH2-CH3, -CF3, -OCONH2 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)ORa, -(CH2)m- OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m- C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, - (CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, - (CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa, -(CH2)m- NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m- NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m- P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, - (CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa ,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl
with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 , ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from hydrogen,-CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, - CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -C6H5— CH2C6H5
In some embodiments, in particular according to any one of the sub aspects 1 1 or 24 to 26, E is
Figure imgf000052_0001
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly
1 , and
with each R independently from any other R being
- -OH, -F, -CI, Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -
N02,
- a substituted or unsubstituted C5-C6 heterocycle,
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
- a substituted or unsubstituted C6 aryl.
In some embodiments, in particular according to any one of the sub aspects 1 1 or 24 to 26,
E is
Figure imgf000052_0002
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n beingl , and with each R independently from any other R being -OH, -F, -CI, I, -CN, -OCH3, -OCF3, -CONH2 or -CF3.
In some embodiments, in particular according to any one of the sub aspects 1 1 or 24 to 26, E is
Figure imgf000053_0001
with n of R n being 5 and R is F, or
with n of R n being 5, and one to four of R being F and the other ones of R being selected independently from any other R from -H, -OH, -CI, I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular from -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
with n of R n being 1 , and R being selected from -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or with n of R n being 5, and one to three of R being F and the other ones of R being selected independently from any other R from -H, -OH, -CI, I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
with n of R n being 2, and each R being selected independently from any other R from -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
with n of R n being 5, and one or two of R being F and the other ones of R being selected independently from any other R from -H,-OH, -CI, I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
with n of R n being 3, and each R being selected independently from any other R from -OH, -OCH3, -OCF3, -OCONH2 or -CF3.
In some embodiments, in particular according to any one of the sub aspects 1 1 or 24 to 26, E is
Figure imgf000053_0002
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n being 1 , and with each R independently from any other R being -OH, OCH3, -F, - OCONH2 or -CF3. In some embodiments, in particular according to any one of the sub aspects 1 1 or 24 to 26, E is
Figure imgf000054_0001
with n of R n being 1 , 2, 3, 4 or 5, in particular n of R n being 1 , 2 or 3,
with one R being a substituent Q, with Q being selected from
- -(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,-(CH2)m-0- S(02)OH, -(CH2)m-0-S(02)ORa, in particular -(CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, with m being selected from 0, 1 or 2, in particular from 0 or 1 , with Ra being -CH3, - CH2CH3, -C6H5 -CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
- -C(=0)-0-Ra, -0-C(=0)-Ra, in particular -0-C(=0)-Ra, with Ra being a substituted or unsubstituted C Ci6 alkyl, in particular an unsubstituted C Ci4 alkyl,
- -(CH2)m-[(CH2)m1-0-C(=0)-(CH2)m2]p1-C(=0)ORd, in particular -(CH2)-[-0-C(=0)-(CH2)2]p1- C(=0)ORd with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
- -(CH2)m-[(CH2)m1-0-(CH2)m2]p1-ORd, in particular -[-0-(CH2)2]p1-ORd, with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
- -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), in particular from -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa),
- with Raa and Rba being selected, where applicable, independently from each other from -Ra or -ORa and
- with Ra being hydrogen, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -C6H5 - CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
- with m being selected from 0, 1 or 2, in particular 0 or 1 , - with q being selected from 0, 1 or 2, in particular 0 or 1 , and with the other R being selected independently from each other R from -OH,
-F, -CI, -I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular from -OH, -F, -OCH3, -OCF3, -
OCONH2 or -CF3.
In some embodiments, in particular according to any one of the sub aspects 1 1 or 24 to 26, E is
Figure imgf000055_0001
with n of R n being 5, and one to four of R being F, one R being the substituent Q, and, where applicable, the other ones of R being selected independently from any other R from -H, -OH, -CI, -I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular from - OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
with n of R n being 5, and one to three of R being F, one R being the substituent Q, and, where applicable, the other ones of R being selected independently from any other R from -H,-OH, -CI, -I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular -OH, - OCH3, -OCF3, -OCONH2 or -CF3, or
with n of R n being 5, and one or two of R being F, one R being the substituent Q, and, where applicable, the other ones of R being selected independently from any other R from -H,-OH, -CI, -I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular -OH, - OCH3, -OCF3, -OCONH2 or -CF3, or
with n of R n being 5, and one of R being F, one R being the substituent Q, and, where applicable, the other ones of R being selected independently from any other R from -H,-OH, -CI, -I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular -OH, -OCH3, - OCF3, -OCONH2 or -CF3, or
with n of R n being 3, one R being the substituent Q, and the other R being selected independently from each other R from -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or with n of R n being 2, one R being the substituent Q and the other R being -H,-OH, - OCH3, -OCF3, -OCONH2 or -CF3, or
with n of R n being 1 with R being the substituent Q, with Q having the same meaning as defined previously, and wherein in particular Q is in para position with respect to the attachment position of the phenyl moiety of E to the parent moiety,
and wherein in particular any hydrogen of the phenyl group may be substituted with F.
In some embodiments, in particular according to any one of the sub aspects 1 1 or 24 to 26,
E is
Figure imgf000056_0001
with each T being selected independently from each other from -CH2, -NH, -S or -O, - CHCH3, -C(CH3)2 or -NRc,
- with Rc being -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, and
- with T being selected from -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2 or -NRC, and
with T" being selected from -CH or =N, and
with R5 and R6 being selected independently from each other from -H, -F, -CH3, - CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with R5 and R6 being selected independently from each other from H, -F or -CH3, and
- with R6 being selected from -OH, -OCH3, -OCH2CH3 or -CH3,
with R7 being selected from =NH, =S or =0, and
with m of R9m being selected from 0, 1 , 2 or 3, and each R9 being selected independently from each other from -CI, -F, Br, -I, -OH, -CCH, -CN -CH3, -CH2CH3, -OCH3, -COOH, - COORb, -C(0)NH2, -C(0)NH(Rb); -NHC(=0)ORb, -NRbC(=0)ORb, -NRbC(=0)OH, - C(0)N(Rb)2 -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3,
with Rb being a substituted or unsubstituted CrC5 alkyl, a substituted or unsubstituted C2-C5 alkenyl, a substituted or unsubstituted C2-C5 alkynyl, or a CrC5 haloalkyl.
In some embodiments, in particular according to any one of the sub aspects 1 1 or 24 to 26, E is
Figure imgf000057_0001
- with m of R9m being 0, and
- with each T being selected independently from each other from -CH2, -CHCH3, - C(CH3)2, -NH, NRC, -S or -O, in particular form -C(CH3)2, -NH, -S or -O,
- with Rc being -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2,
- with T being selected from -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2 or -NRC, in particular from -O, -S or -NH, and
- with T" being selected from -CH or =N, in particular T" is =N, and
- with R5 and R6 being selected independently from each other from -H, -F -CH3, - CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with R5 and R6 being selected independently from each other from H, -F or CH3, and
- with R6 being selected from OH, -OCH3, -OCH2CH3 or -CH3,
- with R7 being selected from =NH, =S or =0, in particular R7 is =0.
In some embodiments, in particular according to any one of the sub aspects 1 1 or 24 to 26,
E is selected from
Figure imgf000058_0001
In some embodiments, in particular according to any one of the sub aspects 12, 13 or 27 to 32,
n of R n is 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly 1 , and each R independently from any other R is selected from
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, - CH2-CH3, -CF3, -OCONH2 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, -(CH2)m-
OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-
C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-
OC(=S)Ra, -(CH2)m-OC(=S)ORa, -(CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-
SRa, -(CH2)m-S(=0)Ra, -(CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-
OS(02)ORa, -(CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa, -(CH2)m-
NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m-
NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, -(CH2)m-0-C(=0)-(M)-
C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m- C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0- (CH2)q-S(02)ORa,
with Raa being selected independently from each other being -Ra or -ORa,
with Rba being selected independently from each other being -Rb or -ORb,
with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted Ci- C8 alkyl
with m being selected from 0, 1 or 2, in particular 0 or 1 , with q being selected from 0, 1 or 2, in particular 0 or 1 ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen, -CN
- a substituted or unsubstituted C Ci6 alkyl, a substituted or
unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C Ci6 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted CrC8 haloalkyl, a substituted or unsubstituted C3- Cio cycloalkyl, or a substituted or unsubstituted C3-Cio halo cycloalkyl,
- a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl,
- a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Cio halo heterocycle, in particular a substituted or unsubstituted C4-Ci0 heterocycle or a substituted or unsubstituted C4-Cio halo heterocycle,
- a substituted or unsubstituted C5-Cio heteroaryl,
- a substituted or unsubstituted C6-Cio aryl.
In some embodiments, in particular according to any one of the sub aspects 12, 13 or 27 to 32, with n of R n of BA being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n 1 , and
- with each R independently from any other R being selected from - -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NH CH3, -N(CH3)2, -CH3, -CH2-CH3, -CF3, -OCONH2 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)ORa, -(CH2)m- OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m- C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, - (CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, - (CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa, -(CH2)m- NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m- NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m- P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, - (CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl
with m being selected from 0, 1 or 2, in particular 0 or 1 , with q being selected from 0, 1 or 2, in particular 0 or 1 ,
- with each Ra, Rb or Rc being selected, where applicable,
independently from each other from hydrogen, -CH3, -CH2CH3, - CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, - C(CH3)3, -C6H5— CH2CeH5.
In some embodiments, in particular according to any one of the sub aspects 12, 13 or 27 to 32,
n of R n is 0, 1 , 2, 3, 4 or 5, in particular n of R n is 0, 1 , 2 or 3, more particularly 1 , and with each R independently from any other R being
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, - OCONH2 or -N02,
a substituted or unsubstituted C5-C6 heterocycle, - a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F, a substituted or unsubstituted C6 aryl.
In some embodiments, in particular according to any one of the sub aspects 12, 13 or 27 to 32,
n of R n is 0, 1 , 2, 3, 4 or 5, in particular n of R n is 0, 1 , 2 or 3, more particularly 1 , and with each R independently from any other R being -OH, -F, -CI, -I, -CN, -OCH3, -OCF3 - OCONH2 or -CF3.
In some embodiments, in particular according to any one of the sub aspects 12, 13 or 27 to 32,
n of R n is 5 and R is F, or
n of R n is 5, and one to four of R being F and the other ones of R are selected independently from any other R from -H, -OH, -CI, -I, -CN, -OCH3, -OCF3, -OCONH2 or - CF3, in particular from -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
- n of R n is 1 , and R are selected from -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
n of R n is 5, and one to three of R are F and the other ones of R are selected independently from any other R from -H, -OH, -CI, -I, -CN, -OCH3, -OCF3, -OCONH2 or - CF3, in particular from -OH, -OCH3, -OCF3 or -CF3, or
n of R n is 2, and each R is selected independently from any other R from -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
n of R n is 5, and one or two of R are F and the other ones of R are selected independently from any other R from -H,-OH, -CI, I, -CN, -OCH3, -OCF3, -OCONH2 or - CF3, in particular from -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
n of R n is 3, and each R is selected independently from any other R from -OH, -OCH3, -OCF3, -OCONH2 or -CF3.
In some embodiments, in particular according to any one of the sub aspects 12, 13 or 27 to 32, n of R n is 0, 1 , 2, 3, 4 or 5, in particular n of R n is 0, 1 , 2 or 3, more particularly n of R n is 1 , and with each R independently from any other R being -OH, OCH3, -F or -CF3.
In some embodiments, in particular according to any one of the sub aspects 12, 13 or 27 to 32,
n of R n is 1 , 2, 3, 4 or 5, in particular n of R n is 1 , 2 or 3,
with one R being a substituent Q, with Q being selected from
- -(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa, -(CH2)m-0-
S(02)OH, -(CH2)m-0-S(02)ORa, in particular -(CH2)m-0-S(02)OH, -(CH2)m-0- S(02)ORa, with m being selected from 0, 1 or 2, in particular from 0 or 1 , with Ra being -CH3, -CH2CH3, -C6H5 -CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para- methoxybenzyl
- -C(=0)-0-Ra, -0-C(=0)-Ra, in particular -0-C(=0)-Ra, with Ra being a substituted or unsubstituted C Ci6 alkyl, in particular an unsubstituted C Ci4 alkyl,
- -(CH2)m-[(CH2)m1-0-C(=0)-(CH2)m2]p1-C(=0)ORd, in particular -(CH2)-[-0-C(=0)-
(CH2)2]p1-C(=0)ORd with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
- -(CH2)m-[(CH2)m1-0-(CH2)m2]p1-ORd, in particular -[-0-(CH2)2]p1-ORd, with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
- -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), in
particular from -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa),
- with Raa and Rba being selected, where applicable, independently from each other from -Ra or -ORa and
- with Ra being hydrogen, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -C6H5 - CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
- with m being selected from 0, 1 or 2, in particular 0 or 1 , - with q being selected from 0, 1 or 2, in particular 0 or 1 ,
and with the other R being selected independently from each other R from -OH, -F, -CI, I, - CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular from -OH, -F, -OCH3, -OCF3, -OCONH2 or -CF3.
In some embodiments, in particular according to any one of the sub aspects 12, 13 or 27 to 32,
n of R n is 5, and one to four of R are F, one R is the substituent Q, and, where applicable, the other ones of R are selected independently from any other R from -H, - OH, -CI, I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular from -OH, -OCH3, -OCF3, - OCONH2 or -CF3, or
n of R n is 5, and one to three of R are F, one R is the substituent Q, and, where applicable, the other ones of R are selected independently from any other R from -H,- OH, -CI, I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular -OH, -OCH3, -OCF3, - OCONH2 or -CF3, or
n of R n is 5, and one or two of R are F, one R is the substituent Q, and, where applicable, the other ones of R are selected independently from any other R from -H,- OH, -CI, I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular -OH, -OCH3, -OCF3, - OCONH2 or -CF3, or
n of R n is 5, and one of R is F, one R is the substituent Q, and, where applicable, the other ones of R are selected independently from any other R from -H,-OH, -CI, I, -CN, - OCH3, -OCF3, -OCONH2 or -CF3, in particular from -OH, -OCH3, -OCF3, -OCONH2 or - CF3, or
n of R n is 3, one R is the substituent Q, and the other R are selected independently from each other R from -OH, -OCH3, -OCF3, -OCONH2 or -CF3, or
n of R n is 2, one R is the substituent Q and the other R is -H,-OH, -OCH3, -OCF3, - OCONH2 or -CF3, or
n of R n is 1 , with R being the substituent Q,
with Q having the same meaning as defined previously, and wherein in particular Q is in para position with respect to the attachment position of the phenyl moiety of E to the parent moiety,
and wherein in particular any hydrogen of the phenyl group may be substituted with F.
In some embodiments, in particular according to any one of the sub aspects 1 1 to 13 or 24 to 31 , R2 and R3 are selected, where applicable, independently from each other from -H, -F, - CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl.
In some embodiments, in particular according to any one of the sub aspects 1 1 to 13 or 24 to 31 , R2 and R3 are selected, where applicable, independently from each other from -H, -F, - CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3.
In some embodiments, in particular according to any one of the sub aspects 1 1 to 13 or 24 to 31 , R2 and R3 are selected independently from each other from -H, -F or -CH3.
In some embodiments, X1 is selected from
Figure imgf000064_0001
, with R8 being selected from H or CH3, in particluar R8 is H and with V being selected from O, NH or S, in particular from O or NH.
In some embodiments, X1 is selected from
Figure imgf000064_0002
with R8 being selected from H or CH3, in particluar R8 is H.
Figure imgf000065_0001
64
Figure imgf000066_0001
65
Figure imgf000067_0001
In some embodiments, BB is
Figure imgf000067_0002
with each R 3 independently from any other R 3 being
-OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2CH3, -CF3 or -N02, in particular -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, - OCH3, -OCF3, -, -CH3, -CH2CH3 or -CF3,
with each R 3 independently from any other R 3 being
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2CH3, -CH3, -CF3 or -N02, in particular -OH, -F, -CI, -Br, -I, -CCH, - CN, -N3, -OCH3, -OCF3, -, -CH3, -CH2CH3 or -CF3, wherein, each carbon atom of the cyclic system which comprises no substituent R 3 comprises F instead of H. In some embodiments, BB is
Figure imgf000068_0001
with n of R 3 n being 0, or
with n of R 3 n being 1 , 2, 3 or 4 with each R 3 being F, in particular n is 4 and each R 3 is F.
In some embodiments, in particular according to any one of the sub aspects 1 to 12 or 14 to 38, BC is selected from
Figure imgf000068_0002
with p being 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and
with r being 2, 3, 4 or 5, in particular r being 2,
with L , L2, L4, L5 being selected independently from each other from side chains of amino acids such as -H (Gly), -CH3 (Ala), -CH2CH2CH2NHC(NRc)N(Rb)(Ra) (Arg), -CH2CON(Rb)(Ra) (Asn), -CH2C(=0)ORa (Asp), -CH2SRa (Cys), -CH2CH2C(=0)N(Rb)(Ra) (Gin), - CH2CH2C(=0)ORa (Glu), -CH2(C3H3N2) (His), -CH2CH2CH2CH2 (Lys), -CH2CH2SCH3 (Met), - CH2(C6H5) (Phe), -CH2CH2CH2- (Pro), -CH2ORa (Ser), -CH(ORa)CH3 (Thr), -CH2(C8H6N)ORa (Trp), -CH2(C6H4)ORa (Tyr), -CH(CH3)2 (Val),
or from
-CCH, -CN, -OCH3, -CH3, -CF3, -Ra, -CH(Rb)(Ra), -CH2ORa -CH2C(=0)Ra, -C(=0)ORa, - OC(=0)NRbRa, -C(=0)NRbRa, -CH2C(=0)NRb(ORa), -CH2S(02)Ra, -S(02)ORa, - CH2S(02)ORa, -CH2NHC(=0)Ra, -CH2NRbS(02)Ra, -CH2P(=0)(ORb)(ORa), - CH2P(=0)(ORb)(Ra), ), -CH2P(=0)(Rb)(Ra) or -CH2S(02)NRbRa,
- with Ra and Rb being selected, where applicable, independently from each other from
- a substituted or unsubstituted Ci-C4 alkyl, a substituted or
unsubstituted Ci-C4 alkoxy, a substituted or unsubstituted Ci-C4 carboxy, a substituted or unsubstituted C2-C4 alkenyl, a substituted or unsubstituted C2-C4 alkynyl, or a Ci -C4 haloalkyl, or
- a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-Ci o heterocycle or a substituted or unsubstituted C4-Ci o halo heterocycle, or
- a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Ci o aryl, and with
L3 being selected from -CH3, -CH2CH3, -OCH3, -OCH2CH3, a Ci -C2-fluoro alkyl,
with Y being -CN, -C(=0)OH , -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)NHCH3, - C(=0)NHCH2CH3, -C(=0) N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3) or - C(=0) NH2, in particular Z is H and Y is CN and -C(=0)NH2, and wherein
with Z being -H , -OH , -CH3, -CH2CH3, -OCH3 -NH2 NHCH3, N(CH3)2 N(CH3)3 +.
In some embodiments L , L2, L3, L4 and L5 comprise the structure elements of amino acids and their derivatives. The respective amino acid is named in brackets.
In some embodiments, in particular according to any one of the sub aspects 1 to 12 or 14 to 38, BC is selected from
Figure imgf000069_0001
with p being 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and
with r being 2, 3, 4 or 5, in particular r being 2,
with L , L2, L4, L5 being selected independently from each other from side chains of amino acids such as -H (Gly), -CH3 (Ala), -CH2CH2CH2NHC(NRc)N(Rb)(Ra) (Arg), -CH2CON(Rb)(Ra) (Asn), -CH2C(=0)ORa (Asp), -CH2SRa (Cys), -CH2CH2C(=0)N(Rb)(Ra) (Gin), - CH2CH2C(=0)ORa (Glu), -CH2(C3H3N2) (His), -CH2CH2CH2CH2 (Lys), -CH2CH2SCH3 (Met), - CH2(C6H5) (Phe), -CH2CH2CH2- (Pro), -CH2ORa (Ser), -CH(ORa)CH3 (Thr), -CH2(C8H6N)ORa (Trp), -CH2(C6H4)ORa (Tyr), -CH(CH3)2 (Val),
or from
-CCH, -CN, -OCH3, -CH3, -CF3, -Ra, -CH2ORa -CH2C(=0)Ra, -C(=0)ORa, -OC(=0)NRbRa, - C(=0)NRbRa, -CH2C(=0)NRb(ORa), -CH2S(02)Ra, -S(02)ORa, -CH2S(02)ORa, - CH2NHC(=0)Ra, -CH2NRbS(02)Ra, -CH2P(=0)(ORb)(ORa), -CH2P(=0)(ORb)(Ra), ), - CH2P(=0)(Rb)(Ra) or -CH2S(02)NRbRa,
- with Ra and Rb being selected, where applicable, independently from each other from CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, - CH2CH(CH3)2, -C(CH3)3, -C6H5 ,-CH2C6H5, mono methoxybenzyl, in particular para-methoxybenzyl, or dimethoxybenzyl or trimethoxybenzyl
L3 being selected from -CH3, -CH2CH3, -OCH3, -OCH2CH3, a Ci-C2-fluoro alkyl,
with Y being -CN, -C(=0)OH, -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)NHCH3, - C(=0)NHCH2CH3, -C(=0)N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3) or - C(=0)NH2, in particular Z is H and Y is CN and -C(=0)NH2, and wherein
with Z being -H, -OH, -CH3, -CH2CH3 , -OCH3, -NH2 NHCH3, N(CH3)2 or N(CH3)3 +.
In some embodiments, in particular according to any one of the sub aspects 1 to 12 or 14 to 38, BC is selected from
Figure imgf000070_0001
with L or L4 being selected independently from each other from side chains of amino acids such as -H (Gly), -CH3 (Ala), -CH2CH2CH2NHC(NRc)N(Rb)(Ra) (Arg), -CH2CON(Rb)(Ra) (Asn), -CH2C(=0)ORa (Asp), -CH2SRa (Cys), -CH2CH2C(=0)N(Rb)(Ra) (Gin), - CH2CH2C(=0)ORa (Glu), -CH2(C3H3N2) (His), -CH2CH2CH2CH2 (Lys), -CH2CH2SCH3 (Met), - CH2(C6H5) (Phe), -CH2CH2CH2- (Pro), -CH2ORa (Ser), -CH(ORa)CH3 (Thr), -CH2(C8H6N)ORa (Trp), -CH2(C6H4)ORa (Tyr), -CH(CH3)2 (Val),
or from
-CCH, -CN, -OCH3, -CH3, -CF3, -Ra, -CH(Rb)(Ra), -CH2ORa -CH2C(=0)Ra, -C(=0)ORa, - OC(=0)NRbRa, -C(=0)NRbRa, -CH2C(=0)NRb(ORa), -CH2S(02)Ra, -S(02)ORa, - CH2S(02)ORa, -CH2NHC(=0)Ra, -CH2NRbS(02)Ra, -CH2P(=0)(ORb)(ORa), - CH2P(=0)(ORb)(Ra), ), -CH2P(=0)(Rb)(Ra) or -CH2S(02)NRbRa, - with Ra and Rb being selected, where applicable, independently from each other from
- a substituted or unsubstituted CrC4 alkyl, a substituted or
unsubstituted Ci -C4 alkoxy, a substituted or unsubstituted Ci -C4 carboxy, a substituted or unsubstituted C2-C4 alkenyl, a substituted or unsubstituted C2-C4 alkynyl, or a Ci -C4 haloalkyl, or
- a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-Ci o heterocycle or a substituted or unsubstituted C4-Ci o halo heterocycle, or
- a substituted or unsubstituted C5-C10 heteroaryl, or
- a substituted or unsubstituted C6-Ci o aryl, and with
with Y being -CN, -C(=0)OH , -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)NHCH3, - C(=0)NHCH2CH3, -C(=0) N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3) or - C(=0) NH2, in particular Z is H and Y is CN and -C(=0)NH2, and wherein
with Z being -H , -OH , -CH3, -CH2CH3, -OCH3 -NH2 NHCH3, N(CH3)2 N(CH3)3 +.
In some embodiments, in particular according to any one of the sub aspects 1 to 12 or 14 to 38, BC is selected from
Figure imgf000071_0001
with L or L4 being selected independently from each other from side chains of amino acids such as -H (Gly), -CH3 (Ala), -CH2CH2CH2NHC(NRc)N(Rb)(Ra) (Arg), -CH2CON(Rb)(Ra) (Asn), -CH2C(=0)ORa (Asp), -CH2SRa (Cys), -CH2CH2C(=0)N(Rb)(Ra) (Gin), - CH2CH2C(=0)ORa (Glu), -CH2(C3H3N2) (His), -CH2CH2CH2CH2 (Lys), -CH2CH2SCH3 (Met), - CH2(C6H5) (Phe), -CH2CH2CH2- (Pro), -CH2ORa (Ser), -CH(ORa)CH3 (Thr), -CH2(C8H6N)ORa (Trp), -CH2(C6H4)ORa (Tyr), -CH(CH3)2 (Val),
or from
-CCH, -CN, -OCH3, -CH3, -CF3, -Ra, -CH2ORa -CH2C(=0)Ra, -C(=0)ORa, -OC(=0)NRbRa, - C(=0)NRbRa, -CH2C(=0)NRb(ORa), -CH2S(02)Ra, -S(02)ORa, -CH2S(02)ORa, - CH2NHC(=0)Ra, -CH2NRbS(02)Ra, -CH2P(=0)(ORb)(ORa), -CH2P(=0)(ORb)(Ra), ), - CH2P(=0)(Rb)(Ra) or -CH2S(02)NRbRa,
with Ra and Rb being selected, where applicable, independently from each other from CH3, - CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -C6H5 ,- CH2C6H5, mono methoxybenzyl, in particular para methoxybenzyl, or dimethoxybenzyl or trimethoxybenzyl.
In some embodiments, in particular according to any one of the sub aspects 1 to 12 or 14 to 38, BC is selected from
Figure imgf000072_0001
with L or L4 being selected independently from each other from side chains of amino acids such as - H (Gly), -CH3 (Ala), -CH2CH2CH2NHC(NRc)N(Rb)(Ra) (Arg), -CH2CON(Rb)(Ra) (Asn), -CH2C(=0)ORa (Asp), -CH2SRa (Cys), -CH2CH2C(=0)N(Rb)(Ra) (Gin), - CH2CH2C(=0)ORa (Glu), -CH2(C3H3N2) (His), -CH2CH2CH2CH2 (Lys), -CH2CH2SCH3 (Met), - CH2(C6H5) (Phe), -CH2CH2CH2- (Pro), -CH2ORa (Ser), -CH(ORa)CH3 (Thr), -CH2(C8H6N)ORa (Trp), -CH2(C6H4)ORa (Tyr), -CH(CH3)2 (Val),
or from
-CCH, -CN, -OCH3, -CH3, -CF3, -Ra, -CH(Rb)(Ra), -CH2ORa -CH2C(=0)Ra, -C(=0)ORa, - OC(=0)NRbRa, -C(=0)NRbRa, -CH2C(=0)NRb(ORa), -CH2S(02)Ra, -S(02)ORa, - CH2S(02)ORa, -CH2NHC(=0)Ra, -CH2NRbS(02)Ra, -CH2P(=0)(ORb)(ORa), - CH2P(=0)(ORb)(Ra), ), -CH2P(=0)(Rb)(Ra) or -CH2S(02)NRbRa,
- with Ra and Rb being selected, where applicable, independently from each other from
- a substituted or unsubstituted Ci-C4 alkyl, a substituted or
unsubstituted Ci-C4 alkoxy, a substituted or unsubstituted Ci-C4 carboxy, a substituted or unsubstituted C2-C4 alkenyl, a substituted or unsubstituted C2-C4 alkynyl, or a Ci -C4 haloalkyl, or
- a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-Ci o heterocycle or a substituted or unsubstituted C4-Ci o halo heterocycle, or
- a substituted or unsubstituted C5-C10 heteroaryl, or
- a substituted or unsubstituted C6-Ci o aryl, and with
with Y being -CN, -C(=0)OH , -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)NHCH3, - C(=0)NHCH2CH3, -C(=0) N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3) or - C(=0) NH2, in particular Z is H and Y is CN and -C(=0)NH2, and wherein
with Z being -H , -OH , -CH3, -CH2CH3, -OCH3 -NH2 NHCH3, N(CH3)2 N(CH3)3 +.
In some embodiments, in particular according to any one of the sub aspects 1 to 12 or 14 to 38, BC is selected from
Figure imgf000073_0001
, in particular
Figure imgf000073_0002
with L or L4 being selected independently from each other from side chains of amino acids such as H (Gly), -CH3 (Ala), -CH2CH2CH2NHC(NRc)N(Rb)(Ra) (Arg), -CH2CON(Rb)(Ra) (Asn), -CH2C(=0)ORa (Asp), -CH2SRa (Cys), -CH2CH2C(=0)N(Rb)(Ra) (Gin), -CH2CH2C(=0)ORa (Glu), -CH2(C3H3N2) (His), -CH2CH2CH2CH2 (Lys), -CH2CH2SCH3 (Met), -CH2(C6H5) (Phe), - CH2CH2CH2- (Pro), -CH2ORa (Ser), -CH(ORa)CH3 (Thr), -CH2(C8H6N)ORa (Trp), - CH2(C6H4)ORa (Tyr), -CH(CH3)2 (Val),
or from -CCH, -CN, -OCH3, -CH3, -CF3, -Ra, -CH2ORa -CH2C(=0)Ra, -C(=0)ORa, -OC(=0)NRbRa, - C(=0)NRbRa, -CH2C(=0)NRb(ORa), -CH2S(02)Ra, -S(02)ORa, -CH2S(02)ORa, - CH2NHC(=0)Ra, -CH2NRbS(02)Ra, -CH2P(=0)(ORb)(ORa), -CH2P(=0)(ORb)(Ra), ), - CH2P(=0)(Rb)(Ra) or -CH2S(02)NRbRa,
with Ra and Rb being selected, where applicable, independently from each other from CH3, - CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -C6H5 ,- CH2C6H5, mono methoxybenzyl, in particular para methoxybenzyl, or dimethoxybenzyl or trimethoxybenzyl.
In some embodiments, in particular according to any one of the sub aspects 1 to 12 or 14 to 38, BC is selected from
Figure imgf000074_0001
with L or L4 being selected independently from each other from side chains of amino acids such as -H (Gly), -CH3 (Ala), -CH2CH2CH2NHC(NRc)N(Rb)(Ra) (Arg), -CH2CON(Rb)(Ra) (Asn), -CH2C(=0)ORa (Asp), -CH2SRa (Cys), -CH2CH2C(=0)N(Rb)(Ra) (Gin), - CH2CH2C(=0)ORa (Glu), -CH2(C3H3N2) (His), -CH2CH2CH2CH2 (Lys), -CH2CH2SCH3 (Met), - CH2(C6H5) (Phe), -CH2CH2CH2- (Pro), -CH2ORa (Ser), -CH(ORa)CH3 (Thr), -CH2(C8H6N)ORa (Trp), -CH2(C6H4)ORa (Tyr), -CH(CH3)2 (Val),
or from
-CCH, -CN, -OCH3, -CH3, -CF3, -Ra, -CH(Rb)(Ra), -CH2ORa -CH2C(=0)Ra, -C(=0)ORa, - OC(=0)NRbRa, -C(=0)NRbRa, -CH2C(=0)NRb(ORa), -CH2S(02)Ra, -S(02)ORa, - CH2S(02)ORa, -CH2NHC(=0)Ra, -CH2NRbS(02)Ra, -CH2P(=0)(ORb)(ORa), - CH2P(=0)(ORb)(Ra), ), -CH2P(=0)(Rb)(Ra) or -CH2S(02)NRbRa,
- with Ra and Rb being selected, where applicable, independently from each other from
- a substituted or unsubstituted Ci-C4 alkyl, a substituted or
unsubstituted Ci-C4 alkoxy, a substituted or unsubstituted Ci-C4 carboxy, a substituted or unsubstituted C2-C4 alkenyl, a substituted or unsubstituted C2-C4 alkynyl, or a Ci-C4 haloalkyl, or
- a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl, or
- a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Cio halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted
C4-C10 halo heterocycle, or
- a substituted or unsubstituted C5-C10 heteroaryl, or
- a substituted or unsubstituted C6-Ci o aryl, and with
with Y being -CN, -C(=0)OH, -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)NHCH3, - C(=0)NHCH2CH3, -C(=0)N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3) or - C(=0)NH2, in particular Z is H and Y is CN and -C(=0)NH2, and wherein
with Z being -H, -OH, -CH3, -CH2CH3, -OCH3 -NH2 NHCH3, N(CH3)2 N(CH3)3 +.
In some embodiments, in particular according to any one of the sub aspects 1 to 12 or 14 to 38, BC is selected from
Figure imgf000075_0001
with L or L4 being selected independently from each other from side chains of amino acids such as H (Gly), -CH3 (Ala), -CH2CH2CH2NHC(NRc)N(Rb)(Ra) (Arg), -CH2CON(Rb)(Ra) (Asn), -CH2C(=0)ORa (Asp), -CH2SRa (Cys), -CH2CH2C(=0)N(Rb)(Ra) (Gin), -CH2CH2C(=0)ORa (Glu), -CH2(C3H3N2) (His), -CH2CH2CH2CH2 (Lys), -CH2CH2SCH3 (Met), -CH2(C6H5) (Phe), - CH2CH2CH2- (Pro), -CH2ORa (Ser), -CH(ORa)CH3 (Thr), -CH2(C8H6N)ORa (Trp), - CH2(C6H4)ORa (Tyr), -CH(CH3)2 (Val),
or from
-CCH, -CN, -OCH3, -CH3, -CF3, -Ra, -CH2ORa -CH2C(=0)Ra, -C(=0)ORa, -OC(=0)NRbRa, - C(=0)NRbRa, -CH2C(=0)NRb(ORa), -CH2S(02)Ra, -S(02)ORa, -CH2S(02)ORa, - CH2NHC(=0)Ra, -CH2NRbS(02)Ra, -CH2P(=0)(ORb)(ORa), -CH2P(=0)(ORb)(Ra), ), - CH2P(=0)(Rb)(Ra) or -CH2S(02)NRbRa,
with Ra and Rb being selected, where applicable, independently from each other from CH3, - CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -C6H5 ,- CH2C6H5, mono methoxybenzyl, in particular para methoxybenzyl, or dimethoxybenzyl or trimethoxybenzyl. In some embodiments, in particular according to any one of the sub aspects 1 to 12 or 14 to 38, -D2-BC- is
Figure imgf000076_0001
p being 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and with, where applicable, each R8 being selected independently from each other from -H, -CH3, -CH2CH3, -OCH3, -OCF3, -CH2CF3, - CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with each R8 being selected independently from each other from H or CH3, more particularly each R8 being H.
In some embodiments, in particular according to any one of the sub aspects 1 to 12 or 14 to 38, -D2-BC- is
Figure imgf000076_0002
p being 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and with R8 being H or CH3.
In some embodiments, in particular according to any one of the sub aspects 1 or 2, BD is
Figure imgf000076_0003
with each R 2 independently from any other R 2 being
-OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2CH3, -CF3 or -N02, in particular -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, - OCH3, -OCF3, -, -CH3, -CH2CH3 or -CF3, or
with each R 2 independently from any other R 2 being
-OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, - N(CH3)2, -CH3, -CH2CH3, -CH3, -CF3 or -N02, in particular -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -, -CH3, -CH2CH3 or -CF3, wherein each carbon atom of the cyclic system which comprises no substituent R 2
comprises F instead of H.
In some embodiments, in particular according to any one of the sub aspects 1 or 2, BD is
Figure imgf000077_0001
with n of R 2 n being 0, or
with n of R 2 n being 1 , 2, 3 or 4 with each R 2 being F, in particular n is 4 and each R 3 is F.
In some embodiments, in particular according to any one of the sub aspects 1 to 6, 19, 21 , 24 or 27, BE is
Figure imgf000077_0002
with n of R n being 0, 1 , 2, 3 or 4, in particular n of R n being 0, 1 , 2 or 3,
with each R being selected independently from any other R from -OH, -F, -CI, -Br, -I, - CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH2OCH3, - CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, or
with each R being selected independently from any other R from -OH, -F, -CI, -Br, -I, - CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH2OCH3, - CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, wherein, each carbon atom of the cyclic system which comprises no substituent R comprises F instead of H.
In some embodiments, in particular according to any one of the sub aspects 1 to 6, 19, 21 , 24 or 27, BE is
Figure imgf000077_0003
with n of R n being 2, and with each R independently from any other R being -OH, -OCH3 or -OCF3, in particular -OCH3 or -OCF3, more particularly with one R being -OH and the other R being -OCH3 or -OCF3, in particular -OCH3, wherein more particularly OH is in ortho and OCH3 or -OCF3 in meta position with respect to the attachment position of the phenyl moiety of BE to D5, or
with n of R n being 1 , and with R being -OH , wherein in particular OH is in ortho position with respect to the attachment position of the phenyl of BE to D5 or
with n of R n being 1 , and with R being -OCH3 or -OCF3, in particular or -OCH3, wherein more particularly -OCH3 or -OCF3 is in meta position with respect to the attachment position of the phenyl of BE to D5, or
with n of R n being 0, or
with n of R n being 4 and each R is F.
In some embodiments, in particular according to any one of the sub aspects 1 to 6, 19, 21 , 24 or 27, BE is
Figure imgf000078_0001
with n of R n being 1 , 2, 3 or 4, in particular n of R n being 1 , 2 or 3,
with one R being a substituent Q, with Q being selected from
-(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,- (CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, in particular -(CH2)m-0-S(02)OH, - (CH2)m-0-S(02)ORa, with m being selected from 0, 1 or 2, in particular from 0 or 1 , with Ra being -CH3, -CH2CH3, -C6H5, -CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
-C(=0)-0-Ra, -0-C(=0)-Ra, in particular -0-C(=0)-Ra, with Ra being a substituted or unsubstituted C1 -C16 alkyl, in particular an unsubstituted C1 -C14 alkyl,
-(CH2)m-[(CH2)m1-0-C(=0)-(CH2)m2]p1 -C(=0)ORd, in particular -(CH2)-[-0- C(=0)-(CH2)2]p1 -C(=0)ORd with
Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8, -(CH2)m-[(CH2)m1-0-(CH2)m2]p1-ORd, in particular -[-0-(CH2)2]p1-ORd, with
Rd being -CH3, -CH2CH3, -CH2CH2CH3! -CH(CH3)2, ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
- -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), in particular from -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa),
with Raa and Rba being selected, where applicable, independently from each other from -Ra or -ORa and
- with Ra being hydrogen, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -C6H5 , -CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 , and i. with the other R being selected independently from any other R from -OH, -F, - CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, - CH2CH3, -CH2OCH3, -CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, - CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, or ii. with the other R being selected independently from any other R from -OH, -F, - CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, - CH2CH3, -CH2OCH3, -CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, - CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, wherein, each carbon atom of the cyclic system which comprises no substituent R comprises F instead of H.
In some embodiments, in particular according to any one of the sub aspects 1 to 6, 19, 21 , 24 or 27, BE is
Figure imgf000079_0001
with n of R n being 0 or 2, and with one R being Q and the other R being -OCH3 or - OCF3, more particularly Q is in ortho and OCH3 or -OCF3 is in meta position with respect to the attachment position of the phenyl moiety of BB to D5, with Q having the same meaning as defined above. In some embodiments, in particular according to any one of the sub aspects 1 to 3,
-D4-BE is
Figure imgf000080_0001
with each T" being selected from -CH2, -NH, -S, -O, or -NRC, in particular T" is O,
- with Rc being -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2,
with n of R n being 0, 1 , 2 or 3, in particular n of R n being 0, 1 , or 2,
i. with each R being selected independently from any other R from -OH, -F, -CI, - Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, - CH2OCH3, -CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, or
ii. with each R being selected independently from any other R from -OH, -F, -CI, - Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, - CH2OCH3, -CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, wherein, each carbon atom of the cyclic system which comprises no substituent R comprises F instead of H.
In some embodiments, in particular according to any one of the sub aspects 1 to 3,
-D4-BE is
Figure imgf000080_0002
with each T" being selected from -CH2, -NH, -S, -O, or -NRC, in particular T" is O,
- with Rc being -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2,
- with n of R n being 2, and with each R independently from any other R being -OH, -OCH3 or -OCF3, in particular -OCH3 or -OCF3, more particularly with one R being -OH and the other R being -OCH3 or - OCF3, in particular -OCH3, wherein more particularly OH is in ortho and OCH3 or -OCF3 in meta position with respect to the attachment position of the phenyl moiety of BE to D5, or
- with n of R n being 1 , and with R being -OH, wherein in particular OH is in ortho position with respect to the attachment position of the phenyl of BE to D5 or
- with n of R n being 1 , and with R being -OCH3 or -OCF3, in particular or - OCH3, wherein more particularly -OCH3 or -OCF3 is in meta position with respect to the attachment position of the phenyl of BE to D5, or
- with n of R n being 0, or
- with n of R n being 4 and each R is F.
In some embodiments, in particular according to any one of the sub aspects 1 to 3,
-D4-BE is
Figure imgf000081_0001
with each T" being selected from -CH2, -NH, -S, -O, or -NRC, in particular T" is O,
- with Rc being -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, with n of R n being 1 , 2 or 3, in particular n of R n being 1 or 2,
with one R being a substituent Q, with Q being selected from
- -(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORV (CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, in particular -(CH2)m-0-S(02)OH, - (CH2)m-0-S(02)ORa, with m being selected from 0, 1 or 2, in particular from 0 or 1 , with Ra being -CH3, -CH2CH3, -C6H5 ,-CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
- -C(=0)-0-Ra, -0-C(=0)-Ra, in particular -0-C(=0)-Ra, with Ra being a substituted or unsubstituted C1 -C16 alkyl, in particular an unsubstituted C1 -C14 alkyl,
- -(CH2)m-[(CH2)m1-0-C(=0)-(CH2)m2]p1-C(=0)ORd, in particular -(CH2)-[-0- C(=0)-(CH2)2]p1-C(=0)ORd with - Rd being -CH3, -CH2CH3, -CH2CH2CH3! -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
- -(CH2)m-[(CH2)m1-0-(CH2)m2]p1-ORd, in particular -[-0-(CH2)2]p1-ORd, with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
- -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), in particular from -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa),
with Raa and Rba being selected, where applicable, independently from each other from -Ra or -ORa and
- with Ra being hydrogen, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -C6H5 , -CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para-methoxybenzyl with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 , and
with the other R being selected independently from any other R from -OH, -F, - CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, - CH2CH3, -CH2OCH3, -CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, - CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, or with the other R being selected independently from any other R from -OH, -F, - CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, - CH2CH3, -CH2OCH3, -CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, - CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, wherein, each carbon atom of the cyclic system which comprises no substituent R comprises F instead of H. In some embodiments, in particular according to any one of the sub aspects 1 to 3,
-D4-BE is
Figure imgf000083_0001
with each T" being selected from -CH2, -NH, -S, -O, or -NRC, in particular T" is O,
- with Rc being -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, with n of R n being 0 or 2, and with one R being Q and the other R being -OCH3 or - OCF3, more particularly Q is in ortho and OCH3 or -OCF3 is in meta position with respect to the attachment position of the phenyl moiety of BB to D5, with Q having the same meaning as defined above.
In some embodiments, in particular according to any one of the sub aspects 7, 8, 10 to 13, 22, 23, 25, 28, 29 or 32,
R is a substituent Q, with Q being selected from
- -(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,- (CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, in particular -(CH2)m-0-S(02)OH, - (CH2)m-0-S(02)ORa, with m being selected from 0, 1 or 2, in particular from 0 or 1 , with Ra being -CH3, -CH2CH3, -C6H5 ,-CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
- -C(=0)-0-Ra, -0-C(=0)-Ra, in particular -0-C(=0)-Ra, with Ra being a substituted or unsubstituted C Ci6 alkyl, in particular an unsubstituted C Ci4 alkyl,
- -(CH2)m-[(CH2)m1-0-C(=0)-(CH2)m2]p1-C(=0)ORd, in particular -(CH2)-[-0- C(=0)-(CH2)2]p1-C(=0)ORd with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
- -(CH2)m-[(CH2)m1-0-(CH2)m2]p1-ORd, in particular -[-0-(CH2)2]p1-ORd, with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
- -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), in particular from -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa),
with Raa and Rba being selected, where applicable, independently from each other from -Ra or -ORa and
- with Ra being hydrogen, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -C6H5 , -CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 .
In some embodiments, X2 is
-OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH3, -CF3 or -N02,
-B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, -(CH2)m- OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m- OC(=S)Ra, -(CH2)m-OC(=S)ORa, -(CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, - (CH2)m-S(=0)Ra, -(CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m- OS(02)ORa, -(CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa, -(CH2)m- NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m-NRcC(=S)ORa, - (CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or -(CH2)m- S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, -(CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0- C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), - (CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
- with Raa being selected independently from each other from -Ra or -ORa,
- with Rba being selected independently from each other from -Rb or -ORb,
- with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted Ci-C8 alkyl,
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 ,
- with each Ra, Rb or Rc being selected independently from each other from - hydrogen, -CN,
- a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
- a substituted or unsubstituted C6-Cio aryl,
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
- a substituted or unsubstituted C5-C10 heteroaryl,
- a substituted or unsubstituted C1-C16 alkyl, a substituted or unsubstituted C1-C16 alkoxy, a substituted or unsubstituted C1-C16 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C1-C16 haloalkyl, and
wherein a linker D5 may be optionally situated between BE and X2
In some embodiments, X2 is
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, - CH2CH3, -CH3, -CF3 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, -(CH2)m- OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m- OC(=S)Ra, -(CH2)m-OC(=S)ORa, -(CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m- SRa, -(CH2)m-S(=0)Ra, -(CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m- OS(02)ORa, -(CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa, -(CH2)m- NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m-NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or -(CH2)m- S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, -(CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m- 0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
- with Raa being selected independently from each other from -Ra or -ORa,
- with Rba being selected independently from each other from -Rb or -ORb,
- with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl,
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 , - with each Ra, Rb or Rc being selected independently from each other from
- hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, - CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -C6H5,— CH2C6H5,
wherein a linker D5 may be optionally situated between BE and X2
In some embodiments, in particular according to any one of the sub aspects 1 to 9 or 14 to 16, BF is
a substituted or unsubstituted C3-Ci o cycloalkyl or a substituted or unsubstituted C3-Ci o halo cycloalkyl, or
a substituted or unsubstituted C3-Ci 0 heterocycle or a substituted or unsubstituted C3-Ci 0 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Ci o aryl.
In some embodiments, in particular according to any one of the sub aspects 1 to 17, 19, 21 , 24 or 27, BF is
Figure imgf000086_0001
wherein D5 has the same meaning as defined previously, and
with T being selected from
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, - N(CH3)2, -CH3, -CH2-CH3, -CF3 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m- C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m- OC(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m- C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, -(CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, - (CH2)m-SRa, -(CH2)m-S(=0)Ra, -(CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, - (CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, -(CH2)m-NRaRb, -(CH2)m- NRcC(=0)Ra, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m-NRcC(=0)ORa, -(CH2)m- NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m-NRcC(=S)ORa, -(CH2)m- NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or - (CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, -(CH2)m-0-C(=0)- (M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q-
Figure imgf000087_0001
(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl
with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen,
- -CN
- a substituted or unsubstituted C Ci6 alkyl, a substituted or
unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C Ci6 haloalkyl, or
- a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl, or
- a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Cio halo heterocycle, in particular a substituted or unsubstituted C4-Ci0 heterocycle or a substituted or
unsubstituted C4-Cio halo heterocycle, or
- a substituted or unsubstituted C5-Cio heteroaryl, or
- a substituted or unsubstituted C6-Cio aryl,
with n of R 0n being 0, 1 , 2, 3 or 4, in particular n of R 0 n being 0, 1 , 2 or 3, 4, and with each R 0 independently from any other R 0 being selected from
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2-CH3, -CF3 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m- C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, - (CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, - (CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m- NRcC(=0)ORa, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m- NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m- P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, - (CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q-
Figure imgf000088_0001
(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl
with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen, -CN
- a substituted or unsubstituted C Ci6 alkyl, a substituted or
unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C Ci6 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted CrC8 haloalkyl, a substituted or unsubstituted C3- Cio cycloalkyl, or a substituted or unsubstituted C3-Cio halo cycloalkyl,
- a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl,
- a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Cio halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted
C4-C10 halo heterocycle,
- a substituted or unsubstituted C5-C10 heteroaryl,
- a substituted or unsubstituted C6-Cio aryl.
In some embodiments, in particular according to any one of the sub aspects 1 to 17, 19, 21 , 24 or 27, BF is
Figure imgf000089_0001
wherein D5 and T have the same meaning as defined previously,
with n of R n being 0, 1 , 2, 3 or 4, in particular n of R n being 0, 1 , 2 or 3, and
with each R independently from any other R being selected from
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NH CH3, -N(CH3)2, - CH3, -CH2-CH3, -CF3 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, -(CH2)m- OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, -(CH2)m- S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, -(CH2)m- NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m-NRcC(=0)ORa, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m-NRcC(=S)ORa, -(CH2)m- NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or -(CH2)m- S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, -(CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0- (CH2)q-S(02)ORa,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl, in particular Ci to C2 alkyl,
with m being selected from 0, 1 or 2, in particular 0 or 1 , with q being selected from 0, 1 or 2, in particular 0 or 1 ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH(CH3)2, - CH2CH(CH3)2, -C(CH3)3, -C6H5, -CH2CeH5.
In some embodiments, in particular according to any one of the sub aspects 1 to 17, 19, 21 , 24 or 27,
BF is
Figure imgf000090_0001
wherein D5 and T have the same meaning as defined previously,
with n of R 0n being 0, 1 , 2, 3 or 4, in particular n of R 0 n being 0, 1 , 2 or 3, and
with each R 0 independently from any other R 0 being
-OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2CH3, -CH2OCH3, -CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, - S02NHCH3, -CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -
CF3,
a substituted or unsubstituted C5-C6 heterocycle,
a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
a substituted or unsubstituted C5-C6 heteroaryl,
a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F, a substituted or unsubstituted C6 aryl. In some embodiments, in particular according to any one of the sub aspects 1 to 17, 19, 21 , 24 or 27,
BF is
Figure imgf000091_0001
wherein D5 and T have the same meaning as defined previously,
with n of R 0n being 0, 1 , 2, 3 or 4, in particular n of R 0 n being 0, 1 , 2 or 3, and with each R 0 independently from any other R 0 being -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH2OCH3, -CHCH2, -CH2OH, -S02NH2, - S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or - CF3.
In some embodiments, in particular according to any one of the sub aspects 1 to 17, 19, 21 , 24 or 27,
BF is
Figure imgf000091_0002
wherein D5 and T have the same meaning as defined previously,
with n of R 0n being 2, and with each R 0 independently from any other R 0 being
-OH, -OCH3 or -OCF3, in particular OH or -OCH3, more particularly with one R 0 being -OH and the other R 0 being -OCH3, wherein further in particular OH is in meta and OCH3 or - OCF3 in ortho position with respect to the attachment position of the phenyl moiety of BF to D5, or
with n of R 0n being 1 , and with R 0 being -OH, wherein in particular OH is in meta position with respect to the attachment position of the phenyl of BF to D5 or
with n of R 0n being 1 , and with R 0 being -OCH3 or -OCF3,in particular or -OCH3, wherein more particularly -OCH3 or or -OCF3is in ortho position with respect to the attachment position of the phenyl of BF to D5, or
with n of R 0n being 0, or with n of R 0n being 4 and each R 0 is F.
In some embodiments, in particular according to any one of the sub aspects 1 to 17, 19, 21 , 24 or 27,
BF is
Figure imgf000092_0001
wherein D5 and T have the same meaning as defined previously,
with n of R 0n being 0, 1 , 2, 3 or 4, in particular n of R n being 0, 1 , 2 or 3, and with each R 0 independently from any other R 0 being -OH, OCH3, -F or -CF3.
In some embodiments, in particular according to any one of the sub aspects 1 to 17, 19, 21 , 24 or 27,
BF is
Figure imgf000092_0002
wherein D5 and T have the same meaning as defined previously,
with n of R 0n being 1 , 2, 3 or 4, in particular n of R 0 n being 1 , 2 or 3,
with one R 0 being a substituent Q, with Q being selected from
- -(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,- (CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, in particular -(CH2)m-0-S(02)OH, - (CH2)m-0-S(02)ORa, with m being selected from 0, 1 or 2, in particular from 0 or 1 , with Ra being -CH3, -CH2CH3, -C6H5 ,-CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
- -C(=0)-0-Ra, -0-C(=0)-Ra, in particular -0-C(=0)-Ra, with Ra being a substituted or unsubstituted C Ci6 alkyl, in particular an unsubstituted C Ci4 alkyl,
- -(CH2)m-[(CH2)m1-0-C(=0)-(CH2)m2]p1-C(=0)ORd, in particular -(CH2)-[-0- C(=0)-(CH2)2]p1-C(=0)ORd with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
-(CH2)m-[(CH2)m1-0-(CH2) m2]p1 " ORd, in particular -[-0-(CH2)2]pi-ORd, with
Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
-(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), in particular from -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa),
with Raa and Rba being selected, where applicable, independently from each other from -Ra or -ORa and
- with Ra being hydrogen, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -C6H5 - CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 , and with the other R 0 being selected independently from each other R 0 from - OH, -F, -CI, - Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH2OCH3, - CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3.
In some embodiments, in particular according to any one of the sub aspects 1 to 17, 19, 21 ,
24 or 27,
BF is
Figure imgf000093_0001
wherein D5 and T have the same meaning as defined previously,
with n of R 0n being 5, and one to four of R being F, one R 0 being the substituent Q, and, where applicable, the other ones of R 0 being selected independently from any other R from -H, -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH2OCH3, -CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, or
with n of R 0n being 5, and one to three of R 0 being F, one R 0 being the substituent Q, and, where applicable, the other ones of R 0 being selected independently from any other R 0 from -Η,-ΟΗ, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH2OCH3, -CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, or
with n of R 0n being 5, and one or two of R 0 being F, one R 0 being the substituent Q, and, where applicable, the other ones of R 0 being selected independently from any other R 0 from -H,-OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH2OCH3, -CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, or
with n of R 0n being 5, and one of R 0 being F, one R 0 being the substituent Q, and, where applicable, the other ones of R 0 being selected independently from any other R 0 from -H,-OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH2OCH3, -CHCH2, -CH2OH, - S02NH2, -S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or -N02, in particular from - OH, -F, -OCH3, -OCF3 or -CF3, or
with n of R 0n being 3, one R 0 being the substituent Q, and the other R 0 being selected independently from each other R 0 from -H,-OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH2OCH3, -CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, or
with n of R 0n being 2, one R 0 being the substituent Q and the other R 0 being -H,-OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, - N(CH3)2, -CH3, -CH2CH3, -CH2OCH3, -CHCH2, -CH2OH, -S02NH2, - S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or -N02, in particular from -OH, -F, - OCH3, -OCF3 or -CF3, or
with n of R 0n being 1 with R 0 being the substituent Q,
with Q having the same meaning as defined previously, and wherein in particular Q is in ortho position with respect to the attachment position of the phenyl moiety to the parent moiety,
and wherein in particular any hydrogen of the phenyl group may be substituted with F. In some embodiments, in particular according to any one of the sub aspects 1 to 17, 19, 21 , 24 or 27,
BF is
Figure imgf000095_0001
with n of R 0n being 2, and with one R 0 being Q and the other R 0 being -OCH3 or -OCF3, more particularly Q is in meta and OCH3 or -OCF3 is in ortho position with respect to the attachment position of the phenyl moiety of BB to D4, with Q and T having the same meaning as defined above.
In some embodiments, in particular according to any one of the sub aspects 1 to 17, 19, 21 , 24 or 27,
-D5-BF is
Figure imgf000095_0002
with T having the same meaning as defined above,
with each T" being selected from -CH2, -NH, -S, -O, or -NRC, in particular T" is O,
- with Rc being -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, with n of R 0n being 0, 1 , 2 or 3, in particular n of R n being 0, 1 or 2,
with each R 0 being selected independently from any other R 0 from -OH, -F, -CI, -Br, -I, - CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH2OCH3, - CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, or
with each R 0 being selected independently from any other R 0 from -OH, -F, -CI, -Br, -I, - CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -CH2OCH3, - CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, wherein, each carbon atom of the cyclic system which comprises no substituent R 0 comprises F instead of H In some embodiments, in particular according to any one of the sub aspects 1 to 17, 19, 21 , 24 or 27,
-D5-BF is
Figure imgf000096_0001
with T having the same meaning as defined above,
with each T" being selected from -CH2, -NH, -S, -O, or -NRC, in particular T" is O,
- with Rc being -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 with n of R 0n being 2, and with each R 0 independently from any other R 0 being -OH, -OCH3 or -OCF3, in particular -OCH3 or -OCF3, more particularly with one R 0 being -OH and the other R 0 being -OCH3 or -OCF3, in particular -OCH3, wherein more particularly OH is in ortho and OCH3 or -OCF3 in meta position with respect to the attachment position of T, or with n of R 0n being 1 , and with R 0 being -OH, wherein in particular OH is in ortho position with respect to the attachment position of T, or
with n of R 0n being 1 , and with R 0 being -OCH3 or -OCF3, in particular or -OCH3, wherein more particularly -OCH3 or -OCF3 is in meta position with respect to the attachment position of T, or
with n of R 0n being 0, or
with n of R 0n being 4 and each R 0 is F.
In some embodiments, in particular according to any one of the sub aspects 1 to 17, 19, 21 , 24 or 27,
-D5-BF is
Figure imgf000096_0002
with T having the same meaning as defined above, with each T" being selected from -CH2, -NH, -S, -O, or -NRC, in particular T" is O,
- with Rc being -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, with n of R 0n being 1 , 2 or 3, in particular n of R 0 n being 1 or 2,
with one R 0 being a substituent Q, with Q being selected from
- -(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa, - (CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, in particular -(CH2)m-0-S(02)OH, - (CH2)m-0-S(02)ORa, with m being selected from 0, 1 or 2, in particular from 0 or 1 , with Ra being -CH3, -CH2CH3, -C6H5 ,-CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
- -C(=0)-0-Ra, -0-C(=0)-Ra, in particular -0-C(=0)-Ra, with Ra being a substituted or unsubstituted C Ci6 alkyl, in particular an unsubstituted C Ci4 alkyl,
- -(CH2)m-[(CH2)m1-0-C(=0)-(CH2)m2]p1-C(=0)ORd, in particular -(CH2)-[-0- C(=0)-(CH2)2]p1-C(=0)ORd with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
- -(CH2)m-[(CH2)m1-0-(CH2)m2]p1-ORd, in particular -[-0-(CH2)2]p1-ORd, with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
- -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), in particular from -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa),
with Raa and Rba being selected, where applicable, independently from each other from -Ra or -ORa and
- with Ra being hydrogen, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -C6H5 , -CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 , i. with the other R being selected independently from any other R from -OH, -F, - CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, - CH2CH3, -CH2OCH3, -CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, - CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, or ii. with the other R being selected independently from any other R from -OH, -F, - CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, - CH2CH3, -CH2OCH3, -CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, - CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, wherein, each carbon atom of the cyclic system which comprises no substituent R comprises F instead of H.
In some embodiments, in particular according to any one of the sub aspects 1 to 17, 19, 21 , 24 or 27,
-D5-BF is
Figure imgf000098_0001
with T having the same meaning as defined above,
with each T" being selected from -CH2, -NH, -S, -O, or -NRC, in particular T" is O,
- with Rc being -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, with n of R n being 0 or 2, and with one R being Q and the other R being -OCH3 or - OCF3, more particularly Q is in ortho and OCH3 or -OCF3 is in meta position with respect to the attachment position of T, with Q having the same meaning as defined above.
In some embodiments, in particular according to the sub aspect 32, with R being a substituent Q, Q is selected from
-(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,- (CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, in particular -(CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, with Ra being -CH3, -CH2CH3, -C6H5 ,-CH2CH2CH3, - CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
-C(=0)-0-Ra, -0-C(=0)-Ra, in particular -0-C(=0)-Ra, with Ra being a substituted or unsubstituted C Ci6 alkyl, in particular an unsubstituted Cr CM alkyl, -[(CH2)m1-0-C(=0)-(CH2)m2]p1-C(=0)ORd or -[(CH2)m1-0- (CH2)m2]p1-ORd, in particular -[(CH2)m1-0-(CH2)m2]p1-ORd with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8, -[(CH2)m1-0-(CH2)m2]p1-ORd, in particular -[-0-(CH2)2]p1-ORd, with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
-(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), in particular from -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa),
with Raa and Rba being selected, where applicable, independently from each other from -Ra or -ORa and
- with Ra being hydrogen, -OCH3, -OCH2CH3, -CH3, -CH2CH3, - C6H5 , -CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para- methoxybenzyl
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 ,
In some embodiments, in particular according to the sub aspect 32,
with n of R n being 5, and one to four of R being F, one R being the substituent Q, and, where applicable, the other ones of R being selected independently from any other R from - OH, -CI, I, -CN, -OCH3, -OCF3 or -CF3, in particular from -OH, -OCH3, -OCF3 or -CF3, or with n of R n being 5, and one to three of R being F, one R being the substituent Q, and, where applicable, the other ones of R being selected independently from any other R from - OH, -CI, I, -CN, -OCH3, -OCF3 or -CF3, in particular -OH, -OCH3, -OCF3 or -CF3, or with n of R n being 5, and one or two of R being F, one R being the substituent Q, and, where applicable, the other ones of R being selected independently from any other R from - OH, -CI, I, -CN, -OCH3, -OCF3 or -CF3, in particular -OH, -OCH3, -OCF3 or -CF3, or with n of R n being 5, and one of R being F, one R being the substituent Q, and, where applicable, the other ones of R being selected independently from any other R from -OH, - CI, I, -CN, -OCH3, -OCF3 or -CF3, in particular -OH, -OCH3, -OCF3 or -CF3, or
with n of R n being 3, one R being the substituent Q, and the other R being selected independently from each other R from -OH, -OCH3, -OCF3 or -CF3.
with n of R n being 2, one R being the substituent Q and the other R being -OH, -OCH3, - OCF3 or -CF3, or
with n of R n being 1 with R being the substituent Q, and with Q having the same meaning as defined previously, and wherein in particular Q is in para position with respect to the attachment position of the phenyl moiety of E to the parent moiety.
In some embodiments, in particular according to any one of the sub aspects 7, 8, 10, 1 1 to 13, 22, 23, 25, 28, 29 or 32,
R is a substituent Q, with Q being selected from
-(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,- (CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, in particular -(CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, with Ra being -CH3, -CH2CH3, -C6H5 ,-CH2CH2CH3, - CH(CH3)2, -CH2C6H5 or para-methoxybenzy
-C(=0)-0-Ra, -0-C(=0)-Ra, in particular -0-C(=0)-Ra, with Ra being a substituted or unsubstituted C1-C16 alkyl, in particular an unsubstituted Cr Ci4 alkyl, -[(CH2)m1-0-C(=0)-(CH2)m2]p1-C(=0)ORd or -[(CH2)m1-0- (CH2)m2]p1-ORd, in particular -[(CH2)m1-0-(CH2)m2]p1-ORd with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8, -[(CH2)m1-0-(CH2)m2]p1-ORd, in particular -[-0-(CH2)2]p1-ORd, with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
-(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), in particular from -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), with Raa and Rba being selected, where applicable, independently from each other from -Ra or -ORa and
- with Ra being hydrogen, -OCH3, -OCH2CH3, -CH3, -CH2CH3, - C6H5 , -CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para- methoxybenzyl
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 ,
, and, in particular, wherein, each carbon atom of the cyclic system which comprises no substituent R 3 comprises F instead of H.
In some embodiments, in particular according to any one of the sub aspects 7, 8, 10, 1 1 to 13, 22, 23, 25, 28, 29 or 32,
R 0 is a substituent Q, with Q being selected from
-(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa, - (CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, in particular -(CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, with Ra being -CH3, -CH2CH3, -C6H5 ,-CH2CH2CH3, - CH(CH3)2, -CH2C6H5 or para-methoxybenzy
-C(=0)-0-Ra, -0-C(=0)-Ra, in particular -0-C(=0)-Ra, with Ra being a substituted or unsubstituted C Ci6 alkyl, in particular an unsubstituted Cr Ci4 alkyl, -[(CH2)m1-0-C(=0)-(CH2)m2]p1-C(=0)ORd or -[(CH2)m1-0- (CH2)m2]p1-ORd, in particular -[(CH2)m1-0-(CH2)m2]p1-ORd with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8, -[(CH2)m1-0-(CH2)m2]p1-ORd, in particular -[-0-(CH2)2]p1-ORd, with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
-(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), in particular from -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), with Raa and Rba being selected, where applicable, independently from each other from -Ra or -ORa and
- with Ra being hydrogen, -OCH3, -OCH2CH3, -CH3, -CH2CH3, - C6H5 , -CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para- methoxybenzyl
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 ,
and, in particular, wherein, each carbon atom of the cyclic system which comprises no substituent R 3 comprises F instead of H.
some embodiments, in particular according to any one of the sub aspects 10 to 13, 18 to, T is selected from
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, - N(CH3)2, -CH3, -CH2-CH3, -CF3 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m- C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m- OC(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m- C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, -(CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, - (CH2)m-SRa, -(CH2)m-S(=0)Ra, -(CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, - (CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, -(CH2)m-NRaRb, -(CH2)m- NRcC(=0)Ra, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m-NRcC(=0)ORa, -(CH2)m- NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m-NRcC(=S)ORa, -(CH2)m- NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or - (CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, -(CH2)m-0-C(=0)- (M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl
with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 , with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen,
- -CN
- a substituted or unsubstituted C Ci6 alkyl, a substituted or unsubstituted C1-C16 alkoxy, a substituted or unsubstituted C1-C16 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C1-C16 haloalkyi, or
- a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or
unsubstituted C3-C10 halo cycloalkyl, or
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or
unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
- a substituted or unsubstituted C5-C10 heteroaryl, or
- a substituted or unsubstituted C6-Cio aryl,
some embodiments, in particular according to any one of the sub aspects 10 to 13, 18 to, T is selected from
a. -B(OH)2, -CN, -NH2, -OH, -OCH3, -C(=0)NH2, -C(=0)NH(CN), -C(=0)NH(OH), -CH2OH, -CH2C(=0)OH, -CH2C(=0)NH(OH), -CH2C(=0)NH2, - CH2NHS(02)OH, -CH2NHC(=0)OH, -P(=0)(OH)(OH), -CH2P(=0)(OH)(OH), - CH2S(02)OH, -S(02)OH or -S(02)NH2 or
b. -Ra, -CH2Ra, -SRa, -CH2SRa, -S(=0)Ra, -C(=0)NHRa, -CH2C(=0)NHRa, - CH2NHS(02)Ra, -C(=0)ORa, -ORa or -NHRa,-C(=0)ORa -CH2C(=0)NH(ORa), -C(=0)NHORa, -C(=0)NHRa, -(CH2)m-NHC(=0)ORa, -CH2NHS(02)Ra, - CH2ORa, -CH2NHC(=0)Ra, -P(=0)(OH)(ORa), -CH2P(=0)(OH)(ORa), - P(=0)(OH)(Ra), - CH2P(=0)(OH)(Ra), -CH2S(02)ORa, -S(02)ORa, -S(02)Ra or - CH2S(02)Ra, or -S(02)NHRa,
with Ra being selected from
a substituted or unsubstituted C1-C16 alkyl, a substituted or
unsubstituted C1-C16 alkoxy, a substituted or unsubstituted C2-Ci4 alkenyl, a substituted or unsubstituted C2-Ci4 alkynyl, or a C1-C14 haloalkyi, in particular a substituted or unsubstituted C1-C5 alkyl, more particularly Ra is -CH3, -CF3, -CH2CH3, -CH2CF3, -CN, ,-CH2CH2CH3, - CH(CH3)2, -CH2C6H5 or para-methoxybenzy
-[(CH2)mrO-(CH2)m2]p1-ORd, -[(CH2)m1-C(=0)0-(CH2)m2]p1-ORd in particular - [-0-(CH2)2]p1-ORd, -[-C(=0)0-(CH2)2]p1-ORd, with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8, c. -Ra, -CH2Ra, -SRa, -CH2SRa, -S(=0)Ra, -C(=0)NHRa, -CH2C(=0)NHRa, - CH2NHS(02)Ra, -C(=0)ORa, -ORa or -NHRa,
with Ra being
a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Cio halo heterocycle, in particular a substituted or unsubstituted C4-Ci0 heterocycle or a substituted or unsubstituted C4- Cio halo heterocycle, or
a substituted or unsubstituted C5-Cio heteroaryl, or a substituted or unsubstituted C6-Cio aryl.
In some embodiments, in particular according to any one of the sub aspects 10 to 13, 18 to 32, T is selected from
-(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa, -(CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, in particular -(CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, with Ra being - CH3, -CH2CH3, -C6H5 ,-CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para-methoxybenzy
-C(=0)-0-Ra, -0-C(=0)-Ra, in particular -0-C(=0)-Ra, with Ra being a substituted or unsubstituted C Ci6 alkyl, in particular an unsubstituted Ci-Ci4 alkyl, -[(CH2)mrO-C(=0)- (CH2)m2]p1-C(=0)ORd or -[(CH2)m1-0-(CH2)m2]p1-ORd, in particular -[(CH2)m1-0-(CH2)m2]p1-ORd with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8, -[(CH2)m1-0-(CH2)m2]p1-ORd, in particular -[-0-(CH2)2]p1-ORd, with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
-(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), in particular from -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa),
with Raa and Rba being selected, where applicable, independently from each other from -Ra or -ORa and
- with Ra being hydrogen, -OCH3, -OCH2CH3, -CH3, -CH2CH3, - C6H5 , -CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para- methoxybenzyl
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 ,
In some embodiments, in particular according to any one of the sub aspects 10 to 13, 18 to 32, T is -C(=0)ORa
with Ra being
a substituted or unsubstituted C Ci6 alkyl, in particular an unsubstituted C1-C16 alkyl,
-[(CH2)m1-0-(CH2)m2]p1-ORd, -[(CH2)m1-C(=0)0-(CH2)m2]p1-ORd, in particular -[-0-(CH2)2]p1-ORd, -[-C(=0)0-(CH2)2]p1 , , with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8.
In some embodiments, in particular according to any one of the sub aspects 10 to 13, 18 to 32, T is selected from the following compounds
-B(OH)2, -CN, -OH, -CH2OH, -CH2OCH3, -OCH3, -C(=0)NH2, -C(=0)NH(CN), - C(=0)OH, -C(=0)NH(CH3), -C(=0)NH(OH), -S(02)NH2, -CH2C(=0)OH, - CH2C(=0)NHOH, -CH2-NH-S(0)2CF3, -CH2-C(=0)-NH-OCH3, -P(=0)(OH)2, - CH2)P(=0)(OH)2, -P(=0)(OH)(OCH2CH3), -P(=0)(OH)(CH3), -CH2P(=0)(OH)(CH3), - CH2S(0)2(OH), -S(0)2(OH),
Figure imgf000106_0001
105
Figure imgf000107_0001
with each R8 being -H, or, where applicable, with each R8 being selected independently from each other from -H, -CH3, -CH2CH3, -OCH3, -OCF3, - CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with each R8 being selected independently from each other from H or CH3, more particularly R8 being H, and
with V being, where applicable, S, NH or O, in particular V being O.
D1 to D5 may also be a phosphor containing groups, in particular a O-P containing functionality such as -OP(0)2-NH- or alike.
In some embodiments, in particular according to any one of the sub aspects, each D to D5 is selected independently from each other from
Figure imgf000108_0001
with each R8 being -H, or, where applicable, with each R8 being selected independently from each other from -H, -CH3, -CH2CH3, -OCH3, -OCF3, - CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with each R8 being selected independently from each other from H or CH3, more particularly R8 being H, and
with V being, where applicable, S, NH or O, in particular V being O.
In some embodiments, in particular according to any one of the sub aspects, each D to D5 is selected independently from each other from
Figure imgf000108_0002
(D6), with each R8 being -H, or, where applicable, with each R8 being selected independently from each other from -H, -CH3, -CH2CH3, -OCH3, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with each R8 being selected independently from each other from H or CH3, more particularly R8 being H, and
with V being, where applicable, S, NH or O, in particular V being O.
In some embodiments, in particular according to any one of the sub aspects, each D to D5 is selected independently from each other from
Figure imgf000109_0001
(D4),
with each R8 being -H, or, where applicable, with each R8 being selected independently from each other from -H, -CH3, -CH2CH3, -OCH3, -OCF3, - CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with each R8 being selected independently from each other from H or CH3, more particularly R8 being H, and
with V being, where applicable, S, NH or O, in particular V being O.
In some embodiments, in particular according to any one of the sub aspects, each D to D5 is selected independently from each other from
Figure imgf000109_0002
(D4a), in particular from
Figure imgf000110_0001
In some embodiments, in particular according to any one of the sub aspects 1 1 to 13, 24 to 31 , R2 and R3 of BA are selected, where applicable, independently from each other from -H, - F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl , in particular from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3,more particularly with R2 and R3 being selected independently from each other from -H, -F or -CH3.
In some embodiments, in particular according to any one of the sub aspects 2, 4, 6, 8, 9, 14 to 31 each R8 is, where applicable, selected independently from each other from -H, -CH3, - CH2CH3, -OCH3, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with each R8 being selected independently from each other from H or CH3, more particularly each R8 being H.
According to a sub aspect (sub aspect 32) of the first aspect, the invention relates to antibiotically active compounds having a molecular structure as defined by a general formula (34),
Figure imgf000110_0002
(formula
34),
with n of R n being 1 , 2, 3, 4 or 5, in particular n of R n being 1 , 2 or 3, with R of BA being a substituent Q, with Q being selected from
-(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa, - (CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, in particular -(CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, with Ra being -CH3, -CH2CH3, -C6H5 ,-CH2CH2CH3, - CH(CH3)2, -CH2C6H5 or para-methoxybenzyl -C(=0)-0-Ra, -0-C(=0)-Ra, in particular -0-C(=0)-Ra, with Ra being a
substituted or unsubstituted C Ci6 alkyl, in particular an unsubstituted Cr Ci4 alkyl, -[(CH2)m1-0-C(=0)-(CH2)m2]p1-C(=0)ORd or -[(CH2)m1-0- (CH2)m2]p1-ORd, in particular -[(CH2)m1-0-(CH2)m2]p1-ORd with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8, -[(CH2)m1-0-(CH2)m2]p1-ORd, in particular -[-0-(CH2)2]p1-ORd, with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
-(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), in particular from -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa),
with Raa and Rba being selected, where applicable, independently from each other from -Ra or -ORa and
- with Ra being hydrogen, -OCH3, -OCH2CH3, -CH3, -CH2CH3, - C6H5 , -CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para- methoxybenzyl
with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 , ,
and with the other R being selected independently from each other R from -OH,
-F, -CI, -I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular from -OH, -F, -OCH3, -OCF3, -
OCONH2 or -CF3, or
with n of R n being 5, and one to four of R being F, one R being the substituent Q, and, where applicable, the other ones of R being selected independently from any other R from - OH, -CI, -I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular from -OH, -OCH3, -OCF3, - OCONH2 or -CF3, or
with n of R n being 5, and one to three of R being F, one R being the substituent Q, and, where applicable, the other ones of R being selected independently from any other R from - OH, -CI, -I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular -OH, -OCH3, -OCF3, - OCONH2 or -CF3, or with n of R n being 5, and one or two of R being F, one R being the substituent Q, and, where applicable, the other ones of R being selected independently from any other R from - OH, -CI, -I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular -OH, -OCH3, -OCF3, - OCONH2 or -CF3, or
with n of R n being 5, and one of R being F, one R being the substituent Q, and, where applicable, the other ones of R being selected independently from any other R from -OH, - CI, I, -CN, -OCH3, -OCF3, -OCONH2 or -CF3, in particular -OH, -OCH3, -OCF3, -OCONH2 or - CF3, or
with n of R n being 3, one R being the substituent Q, and the other R being selected independently from each other R from -OH, -OCH3, -OCF3, -OCONH2 or -CF3.
with n of R n being 2, one R being the substituent Q and the other R being -OH, -OCH3, - OCF3, -OCONH2 or -CF3, or
with n of R n being 1 with R being the substituent Q, and with Q having the same meaning as defined previously, and wherein in particular Q is in para position with respect to the attachment position of the phenyl moiety of E to the parent moiety, and
R is a substituent Q, with Q being selected from
-(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa, - (CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, in particular -(CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, with Ra being -CH3, -CH2CH3, -C6H5 ,-CH2CH2CH3, - CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
-C(=0)-0-Ra, -0-C(=0)-Ra, in particular -0-C(=0)-Ra, with Ra being a substituted or unsubstituted C1-C16 alkyl, in particular an unsubstituted Cr Ci4 alkyl, -[(CH2)m1-0-C(=0)-(CH2)m2]p1-C(=0)ORd or -[(CH2)m1-0- (CH2)m2]p1-ORd, in particular -[(CH2)m1-0-(CH2)m2]p1-ORd with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8, -[(CH2)m1-0-(CH2)m2]p1-ORd, in particular -[-0-(CH2)2]p1-ORd, with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
Figure imgf000113_0001
in particular from -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa),
with Raa and Rba being selected, where applicable, independently from each other from -Ra or -ORa and
- with Ra being hydrogen, -OCH3, -OCH2CH3, -CH3, -CH2CH3, - C6H5 , -CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para- methoxybenzyl
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 ,
and, in particular, wherein, each carbon atom of the cyclic system which comprises no substituent R comprises F instead of H, and
lected from
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, - N(CH3)2, -CH3, -CH2-CH3, -CF3 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m- C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m- OC(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m- C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, -(CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, - (CH2)m-SRa, -(CH2)m-S(=0)Ra, -(CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, - (CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, -(CH2)m-NRaRb, -(CH2)m- NRcC(=0)Ra, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m-NRcC(=0)ORa,-(CH2)m- NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m-NRcC(=S)ORa, -(CH2)m- NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or - (CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, -(CH2)m-0-C(=0)- (M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl
with m being selected from 0, 1 or 2, in particular 0 or 1 , with q being selected from 0, 1 or 2, in particular 0 or 1 , ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen,
- -CN
- a substituted or unsubstituted C Ci 6 alkyl, a substituted or unsubstituted C1 -C16 alkoxy, a substituted or unsubstituted C1 -C16 carboxy, a substituted or unsubstituted C2-Ci 6 alkenyl, a substituted or unsubstituted C2-Ci 6 alkynyl, or a C1 -C16 haloalkyl, or
- a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or
unsubstituted C3-C10 halo cycloalkyl, or
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or
unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
- a substituted or unsubstituted C5-C10 heteroaryl, or
- a substituted or unsubstituted C6-Ci o aryl, or
with T being selected from
-(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa, - (CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, in particular -(CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, with Ra being -CH3, -CH2CH3, -C6H5 ,-CH2CH2CH3, - CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
-C(=0)-0-Ra, -0-C(=0)-Ra, in particular -0-C(=0)-Ra, with Ra being a substituted or unsubstituted C1 -C16 alkyl, in particular an unsubstituted Cr Ci4 alkyl, -[(CH2)m1-0-C(=0)-(CH2)m2]p1 -C(=0)ORd or -[(CH2)m1-0- (CH2)m2]p1 -ORd, in particular -[(CH2)m1-0-(CH2)m2]p1 -ORd with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8, -[(CH2)m1-0-(CH2)m2]p1 -ORd, in particular -[-0-(CH2)2]p1 -ORd, with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
Figure imgf000115_0001
in particular from -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa),
with Raa and Rba being selected, where applicable, independently from each other from -Ra or -ORa and
- with Ra being hydrogen, -OCH3, -OCH2CH3, -CH3, -CH2CH3, - C6H5 -CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para- methoxybenzyl
with m being selected from 0, 1 or 2, in particular 0 or 1 , with q being selected from 0, 1 or 2, in particular 0 or 1 , or
with T being selected from
-B(OH)2, -CN, -NH2, -OH, -OCH3, -C(=0)NH2, -C(=0)NH(CN), -C(=0)NH(OH), -CH2OH, -CH2C(=0)OH, -CH2C(=0)NH(OH), -CH2C(=0)NH2, - CH2NHS(02)OH, -CH2NHC(=0)OH, -P(=0)(OH)(OH), -CH2P(=0)(OH)(OH), - CH2S(02)OH, -S(02)OH or -S(02)NH2 or
-Ra, -CH2Ra, -SRa, -CH2SRa, -S(=0)Ra, -C(=0)NHRa, -CH2C(=0)NHRa, - CH2NHS(02)Ra, -C(=0)ORa, -ORa or -NHRa,-C(=0)ORa -CH2C(=0)NH(ORa), -C(=0)NHORa, -C(=0)NHRa, -CH2NHS(02)Ra, -(CH2)-NHC(=0)ORa, - CH2ORa, -CH2NHC(=0)Ra, -P(=0)(OH)(ORa), -CH2P(=0)(OH)(ORa), - P(=0)(OH)(Ra), - CH2P(=0)(OH)(Ra), -CH2S(02)ORa, -S(02)ORa, -S(02)Ra or - CH2S(02)Ra, or -S(02)NHRa,
with Ra being selected from
a substituted or unsubstituted C Ci6 alkyl, a substituted or unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C2-Ci4 alkenyl, a substituted or unsubstituted C2-Ci4 alkynyl, or a Ci-Ci4 haloalkyi, in particular a substituted or unsubstituted CrC5 alkyl, more particularly Ra is -CH3, -CF3, -CH2CH3, -CH2CF3, -CN, ,-CH2CH2CH3, - CH(CH3)2, -CH2C6H5 or para-methoxybenzy
-[(CH2)m1-0-(CH2)m2]p1-ORd, -[(CH2)m1-C(=0)0-(CH2)m2]p1-ORd in particular - [-0-(CH2)2]p1-ORd, -[-C(=0)0-(CH2)2]p1-ORd,with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
-Ra, -CH2Ra, -SRa, -CH2SRa, -S(=0) Ra, -C(=0) NH Ra, -CH2C(=0) NH Ra, - CH2NHS(02)Ra, -C(=0)ORa, -ORa or -NH Ra,
with Ra being
a substituted or unsubstituted C3-Ci 0 heterocycle or a substituted or unsubstituted C3-Ci o halo heterocycle, in particular a substituted or unsubstituted C4-Ci 0 heterocycle or a substituted or unsubstituted C4- Ci o halo heterocycle, or
a substituted or unsubstituted C5-Ci o heteroaryl, or a substituted or unsubstituted C6-Ci o aryl, or
with T being is -C(=0)ORa
with Ra being
a substituted or unsubstituted C Ci 6 alkyl, in particular an unsubstituted C1 -C16 alkyl,
-[(CH2)m1-0-(CH2)m2]p1 -ORd, -[(CH2)m1 -C(=0)0-(CH2)m2]p1 -ORd, in particular -[-0-(CH2)2]p1 -ORd, -[-C(=0)0-(CH2)2]p1 , , with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8, or
T is selected from the following compounds
-B(OH)2, -CN, -OH , -CH2OH , -CH2OCH3, -OCH3, -C(=0) NH2, -C(=0)NH(CN) , - C(=0)OH , -C(=0) NH(CH3), -C(=0)NH(OH), -S(02)NH2, -CH2C(=0)OH , - CH2C(=0) NHOH, -CH2-NH-S(0)2CF3, -CH2-C(=0)-NH-OCH3, -P(=0)(OH)2, - CH2) P(=0)(OH)2, -P(=0)(OH)(OCH2CH3), -P(=0)(OH)(CH3), -CH2P(=0)(OH)(CH3), - CH2S(0)2(OH) , -S(0)2(OH) ,
Figure imgf000117_0001
t Q, with Q being selected from
-(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,- (CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, in particular -(CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, with Ra being -CH3, -CH2CH3, -C6H5 ,-CH2CH2CH3, - CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
-C(=0)-0-Ra, -0-C(=0)-Ra, in particular -0-C(=0)-Ra, with Ra being a substituted or unsubstituted C Ci6 alkyl, in particular an unsubstituted Cr Ci4 alkyl, -[(CH2)m1-0-C(=0)-(CH2)m2]p1-C(=0)ORd or -[(CH2)m1-0- (CH2)m2]p1-ORd, in particular -[(CH2)m1-0-(CH2)m2]p1-ORd with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
-[(CH2)m1-0-(CH2)m2]p1-ORd, in particular -[-0-(CH2)2]p1-ORd, with - Rd being -CH3, -CH2CH3, -CH2CH2CH3! -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
Figure imgf000118_0001
in particular from -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa),
with Raa and Rba being selected, where applicable, independently from each other from -Ra or -ORa and
- with Ra being hydrogen, -OCH3, -OCH2CH3, -CH3, -CH2CH3, - C6H5 , -CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para- methoxybenzyl
with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 ,
and, in particular, wherein, each carbon atom of the cyclic system which comprises no substituent R 0 comprises F instead of H, and e. with Y being selected from -CN, -C(=0)OH, -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)NHCH3, - C(=0)NHCH2CH3, -C(=0)N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3) or - C(=0)NH2, and
f. with Z being selected from -H, -OH, -CH3, -CH2CH3 or -OCH3, in particular Z is H and Y is CN or -C(=0)NH2.
In some embodiments, the compounds of the invention comprise the following formula (1 A)
Figure imgf000118_0002
wherein
Z is -H, -OH, -CH3, -CH2CH3 or -OCH3 and Y is -CN, -C(=0)OH, -C(=0)OCH3,
-C(=0)OCH2CH3, -C(=0)NHCH3, -C(=0)NHCH2CH3, -C(=0)N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3) or -C(=0)NH2, in particular Z is H and Y is CN and -C(=0)NH2, and more particularly Z is H and Y is CN, and wherein s
-OH , -F, -CI, -Br, I , -CCH , -CN, -N3, -N02, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2CH3 or -CF3, or
-B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, - (CH2)m-OC(=0) Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0) NRaRb, -(CH2)m-C(=0) NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m-NRcC(=0)ORa, -(CH2)m-C(=S) Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S) NRaRb, -(CH2)m-C(=S) NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, -(CH2)m- S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, -(CH2)m-NRaRb, - (CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0) NRaRb, -(CH2)m-NRcC(=0)ORa, -(CH2)m- NRcC(=S)Ra, -(CH2)m-NRcC(=S) NRaRb, -(CH2)m-NRcC(=S)ORa, -(CH2)m-NRcS(02) Ra, - (CH2)m-P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m- 0-C(=0)-(M)-C(=0)OH, -(CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, - (CH2)m-0-(CH2)q-P(=0)(Rba)(Raa) , -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m- C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
with Raa being selected independently from each other from -Ra or -ORa, with Rba being selected independently from each other from -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl,
with m being selected from 0, 1 or 2,
with q being selected from 0, 1 or 2,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen, -CN,
- a substituted or unsubstituted C3-Ci o cycloalkyl or a substituted or
unsubstituted C3-Ci o halo cycloalkyl, or
- a substituted or unsubstituted C6-Ci o aryl,
- a substituted or unsubstituted C3-Ci 0 heterocycle or a substituted or
unsubstituted C3-Ci o halo heterocycle, in particular a substituted or unsubstituted C4-Ci 0 heterocycle or a substituted or unsubstituted C4-Ci o halo heterocycle, or
- a substituted or unsubstituted C5-Ci o heteroaryl,
- a substituted or unsubstituted C Ci 6 alkyl, a substituted or unsubstituted C1 -C16 alkoxy, a substituted or unsubstituted C1 -C16 carboxy, a substituted or unsubstituted C2-Ci 6 alkenyl, a substituted or unsubstituted C2-Ci 6 alkynyl, or a C1 -C16 haloalkyl, in particular a substituted or unsubstituted d-Cs alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted d-Cs haloalkyi; or wherein
X is
Figure imgf000120_0001
with D being a linker which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting R4 and the parent moiety PM, and with R4 being
a substituted or unsubstituted d-Cs alkyl, a substituted or unsubstituted d-Cs alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted d-Cs haloalkyi, or a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
a substituted or unsubstituted C3-C10 heterocycle or a substituted or
unsubstituted C3-C10 halo heterocycle, in particular a substituted or
unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Cio aryl; or wherein
Figure imgf000120_0002
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH2, -N02, -NHCH3, -NH(CH3)2, a substituted or
unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyi , in particular from -H, -F, -CN, -OH, -NH2, -N02, -NHCH3, -NH(CH3)2, -
CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, - CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3> more particularly with R2 and R3 being selected independently from each other from H, F or CH3, and
with D being a linker which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting the moiety comprising E and the parent moiety,
with E being
a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted Ci-C8 haloalkyi, or a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
a substituted or unsubstituted C3-C10 heterocycle or a substituted or
unsubstituted C3-C10 halo heterocycle, in particular a substituted or
unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C8-Cio aryl; or
with E being
Figure imgf000121_0001
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2, more particularly n being 1 , and
with each R independently from any other R being
- OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -N02, -OCH3, -OCF3, -NH2, - NHCH3, -N(CH3)2, -CH3, -CH2CH3, -OCONH2 or -CF3, or
- B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m- C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m- OC(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m- C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, - (CH2)m-OC(=S)ORa, -(CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m- SRa, -(CH2)m-S(=0)Ra, -(CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m- OS(02)Ra, -(CH2)m-OS(02)ORa, -(CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, - (CH2)m-NRcC(=0)NRaRb, -(CH2)m-NRcC(=0)ORa, -(CH2)m-NRcC(=S)Ra, - (CH2)m-NRcC(=S)NRaRb, -(CH2)m-NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, - (CH2)m-P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, -(CH2)m-0-C(=0)-(M)-C(=0)ORa ! -(CH2)m- 0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m- C(=0)0-(CH2)q-S(02)ORa,
- with Raa being selected independently from each other from -Ra or -
ORa,
- with Rba being selected independently from each other from -Rb or -
ORb,
- with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl,
- with m being selected from 0, 1 or 2,
- with q being selected from 0, 1 or 2,
- with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen, -CN,
- a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl, or
- a substituted or unsubstituted C6-Cio aryl,
- a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Cio halo heterocycle, in particular a substituted or unsubstituted C4-Ci0 heterocycle or a substituted or
unsubstituted C4-Cio halo heterocycle, or
- a substituted or unsubstituted C5-Cio heteroaryl,
- a substituted or unsubstituted C Ci6 alkyl, a substituted or
unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C Ci6 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2- C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl; or with E being selected from
Figure imgf000123_0001
with each T being selected independently from each other from -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2 or -NRc,
- with Rc being -OH, -CH3, -CH2CH3, -CH2CH2CH3! -CH(CH3)2, and
- with T being selected from -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2 or -NRC, and with T" being selected from -CH or =N, and
with R5 and R6 being selected independently from each other from -H, -F, -CH3, -CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with R5 and R6 being selected independently from each other from H, -F or -CH3, and
- with R6 being selected from OH, -OCH3, -OCH2CH3, -CH3,
with R7 being selected from =NH, =S or =0, and
with m of R9m being selected from 0, 1 , 2 or 3, and each R9 being selected independently from each other from -CI, -F, Br, I, -OH, -CCH, -CN -CH3, - CH2CH3, -OCH3, -COOH, -COORb, -C(0)NH2, -C(0)NH(CH3); -C(0)N(CH3)2 - NHC(=0)OCH3, -NCH3C(=0)OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3,
with Rb being a substituted or unsubstituted CrC5 alkyl, a substituted or unsubstituted C2-C5 alkenyl, a substituted or unsubstituted C2-C5 alkynyl, or a C1-C5 haloalkyl, wherein
* indicates a stereo center of a L- or D- enantiomer, which is located on the tertiary carbon atom below the asterisk *, and wherein the compound of the general formula 1 is an essentially pure L-enantiomer, an essentially pure D-enantiomer or a mixture of the L- and D- enantiomer of the same molecular formula. In some embodiments, the compounds of the invention are characterized by the formula 1 L
Figure imgf000124_0001
In some embodiments, the compounds of the invention are characterized by the formula 1 D
Figure imgf000124_0002
In some embodiments, the compounds of the invention relates to a mixture of the L- and D- enantiomer of the same molecular formula.
In some embodiments, Z of the general formula 1 is -H, -OH, -CH3, -CH2CH3 or -OCH3 and Y is -CN, -C(=0)OH, -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)NHCH3, -C(=0)NHCH2CH3,
-C(=0)N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3) or -C(=0)NH2.
In some embodiments, Z of the general formula 1 is -H and Y is -CN or -C(=0)NH2.
In some embodiments, Z of the general formula 1 is -H and Y is -CN.
In some embodiments, the compounds of the invention are characterized by a general formula 1 ,
with X being
- -H, -OH, -F, -CI, -Br, I, -NH2, -CN, -COOH, -N3 or -N02, or
- -NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, -ORa, -OC(=0)Ra -OC(=0)ORa,
-OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa, -C(=0)NHRa, -NHC(=0)ORa, -C(=S)Ra, -C(=S)ORa, -SRa, -OC(=S)Ra, -OC(=S)ORa, -OC(=S)NHRa,
-NHC(=S)Ra, -NHC(=S)NHRa, -C(=S)NHRa or -NHC(=S)ORa,
with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3- C10 halo cycloalkyl, or
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Ci o aryl, wherein
Z is -H, -OH, -CH3, -CH2CH3 or -OCH3 and Y is -CN, -C(=0)OH, -C(=0)OCH3,
-C(=0)OCH2CH3, -C(=0)NHCH3, -C(=0)NHCH2CH3, -C(=0)N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3) or -C(=0)NH2, in particular Z is H and Y is CN and -C(=0)NH2, more particularly Z is H and Y is CN.
In some embodiments, the compounds of the invention are characterized by a general formula 1 A,
with X being
- -H, -OH, -F, -CI, -Br, I, -NH2, -CN, -COOH, -N3 or -N02, or
-NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, -ORa or -OC(=0)Ra
- with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or
unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-Ci o cycloalkyl or a substituted or unsubstituted C3-Ci o halo cycloalkyl, or
a substituted or unsubstituted C3-Ci 0 heterocycle or a substituted or unsubstituted C3-Ci 0 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, wherein
Z is -H, -OH, -CH3, -CH2CH3 or -OCH3 and Y is -CN, -C(=0)OH, -C(=0)OCH3,
-C(=0)OCH2CH3, -C(=0)NHCH3, -C(=0)NHCH2CH3, -C(=0)N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3) or -C(=0)NH2, in particular Z is H and Y is CN and -C(=0)NH2, more particularly Z is H and Y is CN.
In some embodiments, X of the general formula 1 A is
- -NRa 2, -NHRa -C(=0)ORa or -ORa, - with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle,or
a substituted or unsubstituted C5-C10 heteroaryl, in particular a substituted or
unsubstituted 1 ,2,3-triazole, a substituted or unsubstituted 1 .2.4-triazole, a substituted or unsubstituted indole, a substituted or unsubstituted isoindole, a substituted or unsubstituted quinoline or a substituted or unsubstituted isoquinoline, wherein
Z is -H, -OH, -CH3, -CH2CH3 or -OCH3 and Y is -CN, -C(=0)OH, -C(=0)OCH3,
-C(=0)OCH2CH3, -C(=0)NHCH3, -C(=0)NHCH2CH3, -C(=0)N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3) or -C(=0)NH2, in particular Z is H and Y is CN and -C(=0)NH2, more particularly Z is H and Y is CN.
In some embodiments, X of the general formula 1 A is
-NRa 2, -NHRa or -C(=0)ORa, in particular X is -NRa 2 or -NHRa,
- with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or
unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted Ci-C8 haloalkyl, wherein
Z is -H, -OH, -CH3, -CH2CH3 or -OCH3 and Y is -CN, -C(=0)OH, -C(=0)OCH3,
-C(=0)OCH2CH3, -C(=0)NHCH3, -C(=0)NHCH2CH3, -C(=0)N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3) or -C(=0)NH2, in particular Z is H and Y is CN and -C(=0)NH2, more particularly Z is H and Y is CN.
In some embodiments, the compound of the general formula 1 is an essentially pure L- enantiomer, an essentially pure D-enantiomer or a mixture of the L- and D-enantiomer of the same molecular formula, wherein in particular the compound of the general formula 1 is an essentially pure L-enantiomer or an essentially pure D-enantiomer, more particularly an essentially pure L-enantiomer.
In some embodiments, the compound of the invention is characterized by the formula 1 , wherein
Z is -H, -OH, -CH3, -CH2CH3 or -OCH3 and Y is -CN, -C(=0)OH, -C(=0)OCH3,
-C(=0)OCH2CH3, -C(=0)NHCH3, -C(=0)NHCH2CH3, -C(=0)N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3) or -C(=0)NH2, in particular Z is H and Y is CN and -C(=0)NH2, and wherein the compound of the general formula 1 A is an essentially pure L-enantiomer, an essentially pure D-enantiomer or a mixture of the L- and D-enantiomer of the same molecular formula, and wherein
X is
Figure imgf000127_0001
with D being a linker which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting R4 and the parent moiety PM, and
with R4 being
a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Cio aryl; or wherein
Figure imgf000127_0002
- with R2 and R3 being selected, where applicable, independently from each other from - H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl , in particular from -H, -F, -CN, -OH, -NH2, -N02, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, - OCH2CH3, -OCH2CH2CH3! -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, - CH2F or -CF3,more particularly with R2 and R3 being selected independently from each other from H, F or CH3, and
- with D being a linker which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting the moiety comprising E and the parent moiety PM,
- with E being
a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl, or
a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Cio halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C8-Cio aryl; or
- with E being
Figure imgf000128_0001
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -N02, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, -OCONH2 or -CF3, or
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, - (CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, - (CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, -(CH2)m- OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, -(CH2)m- S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, -(CH2)m- NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m-NRcC(=0)ORa, - (CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m-NRcC(=S)ORa, -(CH2)m- NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or -(CH2)m- S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, -(CH2)m-0-C(=0)-(M)-C(=0)ORa, - (CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0- (CH2)q-S(02)ORa,
with Raa being selected independently from each other from -Ra or -ORa, with Rba being selected independently from each other from -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl,
with m being selected from 0, 1 or 2,
with q being selected from 0, 1 or 2,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen, -CN,
- a substituted or unsubstituted C3-Ci o cycloalkyl or a substituted or
unsubstituted C3-Ci o halo cycloalkyl, or
- a substituted or unsubstituted C6-Ci o aryl,
- a substituted or unsubstituted C3-Ci 0 heterocycle or a substituted or unsubstituted C3-Ci o halo heterocycle, in particular a substituted or unsubstituted C4-Ci 0 heterocycle or a substituted or unsubstituted C4-Ci o halo heterocycle, or
- a substituted or unsubstituted C5-Ci o heteroaryl,
- a substituted or unsubstituted C Ci 6 alkyl, a substituted or unsubstituted C1 -C16 alkoxy, a substituted or unsubstituted C1 -C16 carboxy, a substituted or unsubstituted C2-Ci 6 alkenyl, a substituted or
unsubstituted C2-Ci 6 alkynyl, or a C1 -C16 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted Ci -C8 haloalkyl;
E being
Figure imgf000129_0001
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly n being 1 , and
with each R independently from any other R being -OH, -F, -CI, -Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, - OCONH2 or -N02, or
-NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra, -OC(=0)ORa, -OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa, -C(=0)NHRa or - NHC(=0)ORa,
with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyi, or a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl, or
a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Cio halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Cio aryl, or
eing
Figure imgf000130_0001
with each T being selected independently from each other from -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2 or -NRc,
- with Rc being -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, and with T being selected from -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2 or -NRC, and with T" being selected from -CH or =N, and with R5 and R6 being selected independently from each other from -H, -F, -CH3, -CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with R5 and R6 being selected independently from each other from H, -F or -CH3, and
- with R6 being selected from -OH, -OCH3, -OCH2CH3, -CH3,
with R7 being selected from =NH, =S or =0, and
with m of R9m being selected from 0, 1 , 2 or 3, and each R9 being selected independently from each other from -CI, -F, -Br, -I, -OH, -CCH, -CN -CH3, - CH2CH3, -OCH3, -COOH, -COORb, -C(0)NH2, -C(0)NH(CH3); -C(0)N(CH3)2, - NHC(=0)OCH3, -NCH3C(=0)OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3,
with Rb being a substituted or unsubstituted CrC5 alkyl, a substituted or unsubstituted C2-C5 alkenyl, a substituted or unsubstituted C2-C5 alkynyl, or a C1-C5 haloalkyl.
In some embodiments, D of the general formula 1 A is selected from
Figure imgf000131_0001
(D13), (D13'), (D13"),
Figure imgf000132_0001
(D14), R (D15) or (D16),
Figure imgf000132_0002
with each R8 being -H, or, where applicable, with each R8 being selected independently from each other from -H, -CH3, -CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or - CF3 , in particular each R8 is selected independently from each other from H or CH3, and with V being, where applicable, S, NH or O, in particular V being O.
In some embodiments, D of the general formula 1 A is selected from
Figure imgf000132_0003
, (D1 1 ) or · (D12), with each R8 being -H, or, where applicable, with each R8 being selected independently from each other from -H, -CH3, -CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or - CF3, in particular each R8 is selected independently from each other from H or CH3, more particularly R8 is -H, and
with V being, where applicable, S, NH or O, in particular V being O.
In some embodiments, D of the general formula 1 A is selected from
Figure imgf000133_0001
with each R8 being -H, or, where applicable, with each R8 being selected independently from each other from -H, -CH3, -CH2CH3, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or - CF3, in particular each R8 is selected independently from each other from H or CH3, more particularly R8 is -H, and
with V being, where applicable, S, NH or O, in particular V being O.
In some embodiments, D of the general formula 1 A is selected from
Figure imgf000133_0002
(D4),
with each R8 being -H, or, where applicable, with each R8 being selected independently from each other from -H, -CH3, -CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or - CF3, in particular each R8 is selected independently from each other from H or CH3, more particularly R8 is -H, and
with V being, where applicable, S, NH or O, in particular V being O. In some embodiments, R4 of the general formula 1 A is
a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl; or
a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl; or
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle; in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl; or
a substituted or unsubstituted C6-Ci o aryl.
In some embodiments, R4 of the general formula 1 A is
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Ci o aryl.
In some embodiments, R4 of the general formula 1 A is
a substituted or unsubstituted Ci-C8 alkyl, a substituted or unsubstituted Ci-C8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a d-Cs haloalkyl, a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
In some embodiments, R4 of the general formula 1 A is
a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the D moiety, or
a substituted or unsubstituted C5-C6 heteroaryl,
a substituted C6 aryl, in particular a bicyclic C6 aryl such as tetralin or indane, a substituted or unsubstituted halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position (in case of a Ce halo heteroaryl) in relation to the attachment position of the heterocycle to the D moiety; or
R4 is selected from the group of substituted or unsubstituted pyrrole, furan, thiophene, benzothiophene, chromene, thiazole, pyrazine, pyridazine, pyridine, 1 ,2,3-triazole, 1 ,2,4- triazole, imidazole, oxazol, thiazol, indole, isoindole, quinoline, isoquinoline,
naphatalene, coumarin, aminocoumarin, umbelliferon, benzotriazole, psoralen, benzofurane, benzothiophene, benzimidazol, benzthiazole, benzoxazole or
benzpyridazin or hydroxylated, methylated or halogenated derivatives thereof..
In some embodiments, R4 of the general formula 1 A is selected from
Figure imgf000135_0001
In some embodiments, R4 of the general formula 1 A is
a substituted or unsubstituted CrC5 alkyl or a substituted or unsubstituted C6-Cio cycloalkyl, a substituted or unsubstituted C5-C10 heteroaryl or a substituted or unsubstituted C6-Cio aryl.
In some embodiments, R4 of the general formula 1 A is
a straight or branched C1-C5 alkyl or a C6-Cio cycloalkyl ring or polyring structure
In some embodiments, X of the general formula 1 A is
Figure imgf000135_0002
with R2 and R3 being selected, where applicable, independently from each other from -H, -F,
-CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl , in particular from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3,more particularly with R2 and R3 being selected independently from each other from H, F or CH3.
It is understood that a general expert will identify - on basis of his basic knowledge - combinations of the above mentioned selection, which will not lead to stable compounds. For example, the first mentioned structure will lead to stable compounds if R2 or R3 are selected from -H or -CH3 but not if they are chosen from -OH or NH2. However, the third mentioned structure will lead to stable compounds if R2 is -OH or NH2.
In some embodiments, X of the general formula 1 A is
Figure imgf000136_0001
with R2 and R3 being selected independently from each other from H or CH3, in particular with R2 being H and R3 being CH3 or R2 being H and R3 being H.
In some embodiments, E of the general formula 1 A is
a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl, or
a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Ci0 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C8-Cio aryl.
In some embodiments, E of the general formula 1 A is
a substituted or unsubstituted Ci-C8 alkyl, a substituted or unsubstituted Ci-C8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a d-Cs haloalkyl, a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
In some embodiments, E of the general formula 1 A is
a substituted or unsubstituted C1 -C5 alkyl, a substituted or unsubstituted C6-Ci o
cycloalkyl, or a substituted or unsubstituted C5-C10 heteroaryl or a substituted or unsubstituted C8-Ci o aryl, or
In some embodiments, E of the general formula 1 A is
a substituted or unsubstituted C3-C10 heterocycle or C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Ci o aryl.
In some embodiments, E of the general formula 1 A is
a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the D moiety, or
a substituted or unsubstituted C5-C6 heteroaryl,
a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the D moiety; or
E is selected from the group of substituted or unsubstituted pyrrole, furan, thiophene, benzothiophene, chromene, thiazole, pyrazine, pyridazine, pyridine, 1 ,2,3-triazole, 1 ,2,4- triazole, imidazole, oxazol, thiazol, indole, isoindole, quinoline, isoquinoline,
naphatalene, coumarin, aminocoumarin, umbelliferon, benzotriazole, psoralen, benzofurane, benzothiophene, benzimidazol, benzthiazole, benzoxazole or
benzpyridazin or hydroxylated, methylated or halogenated derivatives thereof,or
E is selected from .
Figure imgf000138_0001
- with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n being 1 , and
- with each R independently from any other R being selected from
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2-CH3, -CF3, -OCONH2 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m- C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, - (CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, - (CH2)m-NRaRb, -(CH2)m-NRcC(=0)ORa , -(CH2)m-NRcC(=0)Ra, -(CH2)m- NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m- NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m- P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, - (CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
- with Raa being selected independently from each other being -Ra or -ORa,
- with Rba being selected independently from each other being -Rb or -ORb,
- with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl
with m being selected from 0, 1 or 2, - with q being selected from 0, 1 or 2,
- with each Ra, Rb or Rc being selected, where applicable, independently from each other from
hydrogen, -CN
a substituted or unsubstituted C Ci6 alkyl, a substituted or unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C Ci6 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or
unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted Ci-C8 haloalkyl, a substituted or unsubstituted C3-Cio cycloalkyl, or a substituted or unsubstituted C3-Cio halo cycloalkyl, a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl,
a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Cio halo heterocycle, in particular a substituted or unsubstituted C4-Ci0 heterocycle or a substituted or unsubstituted
C4-Cio halo heterocycle,
a substituted or unsubstituted C5-Cio heteroaryl,
a substituted or unsubstituted C6-Cio aryl, in particular
- with each R independently from any other R being -OH, -F, -CI, I, -CN, - OCH3, -OCF3 or -CF3.
In some embodiments, E of the general formula 1 A is
Figure imgf000139_0001
with n of R n being 0, 1 , 2, 3, 4 or 5, or
with n of R n being 0, 1 or 2, or
with n of R n being 0 or 1 , or
with n of R n being 1 , or
with n of R n being 0. In some embodiments, E of the general formula 1 A is
Figure imgf000140_0001
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and
with each R independently from any other R being
-OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -N02, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2CH3, -OCONH2 or -CF3, or
-B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, -(CH2)m- OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m-C(=0)NRaRb, - (CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, -(CH2)m-C(=S)ORa, - (CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, -(CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, - (CH2)m-SRa, -(CH2)m-S(=0)Ra, -(CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, -(CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa, - (CH2)m-NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m- NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m- P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, -(CH2)m-0- C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), - (CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m- C(=0)0-(CH2)q-S(02)ORa,
- with Raa being selected independently from each other from -Ra or -ORa,
- with Rba being selected independently from each other from -Rb or -ORb,
- with M being a substituted or unsubstituted CrC8 alkyl, in particular an
unsubstituted CrC8 alkyl,
- with m being selected from 0, 1 or 2,
- with q being selected from 0, 1 or 2,
- with each Ra, Rb or Rc being selected, where applicable, independently from each other from
hydrogen, -CN,
- a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl, or
a substituted or unsubstituted C6-Cio aryl,
- a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Cio halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl,
- a substituted or unsubstituted C1-C16 alkyl, a substituted or unsubstituted Cr C16 alkoxy, a substituted or unsubstituted C1-C16 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C1-C16 haloalkyi, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2- C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyi.
In some embodiments, E of the general formula 1 A is
Figure imgf000141_0001
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 0 or 1 , and
with each R independently from any other R being
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or - N02, or
- -NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra,
-OC(=0)ORa, -OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa,
-C(=0)NHRa, -NHC(=0)ORa, -C(=S)Ra, -C(=S)ORa, -SRa,
-OC(=S)Ra, -OC(=S)ORa, -OC(=S)NHRa, -NHC(=S)Ra,
-NHC(=S)NHRa, -C(=S)NHRa or -NHC(=S)ORa, in particular
-NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra, -OC(=0)ORa, - OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa, -C(=0)NHRa or -NHC(=0)ORa, ,
- with Ra being a substituted or unsubstituted Ci-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyi, or
- a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3- C10 halo cycloalkyl, or
- a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3- C10 halo heterocycle; in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or - a substituted or unsubstituted C5-C10 heteroaryl, or
- a substituted or unsubstituted C6-Cio aryl; or
In some embodiments, E of the general formula 1 A is
Figure imgf000142_0001
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 0 or 1 , and
a. with each R independently from any other R being
- -OH, -F, -CI, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo
heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
b. with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
c. with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the remaining structure. In some embodiments, E of the general formula 1 A is
Figure imgf000143_0001
with each T being selected independently from each other from -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2 or -NRc,
- with Rc being -OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, and with T being selected from -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2 or -NRC, and with T" being selected from -CH or =N, and
with R5 and R6 being selected independently from each other from -H, -F, -CH3, -CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with R5 and R6 being selected independently from each other from H, -F or -CH3, and
with R6 being selected from OH, -OCH3, -OCH2CH3, -CH3,
with R7 being selected from =NH, =S or =0, and
with m of R9m being selected from 0, 1 , 2 or 3, and each R9 being selected independently from each other from -CI, -F, -Br, -I, -OH, -CCH, -CN -CH3, - CH2CH3, -OCH3, -COOH, -COORb, -C(0)NH2, -C(0)NH(CH3); -C(0)N(CH3)2, - NHC(=0)OCH3, -N CH3C(=0)OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, - CH2F or -CF3,
with Rb being a substituted or unsubstituted CrC5 alkyl, a substituted or unsubstituted C2-C5 alkenyl, a substituted or unsubstituted C2-C5 alkynyl, or a C1-C5 haloalkyl. In some embodiments, E of the general formula 1 A is
Figure imgf000144_0001
with each T being selected independently from each other from -CH, -CH2, -NH, -S or -O, and -CHCH3, -C(CH3)2,=N, -NRC,
with Rc being -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CF3, -CHFCF3, - CF2CF3, -CHF2, -CH2F, -CF3
with R5 and R6 being selected independently from each other from -H, -F,-CH3, -CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular R5 and R6 are selected independently from each other from H, F or CH3, and
with R7 being selected from =NH, =S or =0, and with m of R9 m being selected from 0, 1 , 2 or 3, and each R9 being selected independently from each other from -CI, -F, Br, I, -OH, -CCH, - CH3, -CH2CH3, -OCH3, -COOH, -COORb, -C(0)NH2, -NHC(=0)OCH3, -N CH3C(=0)OCH3, - C(0)NH(CH3); -C(0)N(CH3)2 -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, R2N-
COOH
with Rb being a substituted or unsubstituted CrC5 alkyl, a substituted or unsubstituted C2-C5 alkenyl, a substituted or unsubstituted C2-C5 alkynyl, or a CrC5 haloalkyi.
In some embodiments, E of the general formula 1 A is
Figure imgf000144_0002
with m of R9m being 0, and
with each T being selected independently from each other from -CH, -CH2, -NH, -S or -O, - CHCH3, -C(CH3)2,=N, -NRC,
with Rc being -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CF3, -CHFCF3, - CF2CF3, -CHF2, -CH2F, -CF3and
with R5 and R6 being selected independently from each other from -H, -F, -CH3, -CH2CH3, - OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular R5 and R6 are selected independently from each other from H, F or CH3, and with R7 being selected from =NH, =S or =0.
In some embodiments, E of the general formula 1 A is selected from
Figure imgf000145_0001
In some embodiments, X of the general formula 1 A is
Figure imgf000145_0002
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl , in particular from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 and R3 being selected independently from each other from H, F or CH3, and with D being a linker which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting the moiety comprising R and the parent moiety, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and
E being
Figure imgf000146_0001
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly n being 0 or 1 , and
a. with each R independently from any other R being
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -N02, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2CH3, -OCONH2 or -CF3, or
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, - (CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, - (CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, -(CH2)m-OC(=S)NRaRb, - (CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, -(CH2)m-S(02)Ra, -(CH2)m- S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, -(CH2)m-NRaRb, -(CH2)m- NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m-NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m- P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)- (M)-C(=0)OH, -(CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0- (CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
with Raa being selected independently from each other from -Ra or -ORa, with Rba being selected independently from each other from -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl,
with m being selected from 0, 1 or 2,
with q being selected from 0, 1 or 2,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
hydrogen, -CN, - a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or
unsubstituted C3-C10 halo cycloalkyl, or
a substituted or unsubstituted C6-Cio aryl,
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or
unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl,
- a substituted or unsubstituted C1-C16 alkyl, a substituted or unsubstituted Cr C16 alkoxy, a substituted or unsubstituted C1-C16 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C1-C16 haloalkyi, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2- C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyi;
with each R independently from any other R being
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or - N02, or
- -NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra,
-OC(=0)ORa, -OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa,
-C(=0)NHRa, -NHC(=0)ORa, -C(=S)Ra, -C(=S)ORa, -SRa,
-OC(=S)Ra, -OC(=S)ORa, -OC(=S)NHRa, -NHC(=S)Ra,
-NHC(=S)NHRa, -C(=S)NHRa or -NHC(=S)ORa, in particular
-NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra, -OC(=0)ORa, - OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa, -C(=0)NHRa or -NHC(=0)ORa, ,
- with Ra being a substituted or unsubstituted Ci-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyi, or
- a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3- C10 halo cycloalkyl, or
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3- C10 halo heterocycle; in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
- a substituted or unsubstituted C5-C10 heteroaryl, or
- a substituted or unsubstituted C6-Cio aryl; or
with each R independently from any other R being - -OH, -F, -CI, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo
heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position (in case of a Ce halo heteroaryl) in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
d. with each R independently from any other R being
- -OH, -F, -CI, -I, -CN, -OCH3, -OCF3 or -CF3; or
e. with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the remaining structure.
In some embodiments, X of the general formula 1 A is
Figure imgf000148_0001
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH2, -N02, -NHCH3, -NH(CH3)2, a substituted or unsubstituted Ci-C3 alkyl, a substituted or unsubstituted Ci-C3 alkoxy or a Ci-C3 haloalkyl , in particular from -H, -F, -CN, -OH, -NH2, -N02, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3> more particularly with R2 and R3 being selected independently from each other from H, F or CH3, and with D being
Figure imgf000149_0001
E being
Figure imgf000149_0002
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly n being 0 or 1 , and
a. with each R independently from any other R being
-OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -N02, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2CH3, -OCONH2 or -CF3, or
-B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, - (CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, - (CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, -(CH2)m-OC(=S)NRaRb, - (CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, -(CH2)m-S(02)Ra, -(CH2)m- S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, -(CH2)m-NRaRb, -(CH2)m- NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m-NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m- P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)- (M)-C(=0)OH, -(CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0- (CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
- with Raa being selected independently from each other from -Ra or -ORa,
- with Rba being selected independently from each other from -Rb or -ORb,
- with M being a substituted or unsubstituted CrC8 alkyl, in particular an
unsubstituted CrC8 alkyl,
- with m being selected from 0, 1 or 2,
- with q being selected from 0, 1 or 2, - with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen, -CN,
- a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or
unsubstituted C3-C10 halo cycloalkyl, or
- a substituted or unsubstituted C6-Cio aryl,
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
- a substituted or unsubstituted C5-C10 heteroaryl,
- a substituted or unsubstituted C1-C16 alkyl, a substituted or unsubstituted C1-C16 alkoxy, a substituted or unsubstituted C1-C16 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or
unsubstituted C2-Ci6 alkynyl, or a C1-C16 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl;
ith each R independently from any other R being
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or - N02, or
- -NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra,
-OC(=0)ORa, -OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa,
-C(=0)NHRa, -NHC(=0)ORa, -C(=S)Ra, -C(=S)ORa, -SRa,
-OC(=S)Ra, -OC(=S)ORa, -OC(=S)NHRa, -NHC(=S)Ra,
-NHC(=S)NHRa, -C(=S)NHRa or -NHC(=S)ORa, in particular
-NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra, -OC(=0)ORa, - OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa, -C(=0)NHRa or -NHC(=0)ORa, ,
- with Ra being a substituted or unsubstituted Ci-C8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
- a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3- C10 halo cycloalkyl, or
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3- C10 halo heterocycle; in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or - a substituted or unsubstituted C5-C10 heteroaryl, or
- a substituted or unsubstituted C6-Cio aryl; or
c. with each R independently from any other R being
- -OH, -F, -CI, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo
heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position (in case of a Ce halo heteroaryl) in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
d. with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
e. with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the remaining structure.
In some embodiments, X of the general formula 1 A is
Figure imgf000152_0001
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NO2, -NH2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl , in particular from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 and R3 being selected independently from each other from H, F or CH3, and with D being a linker which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting the moiety comprising R and the parent moiety, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and
a. E is
a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3- C10 halo cycloalkyl, or
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3- C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C8-Cio aryl, or
b. E is
a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted CrC8 haloalkyl, a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
E is
a substituted or unsubstituted C1 -C5 alkyl, a substituted or unsubstituted C6-Ci o cycloalkyl, or a substituted or unsubstituted C5-C10 heteroaryl or a substituted or unsubstituted C8-Ci o aryl, or
E is
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3- C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C8-Ci o aryl, or
E is
a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the 'D moiety, or
a substituted or unsubstituted C5-C6 heteroaryl,
a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the D moiety; or
E is selected from the group of substituted or unsubstituted pyrrole, furan, thiophene, benzothiophene, chromene, thiazole, pyrazine, pyridazine, pyridine, 1 ,2,3-triazole, 1 ,2,4-triazole, imidazole, oxazol, thiazol, indole, isoindole, quinoline, isoquinoline, naphatalene, coumarin, aminocoumarin, umbelliferon, benzotriazole, psoralen, benzofurane, benzothiophene, benzimidazol, benzthiazole, benzoxazole or benzpyridazin or hydroxylated, methylated or halogenated derivatives thereof, or selected from
Figure imgf000154_0001
- with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n being 1 , and
- with each R independently from any other R being selected from
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2-CH3, -CF3, -OCONH2 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m- C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, - (CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, - (CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m- NRcC(=0)ORa, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m- NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m- P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, - (CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
- with Raa being selected independently from each other being -Ra or -ORa,
- with Rba being selected independently from each other being -Rb or -ORb,
- with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl - with m being selected from 0, 1 or 2,
- with q being selected from 0, 1 or 2,
- with each Ra, Rb or Rc being selected, where applicable, independently from each other from
hydrogen, -CN
- a substituted or unsubstituted C Ci6 alkyl, a substituted or
unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C Ci6 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted d-Cs alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or
unsubstituted CrC8 haloalkyl, a substituted or unsubstituted C3-Cio cycloalkyl, or a substituted or unsubstituted C3-Cio halo cycloalkyl,
- a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl,
- a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Cio halo heterocycle, in particular a substituted or unsubstituted C4-Ci0 heterocycle or a substituted or unsubstituted C4- Cio halo heterocycle,
- a substituted or unsubstituted C5-Cio heteroaryl,
- a substituted or unsubstituted C6-Cio aryl, in particular
- with each R independently from any other R being -OH, -F, -CI, I, -CN, -
OCH3, -OCF3, -OCONH2 or -CF3
In some embodiments, X of the general formula 1 A is
Figure imgf000155_0001
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -N02, -OH, -NH2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted Ci-C3 alkyl, a substituted or unsubstituted CrC3 alkoxy or a CrC3 haloalkyi , in particular from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 and R3 being selected independently from each other from H, F or CH3, and with D being
Figure imgf000156_0001
a. E being
a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyi, or
a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3- C10 halo cycloalkyl, or
a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3- C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C8-Cio aryl, or
b. E being
a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted Ci-C8 haloalkyi, a substituted or unsubstituted C3-Cio cycloalkyl, or a substituted or unsubstituted C3-Cio halo cycloalkyl, or c. E being
a substituted or unsubstituted C1-C5 alkyl, a substituted or unsubstituted C6-Cio cycloalkyl, or a substituted or unsubstituted C5-C10 heteroaryl or a substituted or unsubstituted C6-Cio aryl, or
d. E being
a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3- C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Cio aryl, or
ing
a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the D moiety, or
a substituted or unsubstituted C5-C6 heteroaryl,
a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the D moiety; or
E is selected from the group of substituted or unsubstituted pyrrole, furan, thiophene, benzothiophene, chromene, thiazole, pyrazine, pyridazine, pyridine, 1 ,2,3-triazole, 1 ,2,4-triazole, imidazole, oxazol, thiazol, indole, isoindole, quinoline, isoquinoline, naphatalene, coumarin, aminocoumarin, umbelliferon, benzotriazole, psoralen, benzofurane, benzothiophene, benzimidazol, benzthiazole, benzoxazole or benzpyridazin or hydroxylated, methylated or halogenated derivatives thereof, or
E is selected from .
Figure imgf000157_0001
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, particularly n of R n being 1 , and
with each R independently from any other R being selected from - -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2-CH3, -CF3, -OCONH2 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m- C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, - (CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, - (CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m- NRcC(=0)ORa, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m- NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m- P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, - (CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
- with Raa being selected independently from each other being -Ra or -ORa,
- with Rba being selected independently from each other being -Rb or -ORb,
- with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl
- with m being selected from 0, 1 or 2,
- with q being selected from 0, 1 or 2,
- with each Ra, Rb or Rc being selected, where applicable, independently from each other from
hydrogen, -CN
- a substituted or unsubstituted C Ci6 alkyl, a substituted or
unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C Ci6 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted Ci-C8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted Ci-C8 haloalkyl, a substituted or unsubstituted C3-Cio cycloalkyl, or a substituted or unsubstituted C3-Cio halo cycloalkyl,
- a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl, - a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4- C10 halo heterocycle,
- a substituted or unsubstituted C5-C10 heteroaryl,
- a substituted or unsubstituted C6-Ci o aryl, in particular
- with each R independently from any other R being -OH, -F, -CI, I, -CN, - OCH3, -OCF3, -OCONH2 or -CF3.
In some embodiments, X of the general formula 1 A is
Figure imgf000159_0001
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1 -C3 alkyl, a substituted or unsubstituted C1 -C3 alkoxy or a C1 -C3 haloalkyl , in particular from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 and R3 being selected independently from each other from H, F or CH3, and with D being a linker which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting the moiety comprising R and the parent moiety, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and
Figure imgf000160_0001
with each T being selected independently from each other from -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2 or -NRc,
- with Rc being -OH, -CH3, -CH2CH3, -CH2CH2CH3! -CH(CH3)2, and with T being selected from -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2 or -NRC, and with T" being selected from -CH or =N, and
with R5 and R6 being selected independently from each other from -H, -F, -CH3, -CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with R5 and R6 being selected independently from each other from H, -F or -CH3, and
with R6 being selected from -OH, -OCH3, -OCH2CH3, -CH3,
with R7 being selected from =NH, =S or =0, and
with m of R9m being selected from 0, 1 , 2 or 3, and each R9 being selected independently from each other from -CI, -F, Br, I, -OH, -CCH, -CN -CH3, - CH2CH3, -OCH3, -COOH, -COORb, -C(0)NH2, -C(0)NH(CH3); -C(0)N(CH3)2, - NHC(=0)OCH3, -N CH3C(=0)OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, - CH2F or -CF3,
- with Rb being a substituted or unsubstituted CrC5 alkyl, a substituted or unsubstituted C2-C5 alkenyl, a substituted or unsubstituted C2-C5 alkynyl, or a C1-C5 haloalkyl In some embodiments, X of the general formula 1 A is
Figure imgf000161_0001
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl , in particular from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 and R3 being selected independently from each other from H, F or CH3, and with D being a linker which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting the moiety comprising R and the parent moiety, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and
E is
Figure imgf000161_0002
a. with each T being selected independently from each other from -CH, -CH2, -NH, -S or - O, -CHCH3, -C(CH3)2,=N, -NRC, with Rc being -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F, -CF3and with R5 and R6 being selected independently from each other from -H, -F, -CH3,
-CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular R5 and R6 are selected independently from each other from H, F or CH3, and with R7 being selected from =NH, =S or =0, and with m of R9 m being selected from 0, 1 , 2 or 3, and each R9 being selected independently from each other from -CI, -F, Br, I, -OH, - CCH, -CH3, -CH2CH3, -OCH3, -COOH, -COORb, -C(0)NH2, -C(0)NH(CH3); - C(0)N(CH3)2, -NHC(=0)OCH3, -N CH3C(=0)OCH3, -CH2CF3, -CHFCF3, -CF2CF3, - CHF2, -CH2F or -CF3, with Rb being a substituted or unsubstituted C1-C5 alkyl, a substituted or unsubstituted C2-C5 alkenyl, a substituted or unsubstituted C2-C5 alkynyl, or a C1-C5 haloalkyl, or
b. with m of R9 m being 0, and with each T being selected independently from each other from -CH, -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2, =N, -NRC, with Rc being -CH2OH, -CH3, - CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F, -CF3and with R5 and R6 being selected independently from each other from -H, -F, -CH3, -CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular R5 and R6 are selected independently from each other from H, F or CH3, and with R7 being selected from =NH, =S or =0, or
c. with E being selected from
Figure imgf000162_0001
In some embodiments, X of the general formula 1 A is
Figure imgf000163_0001
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl , in particular from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 and R3 being selected independently from each other from H, F or CH3, and with D being
Figure imgf000163_0002
E being
Figure imgf000163_0003
a. with each T being selected independently from each other from -CH, -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2,=N, -NRC, with Rc being -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F, -CF3 and with R5 and R6 being selected independently from each other from -H, -F, -CH3,
-CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular R5 and R6 are selected independently from each other from H, F or CH3, and with R7 being selected from =NH, =S or =0, and with m of R9 m being selected from 0, 1 , 2 or 3, and each R9 being selected independently from each other from -CI, -F, Br, I, -OH, -CCH, - CH3, -CH2CH3, -OCH3, -COOH, -COORb, -C(0)NH2, -C(0)NH(CH3); -C(0)N(CH3)2, - NHC(=0)OCH3, -N CH3C(=0)OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, with Rb being a substituted or unsubstituted C1-C5 alkyl, a substituted or unsubstituted C2- C5 alkenyl, a substituted or unsubstituted C2-C5 alkynyl, or a C1-C5 haloalkyi, or b. with m of R9 m being 0, and with each T being selected independently from each other from -CH, -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2,=N, -NRC, with Rc being -CH2OH, -CH3, - CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F, -CF3 and with R5 and R6 being selected independently from each other from -H, -F, -CH3, -CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular R5 and R6 are selected independently from each other from H, F or CH3, and with R7 being selected from =NH, =S or =0, or
c. with E being selected from
Figure imgf000164_0001
d. with E being selected from
Figure imgf000165_0001
with each T being selected independently from each other from -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2 or -NRc,
- with Rc being -OH, -CH3, -CH2CH3, -CH2CH2CH3! -CH(CH3)2, and
- with T being selected from -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2 or -NRC, and with T" being selected from -CH or =N, and
with R5 and R6 being selected independently from each other from -H, -F, -CH3, -CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with R5 and R6 being selected independently from each other from H, -F or -CH3, and
- with R6 being selected from OH, -OCH3, -OCH2CH3, -CH3,
with R7 being selected from =NH, =S or =0, and
with m of R9m being selected from 0, 1 , 2 or 3, and each R9 being selected independently from each other from -CI, -F, Br, I, -OH, -CCH, -CN -CH3, - CH2CH3, -OCH3, -COOH, -COORb, -C(0)NH2, -C(0)NH(CH3); -C(0)N(CH3)2 , - NHC(=0)OCH3, -N CH3C(=0)OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, - CH2F or -CF3,
with Rb being a substituted or unsubstituted CrC5 alkyl, a substituted or unsubstituted C2-C5 alkenyl, a substituted or unsubstituted C2-C5 alkynyl, or a C1-C5 haloalkyl
In some embodiments, X of the general formula 1 A is
Figure imgf000165_0002
with E-D- being selected from
Figure imgf000166_0001
, with R8 being selected from H or CH3, in particluar R8 is H and with V being selected from O, NH or S, in particular from O or NH.
In some embodiments, X is
H
H
Figure imgf000166_0002
with R8 being selected from H or CH3, in particluar R8 is H.
In some embodiments, X of the general formula 1 A is
Figure imgf000167_0001
Figure imgf000168_0001
 In some embodiments, X of the general formula 1 A is
Figure imgf000169_0001
with R8 being selected from H or CH3, in particluar R8 is H.
In some embodiments, X of the general formula 1 A is
Figure imgf000169_0002
with D being a linker which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting the moiety comprising R and the parent moiety, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and with
a. R4 being
a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl; or
a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3- C10 halo cycloalkyl; or
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3- C10 halo heterocycle; in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl; or
a substituted or unsubstituted C6-Ci o aryl, or
b. R4 being
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3- C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Ci o aryl, or
c. R4 being
a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted Ci -C8 haloalkyl, a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C3-C10 halo cycloalkyl, or d. R4 being
a straight or branched C1 -C5 alkyl or a C6-Ci o cycloalkyl ring or polyring structure e. R4 being
a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the D moiety, or
a substituted or unsubstituted C5-C6 heteroaryl, a substituted C6 aryl, in particular a bicyclic C6 aryl such as tetralin or indane, a substituted or unsubstituted halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position (in case of a Ce halo heteroaryl) in relation to the attachment position of the heterocycle to the D moiety; or
R4 is selected from the group of substituted or unsubstituted pyrrole, furan, thiophene, benzothiophene, chromene, thiazole, pyrazine, pyridazine, pyridine, 1 ,2,3-triazole, 1 ,2,4-triazole, imidazole, oxazol, thiazol, indole, isoindole, quinoline, isoquinoline, naphatalene, coumarin, aminocoumarin, umbelliferon, benzotriazole, psoralen, benzofurane, benzothiophene, benzimidazol, benzthiazole, benzoxazole or benzpyridazin or hydroxylated, methylated or halogenated derivatives thereof, or f. R4 being
a substituted or unsubstituted C1 -C5 alkyl or a substituted or unsubstituted C6-Cio cycloalkyl, a substituted or unsubstituted C5-C10 heteroaryl or a substituted or unsubstituted C6-Ci o aryl, or
g. R4 is selected from
Figure imgf000171_0001
In some embodiments, X of the general formula 1 A is
Figure imgf000171_0002
with D being
Figure imgf000171_0003
a. R4 being a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl; or
a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3- C10 halo cycloalkyl; or
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3- C10 halo heterocycle; in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl; or
a substituted or unsubstituted C6-Ci o aryl, or
b. R4 being
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3- C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Ci o aryl, or
c. R4 being
a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted Ci -C8 haloalkyl, a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C3-C10 halo cycloalkyl, or d. R4 being
a straight or branched C1 -C5 alkyl or a C6-Ci o cycloalkyl ring or polyring structure e. R4 being
a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the D moiety, or
a substituted or unsubstituted C5-C6 heteroaryl,
a substituted C6 aryl, in particular a bicyclic C6 aryl such as tetralin or indane, a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the D moiety; or
R4 is selected from the group of substituted or unsubstituted pyrrole, furan, thiophene, benzothiophene, chromene, thiazole, pyrazine, pyridazine, pyridine, 1 ,2,3-triazole, 1 ,2,4-triazole, imidazole, oxazol, thiazol, indole, isoindole, quinoline, isoquinoline, naphatalene, coumarin, aminocoumarin, umbelliferon, benzotriazole, psoralen, benzofurane, benzothiophene, benzimidazol, benzthiazole, benzoxazole or benzpyridazin or hydroxylated, methylated or halogenated derivatives thereof, f. R4 being
a substituted or unsubstituted C1 -C5 alkyl or a substituted or unsubstituted C6-Cio cycloalkyl, a substituted or unsubstituted C5-C10 heteroaryl or a substituted or unsubstituted C6-Ci o aryl.
In some embodiments, X of the general formula 1 A is
Figure imgf000173_0001
, with R4-D- being selected from
Figure imgf000173_0002
from H or CH3, in particluar R8 is H.
In some embodiments, the compound of the invention is characterised by the general formula CAa
Figure imgf000174_0001
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl , in particular from -H, -F, -CN, -NHCH3, - NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 and R3 being selected independently from each other from H, F or CH3, and
with D being a linker which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting the moiety comprising R and the parent moiety, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 0 or 1 , and with each R independently from any other R being
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- -NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra, -OC(=0)ORa, - OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa, -C(=0)NHRa or -NHC(=0)ORa,
with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or
unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or a substituted or unsubstituted C6-Cio aryl,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the double bond.
In some embodiments, the compound of the invention is characterised by the general formula CAa with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl, in particular from -H, -F, -CN, - NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 and R3 being selected independently from each other from H, F or CH3, in particular R2 and R3 are selected independently from each other from H, F or CH3, and with D being a linker as defined above, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 0 or 1 , and
with each R independently from any other R being
- -OH, -F, -CI, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or - N02, or
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3, wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the double bond.
In some embodiments, the compound of the invention is characterised by the general formula CAa with R2 being H and R3 being CH3 or R2 being H and R3 being H, and with D being a linker as defined above, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and with n of R n being 0 or 1 , in particular n of R n being 1 , and
with R being
- -OH, -F, -CI, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or - N02, or
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety,
- a substituted or unsubstituted C6 aryl; or
with R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the double bond.
In some embodiments, the compound of the invention is characterised by the general formula CAb
Figure imgf000177_0001
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl, in particular from -H, -F, -CN, -NHCH3, - NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 and R3 being selected independently from each other from H, F or CH3, in particular R2 and R3 are selected independently from each other from H, F or CH3, and
with D being a linker which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting the moiety comprising T and the parent moiety, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and
with each T being selected independently from each other from -CH, -CH2, -NH, -S or -O, - CHCH3, -C(CH3)2,=N, -NRC, with Rc being -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F, -CF3 and
with R5 and R6 being selected independently from each other from -H, -F, -CH3, -CH2CH3, - OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular R5 and R6 are selected independently from each other from H, F or CH3.
In some embodiments, the compound of the invention is characterised by the general formula CAb with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a
substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl, in particular from -H, -F, -CN, - NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 and R3 being selected independently from each other from H, F or CH3, in particular R2 and R3 are selected independently from each other from H, F or CH3, and with D being a linker as defined above, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and with R5 and R6 being selected independently from each other from -H, -F, -CH3, -CH2CH3, -OCH3, -CH2CF3, -CHFCF3, - CF2CF3, -CHF2, -CH2F or -CF3, in particular R5 and R6 are selected independently from each other from H, F or CH3, more particularly R5 and R6 are H, and
with each T being selected independently from each other from -CH, -CH2, -NH, -S or - O; -CHCH3, -C(CH3)2,=N, -NRC, with Rc being -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F, -CF3or
with each T being O.
In some embodiments, the compound of the invention is characterised by the general formula CAb with R2 being H and R3 being CH3 or R2 being H and R3 being H, and with D being a linker as defined above, in particular D is a linker selected from the linkers
characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and with R5 and R6 being selected independently from each other from -H, -F or -CH3, in particular R5 and R6 are H, and
with each T being selected independently from each other from -CH, -CH2, -NH, -S or - O; or-CHCH3, -C(CH3)2,=N, -NRC, with Rc being -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F, -CF3
with each T being O.
In some embodiments, the compound of the invention is characterised by the general formula CAc, with D being a linker of the formula D1
Figure imgf000178_0001
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -NHCH3, -NH(CH3)2, a substituted or unsubstituted Ci-C3 alkyl, a substituted or unsubstituted Ci-C3 alkoxy or a Ci-C3 haloalkyl, in particular from -H, -F, -CN, -NHCH3, - NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 and R3 being selected independently from each other from H, F or CH3, in particular R2 and R3 are selected independently from each other from H, F or CH3, and
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and with each R independently from any other R being - -OH, -F, -CI, -Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- -NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra, -OC(=0)ORa, - OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa, -C(=0)NHRa or -NHC(=0)ORa,
with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or
unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-Ci o cycloalkyl or a substituted or unsubstituted C3-Ci o halo cycloalkyl, or
a substituted or unsubstituted C3-Ci 0 heterocycle or a substituted or unsubstituted C3-Ci 0 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Ci o aryl,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the double bond.
In some embodiments, the compound of the invention is characterised by the general formula CAc with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -NHCH3, -NH(CH3)2, a substituted or unsubstituted Ci-C3 alkyl, a substituted or unsubstituted Ci-C3 alkoxy or a Ci-C3 haloalkyl, in particular from -H, -F, -CN, - NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 and R3 being selected independently from each other from H, F or CH3, in particular R2 and R3 are selected independently from each other from H, F or CH3, and with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and
with each R independently from any other R being
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl, - a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the double bond.
In some embodiments, the compound of the invention is characterised by the general formula CAc with R2 being H and R3 being CH3 or R2 being H and R3 being H, and with n of R n being 0 or 1 , in particular n of R n being 1 , and
with R being
- -OH, -F, -CI, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or - N02, or
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3, wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the double bond.
In some embodiments, the compound of the invention is characterised by the general formula CAd, with D being a linker of the formula D1
Figure imgf000181_0001
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl, in particular from -H, -F, -CN,-NHCH3, - NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 and R3 being selected independently from each other from H, F or CH3, in particular R2 and R3 are selected independently from each other from H, F or CH3, and
with each T being selected independently from each other from -CH, -CH2, -NH, -S or -O, - CHCH3, -C(CH3)2,=N, -NRC, with Rc being -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F, -CF3 and
with R5 and R6 being selected independently from each other from -H, -F,-CH3, -CH2CH3, - OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular R5 and R6 are selected independently from each other from H, F or CH3.
In some embodiments, the compound of the invention is characterised by the general formula CAd with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -NHCH3, -NH(CH3)2, a substituted or unsubstituted Ci-C3 alkyl, a
substituted or unsubstituted Ci-C3 alkoxy or a Ci-C3 haloalkyl, in particular from -H, -F, -CN, - NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 and R3 being selected independently from each other from H, F or CH3, in particular R2 and R3 are selected independently from each other from H, F or CH3, and with R5 and R6 being selected independently from each other from -H, -F, -CH3, -CH2CH3, -OCH3, -CH2CF3, -CHFCF3, - CF2CF3, -CHF2, -CH2F or -CF3, in particular R5 and R6 are selected independently from each other from H, F or CH3, more particularly R5 and R6 are H, and with each T being selected independently from each other from -CH, -CH2, -NH, -S or - O; -CHCH3, -C(CH3)2,=N, -NRC, with Rc being -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F, -CF3or
with each T being O.
In some embodiments, the compound of the invention is characterised by the general formula CAd with R2 being H and R3 being CH3 or R2 being H and R3 being H, and with R5 and R6 being selected independently from each other from -H, -F or -CH3, in particular R5 and R6 are H, and
with each T being selected independently from each other from -CH, -CH2, -NH, -S or - O; -CHCH3, -C(CH3)2,=N, -NRC, with Rc being -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F, -CF3or
with each T being O.
In some embodiments, the compound of the invention is characterised by the general formula BAa
Figure imgf000182_0001
with D being a linker which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting the moiety comprising Cy and the parent moiety, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and
with Cy being
a substituted or unsubstituted C3-Ci 0 heterocycle or a substituted or unsubstituted C3-Ci 0 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Ci o aryl.
In some embodiments, the compound of the invention is characterised by the general formula BAa with D being a linker as defined above, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and with
Cy being
a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the D moiety, or
a substituted or unsubstituted C5-C6 heteroaryl,
a substituted C6 aryl, in particular a bicyclic C6 aryl such as tetralin or indane, a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the D moiety; or
Cy being selected from the group of substituted or unsubstituted pyrrole, furan, thiophene, benzothiophene, chromene, thiazole, pyrazine, pyridazine, pyridine, 1 ,2,3-triazole, 1 ,2,4- triazole, imidazole, oxazol, thiazol, indole, isoindole, quinoline, isoquinoline, naphatalene, coumarin, aminocoumarin, umbelliferon, benzotriazole, psoralen, benzofurane,
benzothiophene, benzimidazol, benzthiazole, benzoxazole or benzpyridazin or hydroxylated, methylated or halogenated derivatives thereof.
In some embodiments, the compound of the invention is characterised by the general formula BAb
Figure imgf000183_0001
with D being a linker which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting the moiety comprising R and the parent moiety, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and with each R independently from any other R being - -H, -OH, -F, -CI, -Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or - N02, or
- -NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra, -OC(=0)ORa, - OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa, -C(=0)NHRa or -NHC(=0)ORa,
with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or
unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-Ci o cycloalkyl or a substituted or unsubstituted C3-Ci o halo cycloalkyl, or
a substituted or unsubstituted C3-Ci 0 heterocycle or a substituted or unsubstituted C3-Ci 0 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Ci o aryl,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the D moiety.
In some embodiments, the compound of the invention is characterised by the general formula BAb with D being a linker as defined above, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and
with each R independently from any other R being
- -OH, -F, -CI, Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the D moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the D moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the D moiety.
In some embodiments, the compound of the invention is characterised by the general formula BAb with D being a linker as defined above, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and with n of R n being 0 or 1 , in particular n of R n being 1 , and
with R being
- -OH, -F, -CI, Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the D moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the D moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3, wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the D moiety.
In some embodiments, the compound of the invention is characterised by the general formula BAc with D being a linker of the formula D1
Figure imgf000186_0001
with Cy being
a substituted or unsubstituted C3-C10 heterocycle or substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Ci o aryl.
In some embodiments, the compound of the invention is characterised by the general formula BAc with
Cy being
a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the -C(=0)-NH- moiety, or
a substituted or unsubstituted C5-C6 heteroaryl,
a substituted C6 aryl, in particular a bicyclic C6 aryl such as tetralin or indane, a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the -C(=0)-NH- moiety; or
Cy being selected from the group of substituted or unsubstituted pyrrole, furan, thiophene, benzothiophene, chromene, thiazole, pyrazine, pyridazine, pyridine, 1 ,2,3-triazole, 1 ,2,4- triazole, imidazole, oxazol, thiazol, indole, isoindole, quinoline, isoquinoline, naphatalene, coumarin, aminocoumarin, umbelliferon, benzotriazole, psoralen, benzofurane, benzothiophene, benzimidazol, benzthiazole, benzoxazole or benzpyridazin or hydroxylated, methylated or halogenated derivatives thereof.
In some embodiments, the compound of the invention is characterised by the general formula BAd with D being a linker of the formula D1
Figure imgf000187_0001
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and with each R independently from any other R being
- -OH, -F, -CI, -Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- -NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra, -OC(=0)ORa, - OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa, -C(=0)NHRa or -NHC(=0)ORa,
with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or
unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl, or
a substituted or unsubstituted C3-Ci0 heterocycle or substituted or unsubstituted C3-Ci0 halo heterocycle, in particular a substituted or unsubstituted C4-Ci0 heterocycle or a substituted or unsubstituted C4-Cio halo heterocycle, or
a substituted or unsubstituted C5-Cio heteroaryl, or
a substituted or unsubstituted C6-Cio aryl,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -C(=0)NH- moiety.
In some embodiments, the compound of the invention is characterised by the general formula BAd with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and
with each R independently from any other R being - -OH, -F, -CI, Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the -C(=0)NH- moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the - C(=0)NH- moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, -CN, I, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to th -C(=0)NH- moiety.
In some embodiments, the compound of the invention is characterised by the general formula BAd with n of R n being 0 or 1 , in particular n of R n being 1 , and
with R being
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the -C(=0)NH- moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the - C(=0)NH- moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -C(=0)NH- moiety.
In some embodiments, the compound of the invention is characterised by the general formula PAa
Figure imgf000189_0001
with R2 being selected, where applicable, from -H, -OH, -NH2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted Ci-C3 alkyl, a substituted or unsubstituted Ci-C3 alkoxy or a Cr C3 haloalkyl , in particular from -H, -OH, -NH2, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, - OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 being selected from H or CH3,
with D being a linker which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting the moiety comprising R and the parent moiety, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and with each R independently from any other R being
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- -NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra, -OC(=0)ORa, - OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa, -C(=0)NHRa or -NHC(=0)ORa, with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Cio aryl,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -CR2-D moiety
In some embodiments, the compound of the invention is characterised by the general formula PAa, with R2 being selected, where applicable, from -H, -OH, -NH2, -NHCH3, - NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl , in particular from -H, -OH, -NH2, -NHCH3, -NH(CH3)2, -CH3, - CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, - CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 being selected from H or CH3, with D being a linker as defined above, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and
with each R independently from any other R being
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the - benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CI,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -CR2-D moiety.
In some embodiments, the compound of the invention is characterised by the general formula PAa, with R2 being selected -H or -CH3, in particular with R2 being -H, with D being a linker as defined above, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and with n of R n being 0 or 1 , in particular n of R n being 1 , and
with R being
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CI, wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -CR2-D moiety.
In some embodiments, the compound of the invention is characterised by the general formula PAb with D being a linker of the formula D1
Figure imgf000192_0001
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and with each R independently from any other R being
- -OH, -F, -CI, -Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- -NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra, -OC(=0)ORa, - OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa, -C(=0)NHRa or -NHC(=0)ORa,
with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or
unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl, or
a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Ci0 halo heterocycle, in particular a substituted or unsubstituted C4-Ci0 heterocycle or a substituted or unsubstituted C4-Cio halo heterocycle, or
a substituted or unsubstituted C5-Cio heteroaryl, or
a substituted or unsubstituted C6-Cio aryl,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -CH2-D- moiety.
In some embodiments, the compound of the invention is characterised by the general formula PAb with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and
with each R independently from any other R being - -OH, -F, -CI, Br, I, CCH,-CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CI,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -CH2-D- moiety.
In some embodiments, the compound of the invention is characterised by the general formula PPa
Figure imgf000193_0001
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted Ci-C3 alkyl, a substituted or unsubstituted Ci-C3 alkoxy or a Ci-C3 haloalkyl, in particular from -H, -F, -CN, - OH, -NH2, -N02, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3,more particularly with R2 and R3 being selected independently from each other from H, F or CH3, in particular R2 and R3 are selected independently from each other from H, F or CH3, and
with D being a linker which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting the moiety comprising R and the parent moiety, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and with each R independently from any other R being
- -OH, -F, -CI, -Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- -NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra, -OC(=0)ORa, - OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa, -C(=0)NHRa or -NHC(=0)ORa,
with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or
unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl, or
a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Ci0 halo heterocycle, in particular a substituted or unsubstituted C4-Ci0 heterocycle or a substituted or unsubstituted C4-Cio halo heterocycle, or
a substituted or unsubstituted C5-Cio heteroaryl, or
a substituted or unsubstituted C6-Cio aryl,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -C(R2) moiety.
In some embodiments, the compound of the invention is characterised by the general formula PPa with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -N02, -NH2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted Ci-C3 alkyl, a substituted or unsubstituted Ci-C3 alkoxy or a Ci-C3 haloalkyl, in particular from -H, - F, -CN, -OH, -NH2, -N02, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or - CF3,more particularly with R2 and R3 being selected independently from each other from H, F or CH3, in particular R2 and R3 are selected independently from each other from H, F or CH3, and with D being a linker as defined above, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and with each R independently from any other R being
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, -I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -C(R2) moiety.
In some embodiments, the compound of the invention is characterised by the general formula PPa with R2 being H and R3 being CH3 or R2 being H and R3 being H, and with D being a linker as defined above, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and with n of R n being 0 or 1 , in particular n of R n being 1 , and
with R being
- -OH, -F, -CI, -Br,-I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- a substituted or unsubstituted C5-C6 heterocycle - a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -C(R2) moiety.
In some embodiments, the compound of the invention is characterised by the general formula PPb, with D being a linker of the formula D1
Figure imgf000196_0001
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl, in particular from -H, -F, -CN,■ OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3,more particularly with R2 and R3 being selected independently from each other from H, F or CH3, in particular R2 and R3 are selected independently from each other from H, F or CH3, and with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and with each R independently from any other R being
- -OH, -F, -CI, -Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- -NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra, -OC(=0)ORa, - OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa, -C(=0)NHRa or -NHC(=0)ORa,
with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or
unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyi, or
a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl, or
a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Ci0 halo heterocycle, in particular a substituted or unsubstituted C4-Ci0 heterocycle or a substituted or unsubstituted C4-Cio halo heterocycle, or
a substituted or unsubstituted C5-Cio heteroaryl, or
a substituted or unsubstituted C6-Cio aryl,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -C(R2) moiety.
In some embodiments, the compound of the invention is characterised by the general formula PPb with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH2, -N02, -NHCH3, -NH(CH3)2, a substituted or unsubstituted Ci-C3 alkyl, a substituted or unsubstituted Ci-C3 alkoxy or a Ci-C3 haloalkyi, in particular from -H, - F, -CN, -OH, -NH2, -N02, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or - CF3,more particularly with R2 and R3 being selected independently from each other from H, F or CH3, in particular R2 and R3 are selected independently from each other from H, F or CH3, and with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and
with each R independently from any other R being
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- a substituted or unsubstituted C5-C6 heterocycle - a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -C(R2) moiety.
In some embodiments, the compound of the invention is characterised by the general formula PPb with R2 being H and R3 being CH3 or R2 being H and R3 being H, and with n of R n being 0 or 1 , in particular n of R n being 1 , and
with R being
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or - a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -C(R2) moiety.
In some embodiments, the compound of the invention is characterised by the general formula PPc and comprises a benzoic acid structural element or a similar element
Figure imgf000199_0001
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1 -C3 alkyl, a substituted or unsubstituted C1 -C3 alkoxy or a C1 -C3 haloalkyl, in particular from -H, -F, -CN, - OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3,more particularly with R2 and R3 being selected independently from each other from H, F or CH3,
with D being a linker which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting the moiety comprising Cy and the parent moiety, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and
with Cy being
a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or a substituted or unsubstituted C6-Cio aryl.
In some embodiments, the compound of the invention is characterised by the general formula PPc, with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH2, -N02, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl, in particular from -H, -F, -CN, -OH, -NH2, -N02, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or - CF3,more particularly with R2 and R3 being selected independently from each other from H, F or CH3, with D being a linker as defined above, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and with
Cy being
a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the -C(R2) moiety, or
a substituted or unsubstituted C5-C6 heteroaryl,
a substituted C6 aryl, in particular a bicyclic C6 aryl such as tetralin or indane, a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the -C(R2) moiety; or
Cy being selected from the group of substituted or unsubstituted pyrrole, furan, thiophene, thiazole, benzothiophene, chromene, pyrazine, pyridazine, pyridine or halogenated derivatives thereof.
In some embodiments, the compound of the invention is characterised by the general formula PPd
Figure imgf000200_0001
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyi, in particular from -H, -F, -CN, - OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, - OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3,more particularly with R2 and R3 being selected independently from each other from H, F or CH3,
with Cy being
a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Cio aryl.
In some embodiments, the compound of the invention is characterised by the general formula PPd with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH2, -N02, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyi, in particular from -H, - F, -CN, -OH, -NH2, -N02, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, - OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or - CF3,more particularly with R2 and R3 being selected independently from each other from H, F or CH3, with
Cy being
a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the -C(R2) moiety, or
a substituted or unsubstituted C5-C6 heteroaryl,
a substituted C6 aryl, in particular a bicyclic C6 aryl such as tetralin or indane, a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the -C(R2) moiety; or Cy being selected from the group of substituted or unsubstituted pyrrole, furan, thiophene, thiazole, benzothiophene, chromene, pyrazine, pyridazine, pyridine or halogenated derivatives thereof.
In some embodiments, the compound of the invention is characterised by the general formula P,
Figure imgf000202_0001
with R2 being selected, where applicable, from -H, -OH, -NH2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a Cr C3 haloalkyl , in particular from -H, -OH, -CH2OH, -NH2, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 being selected from H or CH3 -, and
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and with each R independently from any other R being
- -H, -OH, -F, -CI, -Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or - N02, or
- -NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra, -OC(=0)ORa, - OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa, -C(=0)NHRa or -NHC(=0)ORa,
with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or
unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl, or
a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Ci0 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Cio aryl, wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -OC(R2) moiety.
In some embodiments, the compound of the invention is characterised by the general formula P with R2 being selected, where applicable, from -H, -OH, -NH2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl , in particular from -H, -OH, -CH2OH, -NH2, -NHCH3, -NH(CH3)2, -CH3, - CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, - CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, more particularly with R2 being selected from H or CH3, in particular R3 is selected from H or CH3, and with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and
with each R independently from any other R being
- -OH, -F, -CI, Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -OC(R3) moiety.
In some embodiments, the compound of the invention is characterised by the general formula P with R2 being CH3 or R3 being H, and with n of R n being 0 or 1 , in particular n of R n being 1 , and with R being
- -OH, -F, -CI, Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -OC(R2) moiety.
In some embodiments, the compound of the invention is characterised by the general formula FAa
Figure imgf000204_0001
with D being a linker which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting the moiety comprising R4 and the parent moiety, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and with R4 being
a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl; or
a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl.
In some embodiments, the compound of the invention is characterised by the general formula FAa with D being a linker as defined above, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and with R4 being a straight or branched C1 -C5 alkyl or a C6-Ci o cycloalkyl ring or polyring structure.
In some embodiments, the compound of the invention is characterised by the general formula FAb with D being a linker of the formula D1
Figure imgf000205_0001
with R4 being
a substituted or unsubstituted Ci -C8 alkyl, a substituted or unsubstituted Ci -C8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl; or
a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl.
In some embodiments, the compound of the invention is characterised by the general formula FAb with D being a linker as defined above, in particular D is a linker selected from the linkers characterized by general formula D1 to D21 , D1 to D12, D1 to D6 or D1 to D4, and with R4 being a straight or branched C1 -C5 alkyl or a C6-Ci o cycloalkyl ring or polyring structure.
In some embodiments, the compound of the invention is characterised by the general formula UAa
Figure imgf000206_0001
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 0 or 1 , and with each R independently from any other R being
- -OH, -F, -CI, -Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- -NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra, -OC(=0)ORa, - OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa, -C(=0)NHRa or -NHC(=0)ORa,
with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or
unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl, or
a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Ci0 halo heterocycle, in particular a substituted or unsubstituted C4-Ci0 heterocycle or a substituted or unsubstituted C4-Cio halo heterocycle, or
a substituted or unsubstituted C5-Cio heteroaryl, or
a substituted or unsubstituted C6-Cio aryl,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -HNC(=0)NH- moiety.
In some embodiments, the compound of the invention is characterised by the general formula UAa with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 0 or 1 , and
with each R independently from any other R being
- -OH, -F, -CI, Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- a substituted or unsubstituted C5-C6 heterocycle - a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -HNC(=0)NH moiety.
In some embodiments, the compound of the invention is characterised by the general formula UAa with n of R n being 0 or 1 , and
with R being
- -OH, -F, -CI, Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -HNC(=0)NH moiety.
In some embodiments, the compound of the invention is characterised by the general formula UAa with n of R n being 0.
In some embodiments, the compound of the invention is characterised by the general formula AMa
Figure imgf000208_0001
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and with each R independently from any other R being
- -OH, -F, -CI, -Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- -NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra, -OC(=0)ORa, - OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa, -C(=0)NHRa or -NHC(=0)ORa,
with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or
unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or a substituted or unsubstituted C6-Cio aryl,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -CH2NH- moiety.
In some embodiments, the compound of the invention is characterised by the general formula BAd with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and
with each R independently from any other R being
- -OH, -F, -CI, Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -CH2NH- moiety.
In some embodiments, the compound of the invention is characterised by the general formula AMa with n of R n being 0 or 1 , in particular n of R n being 1 , and
with R being
- -OH, -F, -CI, Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- a substituted or unsubstituted C5-C6 heterocycle - a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -CH2NH- moiety.
In some embodiments, the compound of the invention is characterised by the general formula SAa
Figure imgf000210_0001
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and with each R independently from any other R being
- -OH, -F, -CI, -Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- -NRa 2, -NHRa, -Ra, -C(=0)Ra, -C(=0)ORa, ORa, -OC(=0)Ra, -OC(=0)ORa, - OC(=0)NHRa, -NHC(=0)Ra, -NHC(=0)NHRa, -C(=0)NHRa or -NHC(=0)ORa, with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl, or
a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Ci o aryl,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -S(02)NH- moiety.
In some embodiments, the compound of the invention is characterised by the general formula SAa with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 or 2, more particularly 1 , and
with each R independently from any other R being
- -OH, -F, -CI, Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or -N02, or
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being - -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -S(02)NH- moiety.
In some embodiments, the compound of the invention is characterised by the general formula SAa with n of R n being 0 or 1 , in particular n of R n being 1 , and
with R being
- -OH, -F, -CI, Br, I, CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -CH3, -CF3, -OCONH2 or
- a substituted or unsubstituted C5-C6 heterocycle
- a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heterocycle to the benzene moiety, or
- a substituted or unsubstituted C5-C6 heteroaryl,
- a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two
halogen atoms selected from CI of F, particularly comprising one CI or one F in para position in relation to the attachment position of the heteroaryl to the benzene moiety, or
- a substituted or unsubstituted C6 aryl; or
with each R independently from any other R being
- -OH, -F, -CI, I, -CN, -OCH3, -OCF3 or -CF3; or
with each R independently from any other R being
- -OH, -F or -CF3,
wherein in particular R is in para position in relation to the attachment position of the benzene moiety to the -S(02)NH- moiety.
Particular embodiments of the invention are the compounds 1 to 50, 70 to 76 as depicted in the experimental section and the following compounds 78 to 1 17. Compound 78:
Figure imgf000213_0001
Chemical Formula: C45H36N601 Exact Mass: 884,2289
Compound 79:
Figure imgf000213_0002
Chemical Formula: C45H38N80-|2 Exact Mass: 882,2609
Compound 80:
Figure imgf000213_0003
Chemical Formula: C45H37N70-|3 Exact Mass: 883,2449 Compound 81 :
Figure imgf000214_0001
Chemical Formula: C45H37N70-|3 Exact Mass: 883,2449
Compound 82:
Figure imgf000214_0002
Chemical Formula: C45H36N60-|4 Exact Mass: 884,2289
Compound 83:
Figure imgf000214_0003
Chemical Formula: C45H38N6013 Exact Mass: 870,2497 Compound 84:
Figure imgf000215_0001
Chemical Formula: C45H40N6Oi 3 Exact Mass: 872,2653
Compound 85:
Figure imgf000215_0002
Chemical Formula: C45H36F2N60-|3 Exact Mass: 906,2308
Compound 86:
Figure imgf000215_0003
Chemical Formula: C44H34F2N60-|3 Exact Mass: 892,2152 Compound 87:
Figure imgf000216_0001
Chemical Formula: C43H34F2N601 Exact Mass: 848,2254
Compound 88:
Figure imgf000216_0002
Chemical Formula: C45H3gFN Exact Mass: 858,2661
Compound 89:
Figure imgf000216_0003
Chemical Formula: C44H34F4N6Oi-| Exact Mass: 898,2222 Compound 90:
Figure imgf000217_0001
Chemical Formula: C45H3gFN Exact Mass: 858,2661
Compound 91 :
Figure imgf000217_0002
Chemical Formula: C44H37FN1 Exact Mass: 844,2504
Compound 92:
Figure imgf000217_0003
Chemical Formula: C45H36FN7O Exact Mass: 869,2457 Compound 93:
Figure imgf000218_0001
Chemical Formula: C45H3gFN| Exact Mass: 874,2610
Compound 94:
Figure imgf000218_0002
Chemical Formula: C44H38N60 2 Exact Mass: 842,2548
Compound 95:
Figure imgf000218_0003
Chemical Formula: C43H35FN( Exact Mass: 830,2348 Compound 96:
Figure imgf000219_0001
Chemical Formula: C45H40N6O12 Exact Mass: 856,2704
Compound 97:
Figure imgf000219_0002
Chemical Formula: C44H38N6012 Exact Mass: 842,2548
Compound 98:
Figure imgf000219_0003
Compound 99:
Figure imgf000220_0001
Chemical Formula: C42H36N80-|2 Exact Mass: 844,24527
Compound 100:
Figure imgf000220_0002
Chemical Formula: C43H37N70-|2 Exact Mass: 843,25002
Compound 101 :
Figure imgf000220_0003
Chemical Formula: C43H38N60-|3S Exact Mass: 878,22176 Compound 102:
Figure imgf000221_0001
Chemical Formula: C43H38N60-|3S Exact Mass: 878,22176
Compound 103:
Figure imgf000221_0002
Chemical Formula: C 4H38N6012
Exact Mass: 842,25477
Compound 104:
Figure imgf000221_0003
Chemical Formula: C42H38N6012 Exact Mass: 818,25477 Compound 105:
Figure imgf000222_0001
Chemical Formula; C. 012 Exact Mass: 843,27517
Compound 106:
Figure imgf000222_0002
Chemical Formula: C42H34N6O10 Exact Mass: 782,2336
Compound 107:
Figure imgf000222_0003
Chemical Formula: C43H36N60-I 1 Exact Mass: 812,2442 Compound 108:
Figure imgf000223_0001
Chemical Formula: C43H36N6O.11 Exact Mass: 812,2442
Compound 109:
Figure imgf000223_0002
Chemical Formula: C44H38N6O-|0 Exact Mass: 810,2649
Compound 1 10:
Figure imgf000223_0003
Chemical Formula: C44H38N60H Exact Mass: 826,2599 Compound 111:
Figure imgf000224_0001
Chemical Formula: C44H38N6 Exact Mass: 826,2599
Compound 112
Figure imgf000224_0002
Compound 113:
Figure imgf000224_0003
Compound 114:
Figure imgf000224_0004
Compound 1 15:
Figure imgf000225_0001
Compound 1 16:
Figure imgf000225_0002
Compound 1 17:
Figure imgf000225_0003
In some embodiments the compounds 1 to 50, 70 to 76 and 78 to 1 17 comprise an essentially pure L-enantiomer structure, an essentially pure D-enantiomer structure or a mixture of the L- and D-enantiomer of the same molecular formula, wherein in particular the compounds 1 to 50, 70 to 76 and 78 to 1 17 comprise an essentially pure L-enantiomer structure.
Figure imgf000226_0001
Further embodiments of the present compounds are compounds 22a-22h. Yet further embodiments of the present compounds may comprise one of the following structures according to formula (1 L)
Figure imgf000227_0001
and formula 1 D),
Figure imgf000227_0002
wherein
R is H or CO(NH2),
R2 is CO(NH2) or CN,
R3 is H or OCH3.
In case of the compounds of formula (1 L) and (1 D) comprising a -OCH3 moiety as R3' the following stereoisomers of formula (1 L1 ), (1 L2), (1 D1 ) and (1 D2) are possible:
Figure imgf000227_0003
formula (1 L2)
Figure imgf000228_0001
wherein
R is H or CO(NH2),
R2 is CO(NH2) or CN,
In some embodiments, concerning antibiotically active natural occurring L-albicidin compounds of the formula (1 L),
a. R is H, R3 is H and R2 is CN (beta-Albicidin), or
b. R is H, R3 is H and R2 is CO(NH2) (Asn-Albicidin), or
c. R is CO(NH2), R3 is H and R2 is CN (Carbamoyl-Albicidin), or
d. R is CO(NH2), R3 is H and R2 is CO(NH2) (Carbamoyl-Asn-Albicidin), or e. R is H, R3 is OCH3 and R2 is CN (beta-OMe-Albicidin), or
f. R is H, R3 is OCH3 and R2 is CO(NH2) (Asn-OMe-Albicidin), or
g. R is CO(NH2), R3 is OCH3 and R2 is CN (Carbamoyl-OMe-Albicidin), or h. R is CO(NH2), R3 is OCH3 and R2 is CO(NH2) (Carbamoyl-OMe-Asn-Albicidin). In some embodiments, concerning antibiotically active synthetic D-albicidin compounds of the formula (1 D),
a. R is H and R2 is CN (Enantio-beta-Albicidin), or
b. R is H, and R2 is CO(NH2) (Enantio-Asn-Albicidin), or
c. R is CO(NH2), and R2 is CN (Enantio-Carbamoyl-Albicidin), or
d. R is CO(NH2), and R2 is CO(NH2) (Enantio-Carbamoyl-Asn-Albicidin), or e. R is H, R3 is OCH3 and R2 is CN (Enantio-beta-OMe-Albicidin), or
f. R is H, R3 is OCH3 and R2 is CO(NH2) (Enantio-Asn-OMe-Albicidin), or g. R is CO(NH2), R3 is OCH3 and R2 is CN (Enantio-Carbamoyl-OMe-Albicidin), or h. R is CO(NH2), R3 is OCH3 and R2 is CO(NH2) (Enantio-Carbamoyl-OMe-Asn- Albicidin).
In some embodiments, concerning antibiotically active natural occurring L-albicidin compounds of the formula (1 L),
a. R is H and R2 is CN (beta-Albicidin), or
b. R is H, and R2 is CO(NH2) (Asn-Albicidin).
In some embodiments, concerning antibiotically active synthetic D-albicidin compounds of the formula (1 D),
a. R is H and R2 is CN (Enantio-beta-Albicidin), or
b. R is H, and R2 is CO(NH2) ( Enantio-Asn-Albicidin).
In some embodiments, concerning antibiotically active natural occurring L-albicidin compounds of the formula (1 L),
a. R is H and R2 is CN (beta-Albicidin).
In some embodiments, concerning antibiotically active synthetic D-albicidin compounds of the formula (1 D),
a. R is H and R2 is CN (Enantio-beta-Albicidin).
In some embodiments, the compounds of the invention relates to a mixture of the L- and D- enantiomer of the same molecular formula.
In some embodiments, the compounds of the invention relates to a mixture of
- beta-Albicidin and Enantio-beta-Albicidin, or
- Asn-Albicidin and Enantio-Asn-Albicidin, or
Carbamoyl-Albicidin and Enantio-Carbamoyl-Albicidin, or
Carbamoyl-Asn-Albicidin and Enantio-Carbamoyl-Asn-Albicidin, or
beta-OMe-Albicidin and Enantio-beta-OMe-Albicidin, or
- Asn-OMe-Albicidin and Enantio-Asn-OMe-Albicidin, or Carbamoyl-OMe-Albicidin and Enantio-Carbamoyl-OMe-Albicidin, or Carbamoyl-OMe-Asn-Albicidin and Enantio-OMe-Carbamoyl-Asn-Albicidin
In some embodiments, the compounds of the invention relates to a mixture of beta-Albicidin and Enantio-beta-Albicidin, or Asn-Albicidin and Enantio-Asn-Albicidin.
In some embodiments, the compounds of the invention relates to a mixture of beta-Albicidin and Enantio-beta-Albicidin.
In a another embodiment the compounds according to formula 1 L, 1 D, 1 L1 , 1 L2, 1 D1 and/or 1 D2 may be exempted from the general formula (1 ). In particular the natural occuring L- albicidin compounds of formula 1 L may be exempted from the general formula I.
It is understood that all the compounds of the general formulae 1 and embodiments thereof may comprise -depending on the selected substituents - at least one further stereocenter with an L- or D- configuration. Thus, the embodiments of the invention encompass a pure compound with the same stereo centers (e.g. a compound only with an L and a D stereo center or two L stereo centers) or a mixture of the respective enantiomers of the same molecular formula.
The compounds of the general formula 1 can also be obtained in the form of their hydrates and/or also can include other solvents used for example for the crystallization of compounds present in the solid form. Depending on the method and/or the reaction conditions, compounds of the general formula 1 can be obtained in the free form or in the form of salts. Particularly in the form of salts of alkali metals, alkaline earth metals, ammonium or alkylammonium.
Pharmaceutically acceptable salts of compounds of the formula (I) mean both their organic and inorganic salts as described in Remington's Pharmaceutical Sciences (17th edition, page 1418 (1985)). Because of the physical and chemical stability and the solubility, preference is given for acidic groups inter alia to sodium, potassium, calcium and ammonium salts; preference is given for basic groups inter alia to salts of maleic acid, fumaric acid, succinic acid, malic acid, tartaric acid, methylsulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid or of carboxylic acids or sulfonic acids, for example as hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malates, gluconates, and salts of amino acids, of natural bases or carboxylic acids. The preparation of pharmaceutically acceptable salts from compounds of the formula (I) which are capable of salt formation, including their stereoisomeric forms, takes place in a manner known per se. The compounds of the formula (I) form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts with basic reagents such as
hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic bases, for example trimethyl- or triethylamine, ethanolamine, diethanolamine or triethanolamine, trometamol or else basic amino acids, for example lysine, ornithine or arginine. Where the compounds of the formula (I) have basic groups, stable acid addition salts can also be prepared with strong acids. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p- toluenesulfonic and tartaric acid. The hydrochloride salt is a preferred salt.
Salts with a pharmaceutically unacceptable anion such as, for example, trifluoroacetate likewise belong within the framework of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in
nontherapeutic, for example in vitro, applications.
The present invention furthermore relates to pharmaceutical preparations (or pharmaceutical compositions) which contain an effective amount of at least one compound of the formula (I) and/or its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier, i. e. one or more pharmaceutically acceptable carrier substances (or vehicles) and/or additives (or excipients). The pharmaceuticals can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneously or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.
The pharmaceutical preparations according to the invention are prepared in a manner known per se and familiar to one skilled in the art, pharmaceutically acceptable inert inorganic and/or organic carrier substances and/or additives being used in addition to the compound(s) of the formula (I) and/or its (their) pharmaceutically acceptable salts and/or its (their) prodrugs. For the production of pills, tablets, coated tablets and hard gelatin capsules it is possible to use, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. Carrier substances for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable carrier substances for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Suitable carrier substances for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. The pharmaceutical preparations normally contain about 0.5 to about 90 % by weight of the compounds of the formula (I) and/or their pharmaceutically acceptable salts and/or their prodrugs. The amount of the active ingredient of the formula (I) and/or its pharmaceutically acceptable salts and/or its prodrugs in the pharmaceutical preparations normally is from about 0.5 to about 1000 mg, preferably from about 1 to about 500 mg.
A prodrug within the meaning of the present invention is a precursor chemical compound of an biological active compound of general formula (1 ). Instead of administering the active compopund or drug, a prodrug might be used instead to improve the absorption, distribution, metabolization and excretion. Prodrugs are often designed to improve bioavailability when a drug itself is poorly absorbed from the gastrointestinal tract. A prodrug may also be used to improve the selectively of the drug. This reduces adverse or unintended effects of a drug, especially important in treatments like chemotherapy, which can have severe unintended and undesirable side effects.
An example of a prodrug withing the context of the present invention is shown below:
Figure imgf000232_0001
wherein X can be a -OP03H or -OS03H moiety each with single or multiple substituents.
A typical reaction scheme for such a prodrug compound is depicted exemplarily in the following:
Figure imgf000232_0002
Figure imgf000233_0001
1 N LiOH dioxane/water
Figure imgf000233_0002
In addition to the active ingredients of the formula (I) and/or their pharmaceutically acceptable salts and to carrier substances, the pharmaceutical preparations can contain one or more additives such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formula (I) and/or their pharmaceutically acceptable salts. In case a pharmaceutical preparation contains two or more compounds of the formula (I) the selection of the individual compounds can aim at a specific overall pharmacological profile of the pharmaceutical preparation. For example, a highly potent compound with a shorter duration of action may be combined with a long-acting compound of lower potency. The flexibility permitted with respect to the choice of substituents in the compounds of the formula (I) allows a great deal of control over the biological and physico-chemical properties of the compounds and thus allows the selection of such desired compounds. Furthermore, in addition to at least one compound of the formula (I) and/or its pharmaceutically acceptable salts, the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients. When using the compounds of the formula (I) the dose can vary within wide limits and, as is customary and is known to the physician, is to be suited to the individual conditions in each individual case. It depends, for example, on the specific compound employed, on the nature and severity of the disease to be treated, on the mode and the schedule of administration, or on whether an acute or chronic condition is treated or whether prophylaxis is carried out. An appropriate dosage can be established using clinical approaches well known in the medical art. In general, the daily dose for achieving the desired results in an adult weighing about 75 kg is from about 0.01 to about 100 mg/kg, preferably from about 0.1 to about 50 mg/kg, in particular from about 0.1 to about 10 mg/kg, (in each case in mg per kg of body weight). The daily dose can be divided, in particular in the case of the administration of relatively large amounts, into several, for example 2, 3 or 4, part administrations. As usual, depending on individual behavior it may be necessary to deviate upwards or downwards from the daily dose indicated.
Furthermore, the compounds of the formula (I) can be used as synthesis intermediates for the preparation of other compounds, in particular of other pharmaceutical active ingredients, which are obtainable from the compounds of the formula 11 for example by introduction of substituents or modification of functional groups.
The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the framework of the invention and are a further aspect of the invention. The compounds of the general formula 1 may be present as optical isomers or as mixtures thereof. The invention relates both to the pure isomers and all possible isomeric mixtures and is hereinafter understood as doing so, even if stereochemical details are not specifically mentioned in every case. Enantiomeric mixtures of compounds of the general
formula 1 , which are obtainable by the process or any other way, may be separated in known manner - on the basis of the physical-chemical differences of their components - into pure enantiomers, for example by fractional crystallisation, distillation and/or chromatography, in particular by preparative HPLC using a chiral HPLC column.
According to the invention, apart from separation of corresponding isomer mixtures, generally known methods of diastereoselective or enantioselective synthesis can also be applied to obtain pure diastereoisomers or enantiomers, e.g. by carrying out the method described hereinafter and using educts with correspondingly suitable stereochemistry.
It is advantageous to isolate or synthesise the biologically more active isomer, provided that the individual compounds have different biological activities.
METHODS OF SYNTHESIS
A compound of the general formula (1 ) can generally be regarded as a chain of up to six building blocks a-b-c-d-e-f, each block being linked to the next by a linker group, for example a peptide (amide) bond.
The six building blocks are
a: BA-J or X -J b: G-BB-J or X -BB-J; c: G-BC-J;
d: G-BD-J e: G-BE-J, or G-BE-X2; f: G-BF or G-X2, with G being a second linking function capable of selectively forming a covalent bond by a reaction with a first linking function J yielding the respective and with X1 , BA, BB, BC, BD, BE, BF and X2 having the same meaning as defined previously.
Thus, derivatives of the six building blocks are employed as intermediates in the synthesis of the invention as building blocks of the general formula
a: (a-J) BA-J; (X1-J): X -J;
b: (b-J) G-BB-J; (X -b-J): X -BB-J;
c: (c-J) G-BC-J;
d: (d-J) G-BD-J;
e: (e-J) G-BE-J; (e-X2): G-BE-X2
f: (G-X2): G-X2
wherein J or G may be activated before a linking reaction (Jact or Gact) or may be reversibly inactivated by a removable protecting group (Jp or Gp)
wherein a removable protecting group is employed, if necessary, to suppress unwanted side reaction. For example, if a first building block employed in a reaction comprise a COOH moiety, which is destined to react specifically with a NH2 moiety of a second building block, wherein said second building block comprises also a COOH moiety, the COOH moiety of said second building block is protected for avoiding a coupling reaction of said second building block with itself. The use of protecting group is a standard procedure for a skilled person and a skilled person will easily determine the necessity of a protecting group and will employ a suitable protecting group.
There are different reaction pathways for providing a compound of the general formula 1 using the above mentioned building blocks.
It is apparent to the skilled person that a suitable reaction pathway will not necessarily involve the isolated building blocks in each case, but will take place between combinations of the above mentioned building blocks in order to arrive at the full sequence of six blocks (a-b-c-d- e-f). Therefore, the above is to be understood as a teaching regarding the sequence of blocks, i.e. which block links to which other one through the linking functions J and G.
For example, the reaction of the building block b with the building block c will yield a building compound b-c. This compound b-c can react as a further building block in subsequent reactions by removing or adding a protection group, if necessary. The further building block b- c can react with a building block a, yielding a compound a-b-c. Said compound a-b-c can function as a reaction partner for the building block d. The same applies to further subsequent reactions in order to arrive at the full sequence of six blocks.
Many ways to achieve the full sequence a-b-c-d-e-f are possible. The following examples show - without being limited to these combinations - three further possible combinations such as
- e + f yielding (e-f), d + (e-f) yielding (d-e-f), c + (d-e-f) yielding (c-d-e-f), a + b yielding (a-b), (a-b) + (c-d-e-f) yielding (a-b-c-d-e-f),
- b + c yielding (b-c), (b-c) + d yielding (b-c-d), e + f yielding (e-f), (b-c-d) + (e-f) yielding (b-c-d-e-f), a + (b-c-d-e-f) yielding (a-b-c-d-e-f) or
- c + d yielding (c-d), b + (c-d) yielding (b-c-d), e + f yielding (e-f), (b-c-d) + (e-f) yielding a + (b-c-d-e-f) yielding (a-b-c-d-e-f).
In embodiments of the synthesis of the invention where one last coupling step is made to arrive at the backbone of the compound of the formula 1 (this "last step" may be followed by subsequent reactions to remove protecting groups or to introduce modifications of the reactive groups), this last step of backbone formation can be:
a + b-c-d-e-f, or
a-b + c-d-e-f, or
a-b-c + d-e-f, or
a-b-c-d + e-f, or
a-b-c-d-e + f.
In embodiments of the synthesis of the invention where one coupling step is made to arrive at the intermediate a-b-c-d-e this step can be:
a + b-c-d-e, or
a-b + c-d-e, or
a-b-c + d-e, or
a-b-c-d + e.
In embodiments of the synthesis of the invention where one coupling step is made to arrive at the intermediate b-c-d-e-f, this step can be:
b-c-d-e +f, or
b-c-d + e-f, or
b-c + d-e-f, or
b +c-d-e-f.
In embodiments of the synthesis of the invention where one coupling step is made to arrive at the intermediate b-c-d-e, this step can be:
b-c-d + e, or
b-c + d-e, or
b +c-d-e.
In the following some of these possible pathways are explained in more detail. Other pathways may be employed in a similar manner.
Thus, a building block G-BC-J (c-J) is reacted with a building block G-BD-J (d-J) yielding a building block
G-BC-D3-BD-J (BZ1 -J). Furthermore, a building block X -BB-J (X -b-J) is reacted with a building block G-BC-D3-BD- Jp (BZ1 -J) yielding a building block
X -BB-D2-BC-D3-BD-J (BZ2a-J).
Alternatively a building block G-BB-J (b-J) is reacted with a building block G-BC-D3-BD-J (BZ1 -J) yielding a building block
G-BB-D2-BC-D3-BD-J (BZ2b-J).
Furthermore, a building block G-BE-J (e-J) is reacted with a building block G-X2 (G-X2) yielding a building block
G-BE-D5-X2 (BZ3a)
Alternatively, a building block G-BE-J (e-J) is reacted with a building block G-BF-J (BF-J) yielding a building block
G-BE-D5-BF (BZ3b).
The building block X -BB-D2-BC-D3-BD-J (BZ2a-J) is reacted with a building block G- BE-X2 (BE-X2), wherein after an eventual removal of possible protecting groups the compound with a molecular structure as defined in formula 1
X -BB-D2-BC-D3-BD-D4-BE-X2
is provided.
Alternatively, the building block X -BB-D2-BC-D3-BD-J (BZ2a-J) is reacted with a building block G-BE-D5-X2 (BZ3a), wherein after an eventual removal of possible protecting groups the compound with a molecular structure as defined in formula 1 ,
X -BB-D2-BC-D3-BD-D4-BE-D5-X2
is provided.
In another alterative, the building block X -BB-D2-BC-D3-BD-J (BZ2a-J) is reacted with a building block G-BE-D5-BF (BZ3b), wherein after an eventual removal of possible protecting groups the compound with a molecular structure as defined in formula 1 , with X2 being -D5- BF,
X -BB-D2-BC-D3-BD-D4-BE-D5-BF
is provided.
In a further alternative, the building block G-BB-D2-BC-D3-BD-J (BZ2b-J) is reacted with a building block G-BE-X2 (BE-X2), wherein a building block
G-BB-D2-BC-D3-BD-D4-BE-X2 (BZ4a) is provided.
The building block G-BB-D2-BC-D3-BD-D4-BE-X2 (BZ4a) is then reacted with a building block BA-J (a-J), wherein after an eventual removal of possible protecting groups the compound with a molecular structure as defined in formula 1 , with X1 being BA-D -
BA-D -BB-D2-BC-D3-BD-D4-BE-X2
is provided.
Alternatively, the building block G-BB-D2-BC-D3-BD-J (BZ2b-J) is reacted with a building block G-BE-D5-X2 (BZ3a), yielding a building block
G- BB- D2- BC-D3-BD- D4- BE-D5-X2 ( BZ4b) .
The building block G-BB-D2-BC-D3-BD-D4-BE-D5-X2 (BZ4b) is reacted with BA-J (a-J), wherein after an eventual removal of possible protecting groups the compound with a molecular structure as defined in formula 1 , with X1 being BA-D -
BA-D -BB-D2-BC-D3-BD-D4-BE-D5-X2
Is provided.
Alternatively, the building block G-BB-D2-BC-D3-BD-J (BZ2b-J) is reacted with a building block G-BE-D5-BF (BZ3b) yielding a building block
G-BB-D2-BC-D3-BD-D4-BE-D5-BF (BZ4c)
The building block G-BB-D2-BC-D3-BD-D4-BE-D5-BF (BZ4c) is reacted with BA-J (a-J), wherein after an eventual removal of possible protecting groups the compound with a molecular structure as defined in formula 1 , with X1 being BA-D - and X2 being D5-BF,
BA-D -BB-D2-BC-D3-BD-D4-BE-D5-BF
is provided.
The method of synthesis is explained in the following with more specific building blocks, without being limited to these specific building blocks.
In most cases J refers to a COOH moiety, wherein said first linking function may be , if necessary, activated (COact) or protected (COOPGA), and G refers to a NH2 moiety, wherein said second linking function may be, if necessary, protected (FN).
Thus, derivatives of the six building blocks are employed as intermediates in the synthesis of the invention as building blocks of the general formula
a: (a-COOH): BA-COOH, (a-COact): BA-COact,
(X -J): X -J; (H2N-b):
(X -b-COact):
Figure imgf000240_0001
Figure imgf000240_0002
ΡεΤΚΡ20ΐ4/052922
Figure imgf000241_0001
GN* coact
Figure imgf000241_0002
Figure imgf000241_0003
Figure imgf000242_0001
wherein
- FN is N or M, wherein
- M is a masked functional group, in particular M is -N02 or -N3, and wherein,
- NPGN, COOPGA or 0PGH signifies an NH2, COOH or OH moiety reversibly inactivated by a removable protecting group, and COact signifies an activated carboxylic acid moiety,
A building block c-COOH
Figure imgf000242_0002
a building block FN-c-CO
Figure imgf000242_0003
is reacted with a building block (H2N-d):
Figure imgf000242_0004
yielding a building block BZ1 a
Figure imgf000243_0001
Subsequently, a building block X -b-COOH or a building block X -b-COa
Figure imgf000243_0002
(X -b-COOH) or (X -b-COact)
is reacted with the building block (BZa1 ) yielding a building block BZ2a
Figure imgf000243_0003
wherein the depicted building block is representative for the other similar building blocks BZ2a derived from a reaction with the building block BZa1 , which may be used in an analogue reaction yielding to analogue compounds. This building block is used further below to describe the further reactions, the other building blocks may be used in a similar manner.
Subsequently the protecting group PGA may be removed and a building block BZ2a-COOH
Figure imgf000243_0004
is provided, which can be optionally activated to provide a building block BZ2a-COact
Figure imgf000244_0001
(BZ2a-COact).
Alternativel a building block HN-c
Figure imgf000244_0002
is reacted with a building block X -b-COOH or a building block X -b-COa the protecting group PGA is removed and the reaction product is reacted with a building block H2N-d yielding a compound BZ2a-COOH
Figure imgf000244_0003
Similar further reactions as discussed concerning BZ2a-COOH
Figure imgf000244_0004
(BZ2a-COOH) apply. Furthermore, a building block e-COOH or a building block e-CO
Figure imgf000244_0005
(e-COauL) is reacted with the building block
Figure imgf000245_0001
yielding a building block BZ3b
Figure imgf000245_0002
of the block BE are not depicted due to simplicity reasons. These variants may be used in a similar manner, yielding analogue building blocks BZ3b. The depicted building blocks BZ3b are used further below to describe the further reactions, the other building blocks may be used in a similar manner
The building block BZ2a-COOH or the building block BZ2a-COact
Figure imgf000245_0003
(BZ2a-COac ) is reacted with a building block BZ3b
Figure imgf000246_0001
wherein after removal of the protecting groups the compound with a molecular structure as defined in formula 1
Figure imgf000246_0002
Figure imgf000247_0001
is provided
An alternative of the second aspect of the invention relates to the synthesis of compounds according to the general formula 1 , wherein
a. X1 is
Figure imgf000247_0002
with D being a linker derived from a reaction of J and G and which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting R4 and the parent moiety, and
with R4 being selected from a substituent group S3, S4 or S5, or
b. X1 is
Figure imgf000247_0003
with R2 and R3 of BA being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH2, -N02, -NHCH3, -NH(CH3)2, a substituted or unsubstituted C1 -C3 alkyl, a substituted or unsubstituted C1 -C3 alkoxy or a C1 -C3 haloalkyl , in particular from -H, -F, -CN, -OH, -NH2, -N02, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, - OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, - CHF2, -CH2F or -CF3,more particularly with R2 and R3 being selected independently from each other from -H, -F or -CH3, and
with D being a linker derived from a reaction of J and G and which comprises carbon, sulphur, nitrogen and/or oxygen atoms and which is covalently connecting the moiety comprising E and the parent moiety,
- with E being selected from a substituent group S3, S4 or S5, or
- with E being
Figure imgf000248_0001
- with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n being 1 ,
- with each R independently from any other R being selected from a substituent group S1 or S2, or
- with E being
Figure imgf000248_0002
with each T being selected independently from each other from -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2 or -NRc,
- with Rc being -CH2OH, -CH3, -CH2CH3, -CH2CH2CH3, and
with T being selected from -CH2, -NH, -S or -O, -CHCH3, -C(CH3)2 or -NRC, and with T" being selected from -CH or =N, and
with R5 and R6 being selected independently from each other from -H, -F, -CH3, -CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with R5 and R6 being selected independently from each other from H, -F or -CH3, and
- with R6 being selected from -OH, -OCH3, -OCH2CH3 or -CH3
with R7 being selected from =NH, =S or =0, and
with m of R9m being selected from 0, 1 , 2 or 3, and each R9 being selected independently from each other from -CI, -F, Br, I, -OH, -CCH, -CH3, -CH2CH3, - OCH3, -COOH, -COORb, -C(0)NH2, -C(0)NH(Rb); -C(0)N(Rb)2 , -NHC(=0)ORb, -NRbC(=0)ORb, -NRbC(=0)OH -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or - CF3,
with Rb being a substituted or unsubstituted CrC5 alkyl, a substituted or unsubstituted C2-C5 alkenyl, a substituted or unsubstituted C2-C5 alkynyl, or a C1-C5 haloalkyl.
In some embodiments, a building block BB1
Figure imgf000249_0001
Figure imgf000250_0001
may be employed, which may be provided analogously to the previously described synthesis, is provided. Said building block BB1 may be described by the general formula GBB1
G— PPM
(GBB1 ),
with PPM being the protected parent moiety
Figure imgf000250_0002
Figure imgf000251_0001
Said building block BB1 and a building block of the general formula
Figure imgf000251_0002
wherein
- COO^A or 0^M signifies a COOH or OH moiety reversibly inactivated by a removable protecting group,
- COact signifies an activated carboxylic acid moiety,
- J is a first linking function which is formed in such a way as to form a covalent bond selectively with a second linking function G and to provide the linker D , and
- E, D, R2, R3, R4, Z and Y have the same meaning as defined above,
are reacted and yield protected compounds of the general formulas
Figure imgf000252_0001
PPM
or (PC6)
After removal of the protecting groups the compound with a molecular structure as defined by the general formulas
Figure imgf000252_0002
are provided,
with PM being the parent moiety
Figure imgf000253_0001
Building blocks B1 and C1 to C6 are known compounds, commercially available or may be produced analogously to known compounds.
Alternatively instead of C6
Figure imgf000253_0002
(C6) the following compound (C6a) may be used in the above described manner, wherein the moiety
Figure imgf000254_0001
may be introduced later by a reaction of the double bond according to literature procedure (Davies et al,J. Am. Chem. Soc. 1993, 1 15, 9468; lUPAC Gold book definition (http:/ / www. iupac. org/ goldbook/ D01745. Pdf); Kishner et al. J. Russ. Phys. Chem. Soc. 43, 1 132 (191 1 ); phenylcyclopropane in Organic Syntheses, Coll. Vol. 5, p.929 (1973); Vol. 47, p.98 (1967); Ludger et al "Biosynthesis and Metabolism of Cyclopropane Rings in Natural Compounds" Chem. Rev., 2003, volume 103, pp 1625- 1648; Coelho et al. Science 339 (61 17): 307-310. doi: 10.1 126/science.1231434; Charette et al., A. Org. React. 2001 , 58, 1 ; Paul et al. J. Am. Chem. Soc; 2006; 128(19) pp 6302 - 6303).
Particular embodiments of the building blocks B1 and C1 to C4 are depicted below:
Figure imgf000254_0002
with n of R n being 0, 1 , 2, 3 or 4, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n being 1 , and with each R independently from any other R being selected from a substituent group S1 or S2.
The connection of two compounds by the first and second linking function (G and J) providing a defined bond (a linker D) between these compounds is known in the art and can be achieved by standard reaction according to basic literature procedures or adapted basic literature procedures. For example, J of one compound may be -CH^OH and G of another compound may be CI. The reaction of these compounds in the presence of NaH yields a - CH2)20- bond (linker D) between the two compounds providing a space of 3 atoms between these compounds. A reaction of
-(C=0)CI (linking function J) with -NH2 (linking function G) yields a -(C=0)-NH- bond (linker D) providing a space of 3 atoms. Exemplary examples are given further below for one linker D . Analogue pathways apply for the other linkers D2 to D5.
In case of D being
Figure imgf000255_0001
with J being COOH or COOact is reacted with a compound of the formula 55
Figure imgf000256_0001
The above mentioned compounds B1 or C1 to C6 are known compounds, commercially available or may be produced analogously to known compounds.
The synthesis of the invention comprises the compound 55, which is prepared according to the reaction athway depicted in scheme 1
Figure imgf000256_0002
55
Scheme 1 :
Compound 52 was reacted with compound 53 in the presence of Bis- (trichloromethyl)carbonate (BTC), 2,4,6-Collodine and A/,/V-diisopropylethylamine (DIPEA) yielding compound 54 (step a). After isolation of compound 54, the N02-moiety of compound 54 is converted with SnCI2 to the NH2-moiety of compound 55 (step b).
The compound 52 and the compound 53 may be synthesised according to scheme 2 or scheme 3.
Figure imgf000257_0001
Scheme 2:
In scheme 2 compound 56 was reacted with compound 57 in the presence of Λ/,/V- Dicyclohexyl-methandiimin (DCC) yielding compound 58 (step a). Alternatively 1 0-(7- azabenzotriazol-1 -yl)-/V,/V,/V,/V-tetramethyluronium hexafluorophosphate (HATU) and N,N- diisopropyl-ethylamine (DIPEA) may be used. Compound 58 was treated with HCI/Dioxane to obtain compound 59 (step b). Subsequently, compound 59 was reacted with compound 60 in the resence of triethylamine, yielding compound 53 (step c).
Figure imgf000257_0002
53
Scheme 3: Scheme 3 describes the reaction of compound 61 with compound 62 in the presence of Bis- (trichloromethyl)carbonate (BTC), 2,4,6-Collidine and Λ/,/V-diisopropylethylamine (DIPEA), yielding compound 63 (step a). After isolation of compound 63, the N02-moiety of compound 47 is converted to the NH2-moiety of compound 53 by the use of SnCI2.
Compounds 57, 60, 61 or 62 are known compounds, commercially available or may be produced analogously to known compounds. Compound 60 can be synthesised according to Adamczyk, M., Fino, J., R., Org. Prep. Proced. Int., 2009, 28, 470-474. For example, compound 61 and 62 may be produced by an adapted procedure according to Tichenor et al. (M. S. Tichenor, D. B. Kastrinsky and D. L. Boger, J. Am. Chem. Soc, 2004, 126, 8396). Comparable compounds to 57, 61 or 62 with different substituents on the phenyl moieties may be employed in a similar reaction to provide the respective building blocks comparable to compound 53.
The method of choice of linking these compounds is a selective coupling reaction between the (activated) carboxylic acid moiety R4-COOH or R4-COOact or E-COOH or E-COOact (acid partner), and the amino moiety (amino partner), whereby other functional groups of the amino and acid partner are protected. The reactive hydroxyl groups need to be transitionally (reversibly) protected by any of the many suitable protection groups for hydroxyl groups (PGH) known in the art. Likewise, the carboxylic acid moiety of the amino partner H2N- will be protected by any of the many suitable protection groups (PGA) known in the art for carboxylic acid groups to prevent homopolymer formation. Furthermore, any amino moiety of the acid partner will likewise be protected by any of the many suitable protection groups for amino groups (PGN) known in the art.
Activation of the carboxylic acid moiety of the acid partner may be applied before the reaction of the acid partner with the amino partner and can be achieved by any of the methods known in the art for increasing the reactivity of carboxylic acids to amide formation with primary amines, in particular reference is made to the activation of the carboxylic acid as discussed.
The reactions are carried out between -30° C to 80 ° C, in particular between 25° C to 60° C and further in particular between 25 to 30 'C.
The PGH protecting groups can be C4H9 (/-Butyl), para-methoxybenzyl (PMB), benzyl or CH2CHCH2 (allyl), in particular CH2CHCH2 (allyl).
The PGA protecting groups can be C4H9 (/-Butyl), para-methoxybenzyl (PMB), benzyl 9- fluorenylmethyl (Fm) or CH2CHCH2 (allyl), in particular CH2CHCH2 (allyl).
The activated carboxyl moiety can be
- (0-(7-azabenzotriazol-1 -yl)-/V,/V,/V,/V-tetramethyluronium hexafluorophosphate) (HATU) ester, achieved by a coupling of the acid with HATU, or Bis-(trichloromethyl)carbonate (BTC) ester, achieved by a coupling of the acid with BTC, or
- acyl chloride, achieved by a coupling of the acid with SOCI2 or
- Ν,Ν'-Diisopropylcarbodiimide (DIC) ester, achieved by a of the acid coupling with DIC, or
- Ν,Ν'-Dicyclohexylcarbodiimide (DCC) ester, achieved by a coupling of the acid with DCC.
The coupling reactions to the activated carboxyl moiety may be supported by addition of bases selected from (A/,/V-diisopropylethylamine) (DIPEA), N-methylmorpholine (NMM), 4- dimethylaminopyridine (DMAP), triethylamine (TEA), 2,4,6-trimethylpyridine (sym-collidine), pyridine, Ν,Ν'-Diisopropylcarbodiimide (DIC), 2,6-di-tert-butyl-4-dimethylaminopyridine (DBDMAP), in particular from A/,/V-diisopropylethylamine (DIPEA) or 2,4,6-Trimethylpyridine (sym-collidine). The addition of bases allows a deprotonation of the carboxylic acid and facilitates the reaction to the respective activated carboxylic acid.
The solvent of the reactions is tetrahydrofuran, dioxane, acetonitrile, tert-butyl methyl ether, dichlormethane, chloroform, 1 -methyl-2-pyrrolidinone, Ν,Ν-dimethylacetamide (DMA), or dimethylformamide, in particular tetrahydrofuran or dimethylformamide. Other solvents may be applied if necessary.
The compound characterized by the general formula 1 is obtained by removal of the protecting groups.
An analogue pathway applies for D being
Figure imgf000259_0001
with R8 being selected from -CH3, -CH2CH3, -OCH3, -OCF3, -CH2CF3, -
CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with R8 being CH3, , and with V being S or O. Reference is made to the description above.
An analogue pathway applies for D being
Figure imgf000259_0002
, with R8 being selected from -H, -CH3, -CH2CH3, -OCH3, -OCF3, -CH2CF3,
CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular R8 being selected from H or CH3, more particularly R8 being H, and with V being S, NH or O. Reference is made to the description above, wherein the respective functional groups are switched. An analogue pathway applies also for D being
Figure imgf000260_0001
or with R8 being selected from -H, -CH3, -
CH2CH3, -OCH3, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with R8 being selected from H or CH3, more particularly R8 being H, and with V being S, NH or O. Reference is made to the description above
An analogue pathway applies also for D being
Figure imgf000260_0002
, with R8 being selected from -H, -CH3, -CH2CH3,
OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, and with V being S, NH or Reference is made to the description above.
An analogue pathway applies also for D being
Figure imgf000260_0003
with R8 being selected from -H, -CH3, -
CH2CH3, -OCH3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3. Reference is made to the description above
An analo ue pathway applies also for D being
Figure imgf000260_0004
or , wherein the coupling step is achieved by a
Williamson-Ether-S nthesis, a known organic name reaction.
Optionally
Figure imgf000260_0005
may be oxidized yielding
Figure imgf000260_0006
as a linker D .
An analogue pathway applies also for D being
Figure imgf000261_0001
, with each R8 being selected independently from each other from -H, CH3, -CH2CH3, -OCH3, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with each R8 being selected independently from each other from H or CH3, more particularly each R8 being H, and with V being S, NH or O. Reference is made to the description above. Concerning the coupling step reference is made to the description below and the experimental section.
An analogue pathway applies also for D being
Figure imgf000261_0002
or , with R8 being selected from -H, -CH3, -CH2CH3, -
OCH3, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with R8 being selected from H or CH3, more particularly R8 being H. Reference is made to the description above. Concerning the coupling step reference is made to the description below and the experimental section.
An analogue pathway applies also for being
Figure imgf000261_0003
, Reference is made to the description above, wherein the coupling step is achieved by a Click reaction, a known organic reaction.
An analogue pathway applies also for D being
Figure imgf000261_0004
, wherine the respective heterocycle is produced with an adapted procedure of Zhang et al. (Org. Lett, 2010, 12 (17), pp 3942-3945), using an aluminum- based Lewis acids promotion for a condensation of substituted a-chloroglycinates with isonitriles or with cyanide ion. In case of D being
'N- H a compound
Figure imgf000262_0001
is reacted with a compound of the formula 64
Figure imgf000262_0002
in the presence of an activation reagent and a base, yielding a compound of the general formula 1 . The above mentioned compounds B1 a or C1 a to C6a are known compounds, commercially available or may be produced analogously to known compounds. Reference is also made to the experimental section.
An analogue pathway applies for D being
Figure imgf000263_0001
, with R8 being selected from -H, -CH3, -CH2CH3, -OCH3, -OCF3, -CH2CF3, -
CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with R8 being selected from H or CH3, more particularly R8 being H. Reference is made to the description above
Similar procedures may be applied where E is one of the moieties below
Figure imgf000263_0002
T, T', T", R5, R6, R6 , R7, m or R9 m having the same meaning as defined previously.
The preparation further comprises a compound
Figure imgf000263_0003
with n, R , R2, R3, D, E, Z and Y having the same meaning as defined above.
In case of D being
Figure imgf000263_0004
a compound
Figure imgf000264_0001
is reacted with a compound of the formula 39
Figure imgf000264_0002
according to the previously described reaction pathway. One specific example is given in scheme 4. Compound 49, 49a or 50 are known compounds, commercially available or may be produced analogously to known compounds. Other compounds for 49, 49a or 50 may be used in a similar way.
Figure imgf000264_0003
BTC THF, RT
2,4,6-Collidine 3 h, 75 %
DIPEA
Figure imgf000264_0004
An analogue synthesis may be applied for the moieties below, with J being COOH or COOact .
Figure imgf000265_0001
or
Concerning the reaction pathway with respect to different D moieties as listed above reference is made to the previously described pathways with these functional groups D .
Scheme 1 to 3 or the reaction with compound 48 show exemplary reaction pathways for compounds with Z being H and Y being CN. It is understood that compounds comprising other substituents Y such as -C(=0)OH, -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)NHCH3, -C(=0)NHCH2CH3, -C(=0)N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3) or
-C(=0)NH2 can be produced according to a similar reactions pathway as depicted in schemes 1 to 3, whereby reactive moieties -C(=0)(NH2) or -C(=0)OH may be protected (- C(=0)NPGN or -C(=0)0PGA until the global deprotection. The same applies for compounds where Z is -H, -OH, -CH3, -CH2CH3 or -OCH3. Different protecting groups may be applied as discussed above.
It is further understood that the same reaction pathways may be used for different building blocks BC, as described above. Furthermore, The reaction of the two linking functions G and J yielding different D moieties (D1 to D21 ) may be employed with respect for the other building block (e.g. a connection between building block BE with BF).
Further examples with variations on different building blocks or different linkers D shall further clarify the systematic approach in providing a compound of the general formula 1 .
An alternative pathway for building blocks comprising different BB or BD moieties is depicted in scheme 5 and scheme 6
Figure imgf000266_0001
Figure imgf000266_0002
Scheme 5: The starting materials may be provided by a reaction of 6-Amineonicotinic acid or allyl protected cinnamic acid with SOCI2 and are coupled with standard coupling procedures described above providing the a-b- building block in form of an ester. The respective acid is provided by a reaction with Dioxane/H20 and LiOH. Said acid (a-b-COOH) is reacted with the c-d-e-f building block (the synthesis of this block is described above) in the presence of Triphosgen and Collidin. The final deprotection is achieved with Phenylsilane and
[Pd(PPh3)4].
CuCI
Figure imgf000267_0001
NHS 1. Boc-Asn-OH, DCC EDC 2. 4 M HCI in Dioxan
3. Nitro-pABA-OSu, TEA
Figure imgf000267_0002
Scheme 6: Shows a reaction pathway for providing a building block -b-c-d-. Details are given in the experimental section.
A reaction pathway to the a-b-c-d-e-f backbone starting from the above depicted building blocks -b-c-d- is depicted in scheme 8.
Figure imgf000268_0001
Figure imgf000268_0002
final deprotection
Figure imgf000268_0003
Scheme 8: Shows a reaction pathway to the a-b-c-d-e-f backbone starting from the building blocks -b-c-d- (A, B, C) of scheme 7. The reaction conditions are similar to the previously discussed reduction, coupling and deprotection conditions (see e.g. Scheme 4). Details are given in the experimental section. An alternative pathway for building blocks comprising a -S02- linker different is depicted in scheme 9 and scheme 10. These examples may be applied for other building blocks as well.
Figure imgf000269_0001
Scheme 9: Shows a reaction pathway to the a-b-c-d-e-f backbone comprising a -S02- linker in place of D4. The reaction conditions are similar to the previously discussed reduction, coupling and deprotection conditions (see e.g. Scheme 4). Details are given in the experimental section.
Figure imgf000270_0001
Scheme 10: Shows a reaction pathway to the a-b-c-d-e-f backbone comprising a -S02- linker in place of D2. The reaction conditions are similar to the previously discussed reduction, coupling and deprotection conditions (see e.g. Scheme 4). Details are given in the experimental section.
An alternative pathway for building blocks comprising different BC moieties is depicted in scheme 1 1 :
65
Figure imgf000271_0001
4 M HCI/Dioxane RT, 6 h, quant.
Figure imgf000271_0002
68
Scheme 1 1 : Compound 65 may be purchased as the respective an amino acid glycine and subsequently protected according to standard procedures. The compound 68 may be used according to scheme 1 to provide an analogue derivative of compound 55, which can be used as an intermediate for the last coupling reaction under similar conditions as described previously, in particular in scheme 4.
An analogue procedure applies to BC moieties selected from
Figure imgf000271_0003
wherein the NH2 or the
COOH moieties may be protected by a suitable protecting group and the COOH, in an analogue way as described above, moiety may be activated- if necessary - in an analogue way as described above. These building blocks (comparable to compound 68) may be used according to scheme 1 to provide an analogue derivative of compound 55, which can be used as an intermediate for the last coupling reaction under similar conditions as described previously, in particular in scheme 4.
Examples of synthetic pathways for a few representative compounds are given in the following. Other compounds with comparable BC moieties may be produced analogously.
Derivatives containing building block BC variations are depicted below. If not mentioned otherwise, the reaction conditions are the same or similar to the previously described coupling reactions. Further details could be found in the experimental section.
Figure imgf000272_0001
(beta-alanine-derivative)
Figure imgf000272_0002
(L-propargylgcycine-derivative)
Figure imgf000272_0003
(threonine-derivative)
Figure imgf000273_0001
(a-aminoisobutyric acid-derivative)
Figure imgf000273_0002
(lysine-derivative)
Figure imgf000273_0003
(proline-containing derivative)
may be synthesized as follows.
For beta-alanine-, L-propargylgcycine- and a-aminoisobutyric acid-derivative, the following boc-protected amino acids were used as starting material:
BocHISL OOH
COOH Ύ BocHN COOH
BocHNT Λ
For threonine- and lysine-derivative the following starting materials were used: BocH
Figure imgf000274_0001
The above mentioned five starting materials were coupled to te/t-butyl 4-aminobenzoate using HATU in DMF yielding the corresponding protected dipeptides
Figure imgf000274_0002
Deprotection of these compounds was carried out using 4 M HCI in dioxanes yielding the following compounds as hydrochlorides.
Figure imgf000274_0003
These compounds were coupled to nitro-pABA succinate ester 60 yielding the following tripeptides:
Figure imgf000274_0004
For the proline-containing derivative the following pathway was used:
Figure imgf000275_0001
L-Proline methyl ester was reacted with 4-nitrobenzoyl chloride yielding a methyl ester which was hydrolysed to carboxylic acid. This acid was coupled with terf-butyl -4-aminobenzoate yielding the protected carboxylic acid moiety which was treated with 4 N HCI in dioxane yielding the tripetide comprising a carboxylic acid.
The tripeptides were coupled to the allyl protected C-terminal dipeptide compound 53 yielding compounds:
Figure imgf000276_0001
These compounds were reacted with Tin(ll) chloride dihydrate yielding the respective terminal NH2 moiety instead of the N02 moiety, and were subsequently coupled with E)-3-(4- (Allyloxy)phenyl)-2-methylacrylic acid yielding a protected compound of the formula 1 . After global deprotection Pd(PPh3)4 and purification via HPLC the beta-alanine-derivative, L- propargylgcycine-derivative, threonine-derivative, a-aminoisobutyric acid-derivative, lysine- derivative or proline-containing derivative, as depicted above, were provided.
Possible ways to obtain derivatives of building blocks, in particular of building blocks BE and BF, are given in scheme 12:
Figure imgf000277_0001
Allyl-I DMF, RT K 2C0 3 12 h, 87 %
Figure imgf000277_0002
EtOH, 60 °C
4 h, 88 %
Figure imgf000277_0003
Figure imgf000277_0004
Figure imgf000278_0001
EtOH, 60 °C
4 h, 88 %
Figure imgf000278_0002
Scheme 12: The 2-hydroxy-3-methoxy-4-nitro-benzaldehyde can be synthesised according to Perez, R., A., Fernandez-Alvarez, E., Nieto, O., Javier Piedrafita, F., J. Med. Chem., 1992, 35, 4584-4588, wherein the other starting materials can be purchased. The compounds may be deprotected or activated for further reactions. Different building blocks, in particular building blocks (e.g. with a heteroaryl moiety or a bicyclic aryl or heteroaryl system, or with different substituents an the phenyl moiety, in particular may be the COOH moiety of building block BF be replaced with the substituent T (as defined above) may be employed in a similar manner.
Examples, without being limited to them, of further building blocks are depicted in the following:
Figure imgf000279_0001
Figure imgf000279_0002
An example for a BA building block comprising a different functional group is given in scheme 13:
Figure imgf000279_0003
COOMe
Figure imgf000280_0001
1 N LiOH dioxane/water
Figure imgf000280_0002
a) To a solution of the cinematic acid in anhydrous DCM was added SOCI2 (1 .2 eq) and the mixture was stirred for 3 hours at room temperature. Anhydrous methanol was added (10 eq) and the Mixture was stirred for 10 min. The solvent was removed under reduced pressure. Column chromatography (n-hexane:ethyl acetate 3:1 ) yielded the ester as a white solid (95 %).
b) To a solution of the ester in anhydrous THF was added Tetrazole (3 eq) and Diallyl A/JV-diisopropylphosphoramidite (2 eq) at 0 'C. The mixture was stirred for 3 hours at room temperature, cooled to 0 °C and te/t-Butyl hydroperoxide (3 eq) was slowly added. Stirring was continued for 1 hour at 0 °C. The Reaction mixture was poured into a solution of NaS03 (10 %) and extracted three times with ethyl acetate. After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (n- hexane:ethyl acetate 2:1 ) yielded the allyl protected ester as a clear oil (50 %), which was taken up in dioxane/1 N LiOH and the mixture was stirred at room temperature for 16 hours. The mixture was acidified to pH 1 with 1 N HCI and extracted three times with ethyl acetate. After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (Chloroform:Methanol 100:1 ) yielded the allyl protected acid as a clear oil (46 %).
c) BTC (0.766 eq, 0.0667 mmol, 19.8 mg) was dissolved in dry THF (10 ml) under an atmospher of argon. The allyl protected acid (2.37 eq, 0.207 mmol, 70 mg) was added, syn- Collidine (8 eq, 0.697 mmol, 91 μΙ) was slowly added via syrringe and the white suspension was stirred at room temperature for 20 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syrringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the fully protected compound as an orange oil (78 mg, 79 %), which was (1 eq, 0.0534 mmol, 60 mg) with phenylsilane (20 eq, 1 .07 mmol, 132 μΙ) dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (1 eq, 0.0534 mmol, 62 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The final product was isolated after preparative HPCL purification as a white powder
Further functional groups may be introduced in the "finished backbone a-b-c-d-e-f according to standard procedures, like fro example oxidation, reduction or halogenations. In an embodiment the synthesis of compounds with the following molecular structure of formula (2)
Figure imgf000282_0001
wherein
R is H or CO(NH2),
R2 is CO(NH2) or CN,
R3 is H or OCH3, and
* indicates a stereo center of a L- or D- enantiomer, which is located on the tertiary carbon atom below the asterisk *, and wherein
the compound of the general formula (1 ) is an essentially pure L-enantiomer, an essentially pure D-enantiomer or a mixture of the L- and D-enantiomer of the same molecular formula, wherein in particular the compound of the general formula (1 ) is an essentially pure L-enantiomer or an essentially pure D-enantiomer.
may be carried out as described in the following.
In case of the compound of above formula 2 the previously mentioned six building blocks are
Figure imgf000282_0002
wherein R is H or CO(NH2), R2 is CN or CO(NH2) and R3 is H or OCH3.
The method of choice of linking these building blocks is a selective coupling reaction between the (activated) carboxylic acid moiety of one block (acid partner), and a amino moiety of another block (amino partner), whereby other functional groups of the amino and acid partner are protected. The reactive hydroxyl groups of block a, e and f need to be transitionally (reversibly) protected by any of the many suitable protection groups for hydroxyl groups (PGH) known in the art. Likewise, the carboxylic acid moiety of the amino partner will be protected by any of the many suitable protection groups (PGA) known in the art for carboxylic acid groups to prevent homopolymer formation. Furthermore, any amino moiety of the acid partner will likewise be protected by any of the many suitable protection groups for amino groups (PGN) known in the art. Additionally, the group R will be transitionally (reversibly) protected by a protecting group R PG, whereby R PG is, in case of R being H, the protection group for hydroxyl groups PGH (0PGH) and, in case of R being -CO(NH2), the protection group for amino groups (PGN) attached to the -CO(NH2) moiety of R (-CO(NPGN)). Likewise, the group R2 will be, in case of R2 being CO(NH2), transitionally (reversibly) protected by a protecting group PGN attached to the -CO(NH2) moiety of R2
(-CO(NPGN)), whereby in case of R2 being CN no protection group is applied.
Activation of the carboxylic acid moiety of the acid partner may be applied before the reaction of the acid partner with the amino partner and can be achieved by any of the methods known in the art for increasing the reactivity of carboxylic acids to amide formation with primary amines, in particular reference is made to the activation of the carboxylic acid as discussed. Thus, derivatives of the six building blocks are employed as intermediates in the synthesis of the invention as building blocks of the general formula
Figure imgf000283_0001
Figure imgf000284_0001
wherein
R1 PG is, for embodiments for which R is H, a hydroxyl protecting group PGH, in other words the 0R pG moiety can be read as an 0PGH moiety, or,
- in case of R being CO(NH2), a -CO(NPGN) moiety, and, in case of R being H, a hydroxyl protecting group PGH yielding a 0PGH moiety, or, in case of R1 being CO(NH2), a - CO(NPGN) moiety, and
- R3 is H or OCH3, and
- R2 is CO(NPGN) or CN, except in case of FN-c-COOH, then R2 is CO(NH2)
- FN is NPGN or M, wherein
- M is a masked functional group, in particular M is -N02 or -N3, and
wherein, - N , COO^A or 0^M signifies an NH2, COOH or OH moiety reversibly inactivated by a removable protecting group, and COact signifies an activated carboxylic acid moiety,
are employed as intermediates, and
i. the carboxylic acid moiety a-COOH or the activated carboxylic acid moiety a- COact of the acid partner a is linked to the amine moiety H2N-b of the amino partner b,
ii. the carboxylic acid moiety b-COOH or the activated carboxylic acid moiety b- COact of the acid partner b is linked to the amine moiety H2N-c of the amino partner c,
iii. the carboxylic acid moiety c-COOH or the activated carboxylic acid moiety c- COact of the acid partner c is linked to the amine moiety H2N-d of the amino partner d,
iv. the carboxylic acid moiety d-COOH or the activated carboxylic acid moiety d- COact of the acid partner d is linked to the amine moiety H2N-e of the amino partner e, and
v. the carboxylic acid moiety e-COOH or the activated carboxylic acid moiety e- COact of the acid partner e is linked to the amine moiety H2N-f of the amino partner f.
In some embodiments, only the activated carboxylic acid moiety of the acid partner is used in one of the steps i. to v., in particular in all the steps i. to v. is the carboxylic acid moiety of the acid partner activated.
It is apparent to the skilled person that the above coupling reactions i. to v. will not necessarily involve the isolated building blocks in each case, but will take place between combinations of the above mentioned building blocks in order to arrive at the full sequence of six blocks (a-b- c-d-e-f). Therefore, the above is to be understood as a teaching regarding the sequence of blocks, i.e. which block links to which other one through the amino and carboxylic acid moiety. In other words, which block will function as an acid partner and which as an amino partner in the above coupling reactions in order to arrive at the full sequence of six blocks (a-b-c-d-e-f).
For example, the reaction of the acid partner b with the amino partner c will yield a building compound b-c, wherein the amino moiety of the block b and the carboxylic acid moiety of block c are protected. This compound b-c can react as an acid partner as well as an amino partner in subsequent reactions. By removing the protection group of the amino moiety of block b a reaction with an acid partner a can be established, yielding compound a-b-c, wherein the carboxylic acid moiety of block c is protected. After removal of the carboxylic acid moiety of block c compound a-b-c can function as an acid partner for the amino partner d. The same applies to further subsequent reactions in order to arrive at the full sequence of six blocks.
It is further possible that by removing the protection group of the carboxylic acid moiety of block c of the compound b-c, the carboxylic acid moiety of block c will function as an acid partner and a reaction with an amino partner d can be established, yielding compound b-c-d. The amino moiety of the block b and the carboxylic acid moiety of block d of the compound b-c-d are protected. Thus, compound b-c-d can function after the removal of the protection group on the amino moiety of block b or on the carboxylic acid moiety of block d, comparable to compound b-c, as an acid partner for a reaction with the amino partner e or as an amino partner for the reaction with the acid partner a. The same applies to further subsequent reactions in order to arrive at the full sequence of six blocks.
Many ways to achieve the full albicidin sequence a-b-c-d-e-f are possible. The following examples show - without being limited to these combinations - three further possible combinations such as
- e + f yielding (e-f), d + (e-f) yielding (d-e-f), c + (d-e-f) yielding (c-d-e-f), a + b yielding (a-b), (a-b) + (c-d-e-f) yielding (a-b-c-d-e-f),
- b + c yielding (b-c), (b-c) + d yielding (b-c-d), e + f yielding (e-f), (b-c-d) + (e-f) yielding (b-c-d-e-f), a + (b-c-d-e-f) yielding (a-b-c-d-e-f) or
- c + d yielding (c-d), b + (c-d) yielding (b-c-d), e + f yielding (e-f), (b-c-d) + (e-f) yielding a + (b-c-d-e-f) yielding (a-b-c-d-e-f),
whereby the coupling of the respective building blocks may be achieved in a similar manner as discussed in the previous sections.
In embodiments of the synthesis of the invention where one last peptide coupling step is made to arrive at the albicidin backbone (this "last step" may be followed by subsequent reactions to remove protecting groups or to introduce modifications of the reactive groups), this last step of backbone formation can be:
a + b-c-d-e-f, or
a-b + c-d-e-f, or
a-b-c + d-e-f, or
a-b-c-d + e-f, or
a-b-c-d-e + f. In embodiments of the synthesis of the invention where one peptide coupling step is made to arrive at the albicidin intermediate a-b-c-d-e this step can be:
a + b-c-d-e, or
a-b + c-d-e, or
a-b-c + d-e, or
a-b-c-d + e.
In embodiments of the synthesis of the invention where one peptide coupling step is made to arrive at the albicidin intermediate b-c-d-e-f, this step can be:
b-c-d-e +f, or
b-c-d + e-f, or
b-c + d-e-f, or
b +c-d-e-f.
In embodiments of the synthesis of the invention where one peptide coupling step is made to arrive at the albicidin intermediate b-c-d-e, this step can be:
b-c-d + e, or
b-c + d-e, or
b +c-d-e.
In certain embodiments a compound (a-b-c-d-e-COact):
Figure imgf000287_0001
is reacted with compound (H2N-f), yielding compound a-b-c-d-e-f
Figure imgf000287_0002
wherein
R PG is, for embodiments for which R is H, a hydroxyl protecting group PGH, in other words the 0R pG moiety can be read as an 0PGH moiety, or, in case of R being CO(NH2), a -CO(NPGN) moiety, wherein in particular R PG is a hydroxyl protecting group PGH with R being H, yielding a 0PGH moiety, and
- R3 is H or OCH3, and
- R2 is CO(NPGN) or CN, and
- NPGN, COOPGA or 0PGH signifies an NH2, COOH or OH moiety reversibly inactivated by a removable protecting group, and COact signifies an activated carboxylic acid moiety,
wherein from compound (a-b-c-d-e-f) albicidin is obtained by removal of the protecting groups PGN, PGH and PGA. Alternatively the not activated carboxyl acid moiety a-b-c-d-e-COOH may be used instead of the activated carboxyl moiety a-b-c-d-e-COact.
In certain embodiments, a compound (a-b-c-d-COact):
Figure imgf000288_0001
is reacted with a compound (H2N-e-f):
Figure imgf000288_0002
R PG is, for embodiments for which R is H, a hydroxyl protecting group PGH, in other words the 0R pG moiety can be read as an 0PGH moiety, or, in case of R being CO(NH2), a -CO(NPGN) moiety, wherein in particular R PG is a hydroxyl protecting group PGH with R being H, yielding a 0PGH moiety, and
R3 is H or OCH3, and - R2 is CO(N ^N) or CN, and
- NPGN, COOPGA or 0PGH signifies an NH2, COOH or OH moiety reversibly inactivated by a removable protecting group, and COact signifies an activated carboxylic acid moiety,
wherein from compound (a-b-c-d-e-f) albicidin is obtained by removal of the protecting groups PGN, PGH and PGA. Alternatively the not activated carboxyl acid moiety a-b-c-d-COOH may be used instead of the activated carboxyl moiety a-b-c-d-COact.
In certain embodiments, a compound (a-b-c-COact)
Figure imgf000289_0001
is reacted with a compound (H2N-d-e-f)
Figure imgf000289_0002
R PG is, for embodiments for which R is H, a hydroxyl protecting group PGH, in other words the 0R pG moiety can be read as an 0PGH moiety, or, in case of R being CO(NH2), a -CO(NPGN) moiety, wherein in particular R PG is a hydroxyl protecting group PGH with R being H, yielding a 0PGH moiety, and
R3 is H or OCH3, and
R2 is CO(NPGN) or CN, and
NPGN, COOPGA or 0PGH signifies an NH2, COOH or OH moiety reversibly inactivated by a removable protecting group, and COact signifies an activated carboxylic acid moiety, wherein from compound (a-b-c-d-e-f) albicidin is obtained by removal of the protecting groups PGN, PGH and PGA. Alternatively the not activated carboxyl acid moiety a-b-c-COOH may be used instead of the activated carboxyl moiety a-b-c-COact.
In certain embodiments, a compound (a-b-COact):
Figure imgf000290_0001
is reacted with a compound (H2N-c-d-e-f)
Figure imgf000290_0002
wherein
R PG is, for embodiments for which R is H, a hydroxyl protecting group PGH, in other words the 0R pG moiety can be read as an 0PGH moiety, or, in case of R being CO(NH2), a -CO(NPGN) moiety, wherein in particular R PG is a hydroxyl protecting group PGH with R being H, yielding a 0PGH moiety, and
- R3 is H or OCH3, and
- R2 is CO(NPGN) or CN, and
- NPGN, COOPGA or 0PGH signifies an NH2, COOH or OH moiety reversibly inactivated by a removable protecting group, and COact signifies an activated carboxylic acid moiety,
wherein from compound (a-b-c-d-e-f) albicidin is obtained by removal of the protecting groups PGN, PGH and PGA. Alternatively the not activated carboxyl acid moiety a-b-COOH may be used instead of the activated carboxyl moiety a-b- COact.
In certain embodiments, compound (a-COact) is reacted with a compound (H2N-b-c-d-e-f):
Figure imgf000291_0001
wherein
R PG is, for embodiments for which R is H, a hydroxyl protecting group PGH, in other words the 0R pG moiety can be read as an 0PGH moiety, or, in case of R being CO(NH2), a -CO(NPGN) moiety, wherein in particular R PG is a hydroxyl protecting group PGH with R being H, yielding a 0PGH moiety, and
- R3 is H or OCH3, and
- R2 is CO(NPGN) or CN, and
- NPGN, COOPGA or 0PGH signifies an NH2, COOH or OH moiety reversibly inactivated by a removable protecting group, and COact signifies an activated carboxylic acid moiety,
wherein from compound (a-b-c-d-e-f) albicidin is obtained by removal of the protecting groups PGN, PGH and PGA as discussed above. Alternatively the not activated carboxyl acid moiety a-COOH may be used instead of the activated carboxyl moiety a-COact.
In some embodiments of the synthesis of the invention the peptide coupling steps to arrive at the albicidin backbone can be achieved by using combined building blocks (a-b); (c-d) and (e- f)-
In some embodiments, compound (e-COact) is reacted with compound (H2N-f), yielding a compound (e-f):
Figure imgf000291_0002
and/or compound (a-COact) is reacted with compound (H2N-b), yielding a compound (a-b):
Figure imgf000292_0001
and/or compound (c-CO; ) is reacted with compound (H2N-d)
yielding a compound (c-d):
Figure imgf000292_0002
wherein
R PG is, for embodiments for which R is H, a hydroxyl protecting group PGH, in
R PG PGH
other words the O moiety can be read as an O moiety, or, in case of R being CO(NH2), a -CO(N ,N) moiety, wherein in particular R PG is a hydroxyl protecting group PGH with R being H, yielding a 0PGH moiety, and
- R3 is H or OCH3, and
- R2 is CO(NPGN) or CN, and
- NPGN, COOPGA or 0PGH signifies an NH2, COOH or OH moiety reversibly inactivated by a removable protecting group, and COact signifies an activated carboxylic acid moiety.
In some embodiments, concerning any step of the synthesis it is possible to use the -COOH building blocks instead of the -COact building blocks, whereby the -COOH moiety may be activated with a catalytic amount of a proton or a lewis acid, as discussed above.
In some embodiments, the carboxyl protecting group PGA of compound (a-b) is selectively removed, yielding a compound (a-b-COOH):
Figure imgf000292_0003
and optionally the carboxylic acid moiety of compound (a-b-COOH) is activated, yielding a compound (a-b-COact ):
Figure imgf000293_0001
and the carboxyl protecting group of compound (c-d) is selectively removed, yielding a compound (c-d-COOH):
Figure imgf000293_0002
and optionally the carboxylic acid moiety of compound (c-d-COOH) is activated, yielding a compound (c-d-COact):
Figure imgf000293_0003
and subsequently compound (c-d-COOH) or compound (c-d-COact) is reacted with (H2N-e-f), yielding a compound (c-d-e-f):
Figure imgf000293_0004
from which the amino-protecting group PGN of FN is selectively removed or the masked functional group M of FN is selectively reduced to -NH2, yielding compound (H2N-c-d-e-f), and
(a-b-COOH) or (a-b-COact) is reacted with (H2N-c-d-e-f), yielding compound (a-b-c-d-e-f), from which albicidin is obtained by removal of the protecting groups PGN, PGH and PGA.
In some embodiments, the amino protecting group PGN of compound (c-d) is selectively removed, yielding a compound (H2N-c-d):
Figure imgf000294_0001
and subsequently, (H2N-c-d) is reacted with compound (a-b-COOH) or with compound (a-b- COact), yielding a compound (a-b-c-d):
Figure imgf000294_0002
and the carboxyl protecting group PGA of compound (a-b-c-d) is selectively removed, yielding compound (a-b-c-d-COOH):
Figure imgf000294_0003
and optionally the carboxylic acid moiety of compound (a-b-c-d-COOH) is activated, yielding compound (a-b-c-d-COact), and subsequently
compound (a-b-c-d-COOH) or compound (a-b-c-d-COact) is reacted with compound (H2N-e-f), yielding compound (a-b-c-d-e-f), from which albicidin is obtained by removal of the protecting groups PGN, PGH and PGA.
In some embodiments, compound (a-b-COact) or compound (a-b-COOH) is reacted with compound (H2N-c), yielding a compound (a-b-c):
Figure imgf000294_0004
thereafter, the carboxyl protecting group PGA of compound (a-b-c) is selectively removed, yielding a compound (a-b-c-COOH):
Figure imgf000295_0001
and optionally the carboxylic acid moiety of compound (a-b-c-COOH) is activated, yielding compound (a-b-c-COact), and
compound (H2N-e-f) is reacted with compound (d-COOH) or (d-COact), yielding a compound
(d-e-f):
Figure imgf000295_0002
and thereafter, the amino-protecting group PGN of FN of compound (d-e-f) is selectively removed or the masked functional group M of FN of compound (d-e-f) is selectively reduced to -NH2, to render compound (H2N-d-e-f), which is thereafter
reacted with compound (a-b-c-COOH) or (a-b-c-COact ), yielding compound (a-b-c-d-e-f), from which albicidin is obtained by removal of the protecting groups PGH and PGA.
In some embodiments, compound (H2N-e-f) is reacted with compound (d-COact) or compound (d-COOH), yielding compound (d-e-f), subsequently, the amino-protecting group PGN of FN of compound (d-e-f) is selectively removed or the masked functional group M of FN of compound (d-e-f) is selectively reacted to -NH2, yielding compound (H2N-d-e-f); then compound (H2N-d-e-f) is reacted with compound (c-COact) or compound (c-COOH), yielding compound (c-d-e-f), from which the amino-protecting group PGN is selectively removed, yielding compound (H2N-c-d-e-f), and compound (H2N-c-d-e-f) is reacted with compound (a-b-COact) or compouind (a-b-COOH), yielding compound (a-b-c-d-e-f), from which albicidin is obtained by removal of the protecting groups PGN, PGH and PGA.
In some embodiments, compound (H2N-e-f) is further reacted
- with compound (d-COOH) or (d-COact), yielding compound (d-e-f), subsequently, the amino-protecting group PGN of FN of compound (d-e-f) is selectively removed or the masked functional group M of FN of compound (d-e-f) is selectively reacted to -NH2, yielding compound (H2N-d-e-f); then - compound (H2N-d-e-f) is reacted with compound (c-COOH) or (c-COact), yielding compound (c-d-e-f), from which the amino-protecting group PGN of FN of compound (c-d-e-f) is selectively removed or the masked functional group M of FN of compound (c-d-e-f) is selectively reacted to -NH2, yielding compound (H2N-c-d-e-f ), and
- compound (H2N-c-d-e-f ) is reacted with compound (a-b-COOH) or (a-b-COact), yielding compound (a-b-c-d-e-f), from which albicidin is obtained by removal of the protecting groups PGN, PGH and PGA.
In some embodiments, compound (b-COOH) or (b-COact) is further reacted
- with compound (H2N-c-d), yielding compound (b-c-d), subsequently, the carboxyl protecting group PGA of compound (b-c-d) is selectively removed, yielding compound (b-c-d-COOH), the carboxylic acid moiety is optionally activated, yielding compound (b-c-d-COact); then
- compound (b-c-d-COOH) or (b-c-d-COact) is further reacted with compound (H2N- e-f), yielding compound (b-c-d-e-f), from which the amino-protecting group PGN of FN of compound (b-c-d-e-f) is selectively removed or the masked functional group M of FN of compound (b-c-d-e-f) is selectively reacted to -NH2, yielding compound (H2N-b-c-d-e-f), and
- compound (H2N-b-c-d-e-f) is reacted with compound (a-COOH) or (a-COact), yielding compound (a-b-c-d-e-f), from which albicidin is obtained by removal of the protecting groups PGN, PGH and PGA.
Alternatively the compound (b-c-d) may be achieved by a reaction of the compound (b-c) with block d in a similar manner.
In some embodiments, compound (FN-c-COOH)
Figure imgf000296_0001
wherein
- R3 is H or OCH3, and
- Ft2 is CO(NH2)
- FN is NPGN or M, wherein
- M is a masked functional group, in particular M is -N02 or -N3, further in particular N02, and wherein, and N signifies an NH2 moiety reversibly inactivated by a removable protecting group,
is reacted with compound (H2N-d) yielding compound (c-d):
Figure imgf000297_0001
compound (c-d) is reacted with compound (H2N-e) yielding compound (c-d-e) :
Figure imgf000297_0002
compound (c-d-e) is reacted with compound (H2N-f) yielding compound (c-d-e-f)
Figure imgf000297_0003
wherein R2 of compound (c-d), (c-d-e) or (c-d-e-f) is, due to the reaction conditions, CN and the protecting group PGA is removed and the COOH-moiety may be activated before the reaction with amino partner, as discussed above. Concerning the combination of the compounds with further building blocks to achieve albicidin (a-b-c-d-e-f) reference is made to the above mentioned methods and combinations.
It is understood that in all the above mentioned embodiments only the activated carboxyl moiety COact may be used for the reactions of the acid partner with the amino partner.
It is further understood that in all the above mentioned embodiments R PG can be a hydroxyl protecting group PGH yielding a 0PGH moiety, and, thus, after removal of the protecting group
Figure imgf000297_0004
In some embodiments, the reactions are carried out between -30° C to 80° C, in particular between 25° C to 60° C and further in particular between 25 to 30 °C.
In some embodiments, the reactions are carried out between -30° C to 30° C, in particular between -30° C and 0° C, in order to suppress racemisation reactions.
In some embodiments, the PGN protecting groups are tert-butyloxycarbonyl (t-Boc), allyloxycarbonyl (Alloc), 9-fluorenylmethoxycarbonyl (Fmoc), para-methoxybenzyl carbamate (Moz) and benzyloxycarbonyl (Z).
In some embodiments, the PGN protecting groups are, in case of a CO(NPGN) moiety, in particular for the amide sidechain of asparagine (building block c), 9-Xanthenyl (Xan), Trityl (Trt), 4-Methyltrityl (Mtt), Cyclopropyldimethylcarbinyl (Cpd), 4,4'-Dimethoxybenzhydryl (Mbh), 2,4,6-Trimethoxybenzyl (Tmob).
In some embodiments, the PGH protecting groups are C4H9 (/-Butyl), para-methoxybenzyl (PMB), benzyl or CH2CHCH2 (allyl).
In some embodiments, the PGA protecting groups are C4H9 (/-Butyl), para-methoxybenzyl (PMB), benzyl 9-fluorenylmethyl (Fm) or CH2CHCH2 (allyl).
In some embodiments, the activated carboxyl moiety is
- (0-(7-azabenzotriazol-1 -yl)-/V,/V,/V,/V-tetramethyluronium hexafluorophosphate) (HATU) ester, achieved by a coupling with HATU, or
- BTC, achieved by a coupling with BTC, or
- acyl chloride, achieved by a coupling with SOCI2 or
Ν,Ν'-Diisopropylcarbodiimide (DIC) ester, achieved by a coupling with DIC, or Ν,Ν'-Dicyclohexylcarbodiimide (DCC) ester, achieved by a coupling with DCC.
In some embodiments the coupling reactions to the activated carboxyl moiety may be supported by addition of bases selected from (A/,/V-diisopropylethylamine) (DIEA), N- methylmorpholine (NMM), 4-dimethylaminopyridine (DMAP), triethylamine (TEA), 2,4,6- trimethylpyridin (sym-collidine), pyridine, Ν,Ν'-Diisopropylcarbodiimid (DIC), 2,6-di-tert-butyl- 4-dimethylaminopyridine (DBDMAP), in particular from A/,/V-diisopropylethylamine (DIEA) or 2,4,6-Trimethylpyridin (sym-collidine). The addition of bases allows a deprotonation of the carboxylic acid and facilitate the reaction to the respective activated carboxylic acid.
In some embodiments, if an acyl halogenide, in particular an acyl chloride, is used as the activated carboxyl moiety, a base selected from Λ/,/V-diisopropylethylamine (DIEA), N- methylmorpholine (NMM), triethylamine (TEA), 4-dimethylaminopyridine (DMAP), 2,4,6- trimethylpyridin (sym-collidine), 2,6-di-tert-butyl-4-dimethylaminopyridine (DBDMAP), in particular from Λ/,/V-diisopropylethylamine) (DIEA), or 2,4,6-trimethylpyridin (sym-collidine), is added in order to prevent a removal of the protecting group due to acidic by-products.
In some embodiments the solvent of the reactions is tetrahydrofuran, dioxane, acetonitrile, tert-butyl methyl ether, dichlormethane, chloroform, 1 -methyl-2-pyrrolidinone, N,N- dimethylacetamide (DMA), or dimethylformamide, in particular tetrahydrofuran or dimethylformamide. Other solvents may be applied if necessary.
In the above described synthesis of albicidin of the formula 2 intermediates are used which acan be described by the following formulas:
a. building block a-b:
i. (a-b):
Figure imgf000299_0001
ii. (a-b-COOH):
Figure imgf000299_0002
iii. (a-b-COact ):
Figure imgf000299_0003
iv. unprotected (a-b):
Figure imgf000299_0004
b. building block a-b-c:
i. (a-b-c): R
Figure imgf000300_0001
(a-b-c-COOH):
Figure imgf000300_0002
iii. -b-c-COact ):
Figure imgf000300_0003
iv. unprotected (a-b-c)
Figure imgf000300_0004
ding block a-b-c-d: i. (a-b-c-d):
Figure imgf000300_0005
ii. (a-b-c-d-COOH):
Figure imgf000301_0001
iii. (a-b-c-d-COact):
Figure imgf000301_0002
iv. unprotected (a-b-c-d)
Figure imgf000301_0003
ding block a-b-c-d-e: i. (a-b-c-d-e):
Figure imgf000301_0004
ii. (a-b-c-d-e-COOH):
Figure imgf000301_0005
iii. (a-b-c-d-e-COact):
Figure imgf000302_0001
iv. unprotected (a-b-c-d-e)
Figure imgf000302_0002
ding block e-f:
i. -f):
Figure imgf000302_0003
(e-f-COOH):
Figure imgf000303_0001
Figure imgf000303_0002
iv. 4-[(4-amino-2-hydroxy-3-methoxy-benzoyl)amino]-2-hydroxy-3- methoxy-benzoic acid (unprotected (e-f))
Figure imgf000303_0003
ding block d-e-f:
i. (d-e-f):
Figure imgf000303_0004
ii. (H2N-d-e-f):
Figure imgf000303_0005
ii. 4-[[4-[(4-aminobenzoyl)amino]-2-hydroxy-3-methoxy-benzoyl]amino]-2- hydroxy-3-methoxy-benzoic acid (unprotected (d-e-f))
Figure imgf000304_0001
h. building block c-d-e-f:
i. (c-d-e-f):
Figure imgf000304_0002
iii. un rotected (c-d-e-f)
Figure imgf000304_0003
i. building block b-c-d-e-f: i. (b-c-d-e-f):
Figure imgf000305_0001
Figure imgf000305_0002
iii. unprotected b-c-d-e-f
Figure imgf000305_0003
lding block b-c:
i. (b-c):
Figure imgf000305_0004
iii. (b-c-COact):
Figure imgf000306_0001
Figure imgf000306_0002
v. un rotected (b-c)
Figure imgf000306_0003
ding block b-c-d:
i. b-c-d):
Figure imgf000306_0004
v. unprotected (b-c-d)
Figure imgf000307_0001
ing block b-c-d-e:
i. (b-c-d-e :
Figure imgf000307_0002
ii. b-c-d-e-COOH):
Figure imgf000307_0003
unprotected (b-c-d-e)
Figure imgf000308_0001
Figure imgf000308_0002
ii. (c-d-COOH):
Figure imgf000308_0003
v. unprotected (c-d)
Figure imgf000308_0004
ing block c-d-e: i. (c-d-e):
Figure imgf000309_0001
Figure imgf000309_0002
Figure imgf000309_0003
Figure imgf000309_0004
v. unprotected (c-d-e)
Figure imgf000309_0005
wherein: R is H or CO(NH2),
R3 or R3 is H or OCH3
R2 is CO(NH2) or CN, and wherein
- R PG is,
in case of R1 being H, a hydroxyl protecting group PGH yielding a 0PGH moiety, or, in case of R being CO(NH2), a -CO(NPGN) moiety, and
- R2 is CO(NPGN) or CN,
- FN is NPGN or M, wherein in particular FN is NPGN, wherein
M is a masked functional group, and wherein,
- NPGN, COOPGA or 0PGH signifies an NH2, COOH or OH moiety reversibly inactivated by a removable protecting group, and COact signifies an activated carboxylic acid moiety, wherein
- each PGH independently of any other PGH is a hydroxyl protecting group selected from CH2CHCH2 (allyl), THP (tetrahydropyranyl), SiR'a (trialkylsilicon), C4H9 (f-Butyl), CH2C6H5 (benzyl), H3CCO (acetyl), CH2C6H4OCH3 (4-methoxybenzyl) or Ci9H15 (Triphenylmethyl),
- with each R' being independently from any other R a Ci to C4 alky I
- each PGA independently of any other PGA is a carboxylic protecting group selected from CH2CHCH2 (allyl), THP (tetrahydropyranyl), SiR'3 (trialkylsilicon), or C4H9 (i-Butyl), CH2C6H5 (benzyl), CH2C6H4OCH3 (4-methoxybenzyl) or C19H15 (Triphenylmethyl),
- with each R' being independently from any other R a Ci to C4 alky I
- each PGN independently of any other PGN is an amino protecting group selected from t-Butyloxycarbonyl (Boc), (CO)OCH2C6H5 (benzyloxycarbonyl), (CO)OCH2C6H4OCH3 (4- methoxybenzyloxycarbonyl) or Allyloxycarbonyl (Alloc),
- M is -N02 or -N3, wherein M is in particular N02 - each COact independently from any other COact is acyl fluoride, acyl chloride, benzotriazole esters or carbodiimide esters, generated by use of the carboxylic acid and coupling agents such as Benzotriazolyloxytris-(dimethylamino)-phosphonium hexafluoro- phosphate (BOB), Benzotriazol-1 -yl-oxy-tripyrrolidino-phosphonium hexafluorophosphate (pyBOP), N,N,N',N'-Tetramethyl-0-(1 H- benzo-triazol-1 -yl)uronium hexafluorophosphate (HBTU), (0-(7- azabenzotriazol-1 -yl)-/V,/V,/V,/V-tetramethyluronium hexafluorophosphate) (HATU), Λ/,/V-Di-cyclohexylcarbodiimide (DCC), Λ/,/V- Di-isopropylcarbodiimid (DIC), 1 -Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC).
In some embodiments, concerning the above mentioned intermediates,
R is H,
R3 or R3 is H or OCH3
R2 is CO(NH2) or CN, in particular R2 is CN, and wherein
- R PG is a hydroxyl protecting group PGH yielding a 0PGH moiety, and
- R2 is -CO(N)PGN or CN, in particular R2 is CN
- FN is NPGN or M, wherein in particular FN is NPGN, wherein
- M is a masked functional group, and wherein,
- NPGN, COOPGA or 0PGH signifies an NH2, COOH or OH moiety reversibly inactivated by a removable protecting group, and COact signifies an activated carboxylic acid moiety, wherein
- each PGH independently of any other PGH is a hydroxyl protecting group selected from CH2CHCH2 (allyl), THP (tetrahydropyranyl), SiR'3 (trialkylsilicon), C4H9 (f-Butyl), CH2C6H5 (benzyl), H3CCO (acetyl) or C19H15 (Triphenylmethyl),
- with each R' being independently from any other R a Ci to C4 alky I
- each PGA independently of any other PGA is a carboxylic protecting group selected from CH2CHCH2 (allyl), THP (tetrahydropyranyl), SiR'3 (trialkylsilicon), or C4H9 (f-Butyl), CH2C6H5 (benzyl) or Ci9H15 (Triphenylmethyl), - with each R' being independently from any other R a Ci to
C4 alky I
- each PGN independently of any other PGN is a amino protecting group selected from t-Butyloxycarbonyl (Boc), (CO)OCH2C6H5 (benzyloxycarbonyl) or Allyloxycarbonyl (Alloc),
M is -NO2 or -N3, wherein M is in particular NO2
each COact independently from any other COact is acyl fluorid, acyl chloride, benzotriazole esters or carbodiimide esters, generated by use of the carboxylic acid and coupling agents such as Benzotriazolyloxytris-(dimethylamino)-phosphonium hexafluoro- phosphat (BOB), Benzotriazol-1 -yl-oxy-tripyrrolidino-phosphonium hexafluorophosphate (pyBOP), N,N,N',N'-Tetramethyl-0-(1 H- benzo-triazol-1 -yl)uronium hexafluorophosphate (HBTU), (0-(7- azabenzotriazol-1 -yl)-/V,/V,/V,/V-tetramethyluronium hexafluorophosphate) (HATU), Λ/,/V-Di-cyclohexylcarbodiimide (DCC), Λ/,/V- Di-isopropylcarbodiimide (DIC), 1 -Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC).
Wherever alternatives for single separable features such as, for example, a moiety R or R2 or R3 a medical indication specifying a particular pathogen or a particular synthetic route are laid out herein as "embodiments", it is to be understood that such alternatives may be combined freely to form discrete embodiments of the invention disclosed herein.
Scheme 14 depicts a general reaction pathway to the compound beta albicidin from the compound (c-d) over (b-c-d) to compound (b-c-d-e-f) and the unprotected (a-b-c-d-e-f).
Figure imgf000313_0001
Figure imgf000313_0002
Figure imgf000313_0003
Alternatively, instead of using a reaction between (FN-c-COOH) and (H2N-d) a reaction between (C-COOH) respectively (c-COact) and (H2N-d) may be applied, wherein the CO(NH2) moiety of R2 of building block c is protected (CO)NPGN.
Scheme 15 depicts a reaction pathway to the compound (b-c-d) and R2 of compound (b-c-d) bein CN.
Figure imgf000314_0001
nicht in der SI
SnCI2*2H20 EtOH, 60 °C
1 h, 79 %
Figure imgf000314_0002
Figure imgf000314_0003
4 M HCI/Dioxane RT, 6 h, quant.
Figure imgf000314_0004
Scheme 15 Scheme 16 depicts a reaction pathway to beta-Albicidin from the compound (b-c-d) over the compound (b-c-d-e-f) to the unprotected compound (a-b-c-d-e-f).
Figure imgf000315_0001
nicht in der SI
Figure imgf000315_0002
Scheme 16 Scheme 17 depicts a reaction pathway to beta-Albicidin from the compound (d-e) over the compound (d-e-f), (c-d-e-f) to the unprotected compound (a-b-c-d-e-f).
OAllyl 0 C| OAllyl
Figure imgf000316_0001
Figure imgf000316_0002
Figure imgf000316_0003
Scheme 17
It is understood that the compound Carbamoyl-Albicidin can be produced according to a similar reactions pathway as depicted in schemes 14 to 17, whereby the CO(NH2) moiety of building block a is protected ((CO)NPGN) until the global deprotection.
Figure imgf000317_0001
Scheme 18
Furthermore, the compound Asn-Albicidin can be produced according to a similar reactions pathway as depicted in schemes 14 to 17, by using a reaction between (C-COOH) respectively (c-COact) and (H2N-d), wherein the CO(NH2) moiety of R2 of building block c is protected (CO)NPGN. The same applies to the compound Carbamoyl-Asn-Albicidin, whereby additionally the CO(NH2) moiety of building block a is protected ((CO)NPGN) until the global deprotection. It is understood that the compounds Asn-Albicidin, Carbamoyl-Albicidin, Carbamoyl-Asn- Albicidin, beta-OMe-Albicidin, Asn-OMe-Albicidin, Carbamoyl-OMe-Albicidin or Carbamoyl- OMe-Asn-Albicidin are producible according to a similar pathway as depicted in the schemes 14 to 17, whereby the L building block c comprises the respective substituents R\ R2 and R3.
It is further understood that the compounds Enantio-beta-Albicidin, Enantio-Asn-Albicidin, Enantio-Carbamoyl-Albicidin, Enantio-Carbamoyl-Asn-Albicidin, Enantio-beta-OMe-Albicidin, Enantio-Asn-OMe-Albicidin, Enantio-Carbamoyl-OMe-Albicidin or Enantio-OMe-Carbamoyl- Asn-Albicidin are producible according to a similar pathway as depicted in the schemes 14 to 17, whereby instead of a L building block c moiety a D building block c moiety is used or generated.
These schemes are only exemplary. Different protecting groups, activations, deprotection and combinations of the respective building blocks may be used. Reference is made in particular to the detailed description und specifically mentioned reagents hereinbefore and hereinafter.
It is further possible to transform one of the above mentioned albicidin compounds (or the respective intermediates) in another. For example is it possible to remove selectively the PGH protecting group of the building block a of the compound (a-b-c-d-e-f) and convert the OH- moiety in a carbamoyl-moiety, wherein subsequently the, e.g. Pd-labile, remaining protecting groups will be removed afterwards yielding another albicidin compound (conversion of e.g. beta-Albicidin to Carbamoyl-Albicidin; see scheme 5). Alternatively the beta-Albacidin may be converted to the Asn-albicidin, as described below. Further conversions are also possible and are part of the invention.
Synthesis of Asn-Albicidin from Albicidin
Albicidin (1 .2 mg) is dissolved in 0.5 mL THF under argon atmosphere at room temperature 21 <Ό. Then one equivalent of an aqueous solution of LiOH (1 mg/mL) is slowly added via a syringe pump. The resulting suspension is stirred at room temperature for 20 min. Stirring is continued for 3 h at room temperature, the process of hydrolysis is controlled by ESI-mass spectrometry. The organic solvent is removed under reduced pressure and EtOAc is added. The mixture is washed successively with saturated NaHC03, water and brine. The organic solvent is dried over Na2S04, filtered and removed under reduced pressure. The product is purified by column chromatography.
Further possible synthetic routes for albicidin are depict in the following schemes 19 and 24.
Figure imgf000319_0001
Allyliodid
K2CO3 K2C03
Figure imgf000319_0002
NaCi02 SiiCI2*2H20
Figure imgf000319_0003
Allyliodid K2C03
Figure imgf000319_0004
Scheme 19
1,SOCI2
Figure imgf000320_0001
Scheme 20
Figure imgf000321_0001
Scheme 21
Figure imgf000322_0001
Scheme 22
Figure imgf000323_0001
PG = protecting group Scheme 23
Figure imgf000323_0002
Scheme 24 The spectral analysis of the albicidin derivatives of formula 2 obtained by the just described method is depicted in the Figures 1 -10 described in detail further below.
General synthetic methods and procedures as applied in the present case are described in the following.
General procedure for synthesis of cinnamic acids
Method A
The aldehyde (1 .00 eq) and the malonic acid (2.00 eq) were dissolved in pyridine and piperidine (2.00 eq) was added. The mixture was stirred at 100 °C for 16 h. After cooling down to room temperature the reaction mixture was poured onto cone. HCI on ice. The precipitated cinnamic acid was filtered and dried in vacuo.
Method B
To a stirred solution of the aldehyde (1 .50 eq) and propanoic acid (1 .00 eq) in dry THF was slowly added TiCU (2.00 eq) at 0 °C. The mixture was stirred for 30 min and TEA (4.00 eq) was added. The reaction was allowed to warm up to room temperature and stirred for an additional 48 h. The reaction was quenched with water and the aqueous layer was extracted 3 x with DCM. The combined organic layers were dried over Na2S04 and the solvent was removed. The crude product was chromatographically purified.
Method C
A mixture of the aldehyde/ketone (1 .00 eq), malonic acid (2.00 eq), SnCI2-H20 (0.50 eq) and pyridine (2.00 eq) were stirred at 80 °C for 72 h. The mixture was filtered through a pad of celite and the solvent was evaporated. The crude product was chromatographically purified.
Several derivatives of cinnamic acid obtained by at least one of the above described methods are depicted below.
Figure imgf000325_0001
Figure imgf000325_0002
Introduction of an Allv rotectina group
The cinnamic acid (1 .0 eq) was dissolved in DMF and Allylbromide (3.0 eq) and K2C03 (3.0 eq) was added. The mixture was stirred at room temperature for 16 h. EtOAc was added and the organic layer was washed with H20 and brine. After drying over Na2S04 the solvent was evaporated. The residue was purified via silica gel column chromatography.
Allyl deprotection
KOH (2.0 eq) was dissolved in MeOH and added to the protected cinnamic acid. After stirring at room temperature for 12 h the mixture was acidified with cone. HCI. The precipitate was collected and dried in vacuo. If no precipitate was formed the MeOH was removed under reduced pressure and the residue was dissolved again in H20. The product was extracted with EtOAc. After drying the organic layer over Na2S04 the solvent was removed and the product dried in vacuo. General procedure for coupling of an acid partner with an amino partner :
Method A
Bis-(trichloromethyl)carbonate (1 .2 eq) and acid partner (3.5 eq) are dissolved in dry THF under argon atmosphere. 2,4,6-Collidine (8.0 eq) is added slowly via a syringe pump. The resulting suspension is stirred at room temperature for 20 min and a solution of the amino partner (1 ; 1 .0 eq) and DIPEA (10.0 eq) in dry THF is added. Stirring is continued for 3 h at room temperature and the reaction is quenched by addition of water. The organic solvent is removed under reduced pressure and EtOAc is added. The mixture is washed successively with saturated NaHC03, water and brine. The organic solvent is dried over Na2S04, filtered and removed under reduced pressure. The product is purified by crystallisation and column chromatography if necessary (TLC control, HPLC control).
Method B
The acid partner (1 eq) is refluxed in SOCI2 for 2h. The solvent is removed under reduced pressure and traces of SOCI2 are removed by coevaporation with toluene. The amino partner (1 , 1 eq) and a base (e. g. DIPEA, 5 eq) in an organic solvent (e. g. THF, c = 0.2 M) are added and the mixture is stirred for 12-16 h. After completion of the reaction (TLC control), the solvent is removed under reduced pressure and the residue is diluted with EtOAc. The organic layer is washed successively with saturated NaHC03, HCI (5 %), water and brine. After drying over Na2S04 and filtration the product is isolated by column chromatography or crystallisation.
Method C
Commercially available acid chlorides (carboxylic acid chloride or sulfonic acid chloride; 3 eq) are added to a solution of DIPEA (5 eq) and the amino partner (1 , 1 eq). The solution is stirred for 16 h at room temperature and quenched by the addition of water. The organic solvent is removed under reduced pressure and the residue diluted with EtOAc. The organic layer is washed successively with saturated NaHC03, HCI (5 %), water and brine. After drying over Na2S04 and filtration the product is isolated by column chromatography or crystallisation.
General procedure for coupling an isocyanate for the synthesis of compounds including an urea moiety:
The amine (1 eq) was dissolved in dry THF under an atmosphere of argon. Isocyanate (5 eq) was added and after stirring for 16 h the solvent was removed under reduced pressure. The product was isolated by column chromatography or crystallisation.
General procedure for reductive amination: Free amine (1 .0 eq) and aldehyde (1 .0 eq) were dissolved in MeOH and acetic acid (3.5 eq) was added. To this solution NaBH3CN (1 .2 eq) was added and the mixture was stirred for 16 h at room temperature. The reaction mixture was quenched with saturated NaHC03 solution and extracted with EtOAc. The organic solvent was dried over Na2S04, filtered and removed under reduced pressure. The residue was dissolved in 4 N HCI in dioxane. After 5 h of stirring at room temperature the organic solvent was removed under reduced pressure. The residue was dissolved in 10% NaHC03 and filtrated. Acidification with cone. HCI precipitated the pure carboxylic acid which was isolated by filtration.
General procedure for synthesizing amine compounds
Carboxylic acid (5 eq) and triethylamine (10 eq) were dissolved in dry DMF HATU (5 eq) was added and the mixture was stirred for 60 min. The amine, dissolved in dry DMF, was added dropwise and the mixture was stirred for 16 h at room temperature. The mixture was diluted with EtOAc and washed successively with brine (3 x), 1 N HCI (2 x) and saturated NaHC03 (2 x) The organic solvent was dried over Na2S04, filtered and removed under reduced pressure. The product was purified by column chromatography or crystallisation.
General procedure for converting a nitro group into an amine:
The nitro compound (1 eq) is dissolved in EtOH and SnCI2 *2H20 (5 eq) and the reaction mixture is stirred at 60 'C until the starting material has disappeared (TLC- and LCMS- monitoring, approximately 4-6 h). The solvent is removed under reduced pressure and the residue diluted with EtOAc. After addition of NaHC03 (saturated) and separation of the phases, the aqueous phase is further extracted with EtOAc (2 x). The combined organic layers are washed with brine (1 x), dried over Na2S04 and filtered. After removing the solvent under reduced pressure, the product was isolated by column chromatography or
crystallisation.
General procedure for coupling of an aldehyde partner with an amino partner under reductive conditions:
The amine (1 .0 eq) and aldehyde (1 .0 eq) were dissolved in dry THF under argon atmosphere and a catalytic amount of acetic acid was added. After stirring for 60 min at room tempearature NaBH3CN (1 .3 eq) was added. The reaction mixture was stirred for 3 h at room temperature and another 1 .3 eq of NaBH3CN was added and the mixture was stirred for 16 h at room temperature. The reaction was quenched by addition of 1 N HCI and extracted three times with EtOAc. The organic solvent was dried over Na2S04, filtered and removed under reduced pressure. The product was purified by column chromatography or crystallisation.
General procedure for removal of protection groups: A fully protected derivative of the compound according to the formula 1 (1 .0 eq) was dissolved in dry THF under argon atmosphere and exclusion of light. Phenylsilane (8.0 eq) and Pd[P(Ph)3]4 (0.5 eq) were added and the reaction mixture was stirred for 10 h at room temperature. AcOH was added, the solvent was removed under reduced pressure and the sample was freeze dried. Purification was achieved by crystallization or preparative HPLC.
General procedure for providing deuterium atoms in the structure:
The provision of deuterium instead of hydrogen in a structure is basic knowledge for the expert in the field. For example, deuterium-containing compounds may be synthesized according to known methods (e.g. David S. Wisharta, Brian D. Sykesa, Frederic M. Richards, Biochimica et Biophysica Acta - Protein Structure and Molecular Enzymology, Volume 1 164, Issue 1 , 1993, Pages 36-46). Furthermore, the respective intermediates may comprise one or more deuterium instead of hydrogen or only deuterium. Thus, by applying the synthesis pathways as discussed above compounds characterized by the general formula 1 are produced, which comprise at least one deuterium in their structure. Such intermediates may be purchased or may be produced to known literature procedures.
Coupling reactions:
Reaction conditions for coupling primary amines or aryl amines with carboxylic acids to yield amide linkages are known to those of ordinary skill in the art and may be found in any compendium of standard synthetic methods or literature related to the synthesis of peptides and proteins. See e.g., March, J., Advanced Organic Chemistry; Reactions, Mechanisms and Structure, 4th ed., 1992; Larock, Comprehensive Organic Transformations, VCH, New York, 1999; Bodanzsky, Principles of Peptide Synthesis, Springer Verlag, 1984; Bodanzsky, Practice of Peptide Synthesis, Springer Verlag, 1984; Lloyd-Williams et al., Chemical Approaches to the Synthesis of Peptides and Proteins, CRC Press, 1997 (see especially pp. 105-1 14); and Atherton & Sheppard, Solid Phase Peptide Synthesis: A Practical Approach, IRL Press, 1989). Alternative reactive groups can be utilized, such as compounds exemplified herein after or discussed above, in methods known in the art or described hereinafter.
Protecting groups
Protection of the /V-terminus of a building block with acid labile protecting groups
Figure imgf000328_0001
The amine (1 eq) and di-te/t-butyl dicarbonate (1 .5 eq) are dissolved in a solvent (e. g. DCM; c = 0.2 M) and a base (e. g. NEt3, 3 eq) is added. The mixture is stirred at room temperature for 16 h. After removing the solvent under reduced pressure the product is isolated after column chromatography or crystallisation.
Protection of the /V-terminus of a building block methoxybenzylcarbamate protecting group
Figure imgf000329_0001
The amine (1 eq) and a base (e. g. NEt3, 1 .1 eq) are dissolved in a solvent (e. g. H20, c = 0.2 M) and Moz-ONC(CN)Ph (1 eq) is added in a solvent (e. g. dioxane, c = 0.1 M). The mixture is stirred at room temperature for 6-12 h and water is added. The mixture is washed with EtOAc and the aqueous layer is adjusted to pH 2 (5 % HCI) and extracted with EtOAc. After drying over Na2S04 and filtration the organic solvent is removed under reduced pressure. The product is isolated after column chromatography or crystallisation.
Protection of /V-terminus with Pd-labile protecting groups
Figure imgf000329_0002
The amine (1 eq) and a base (e. g. pyridine, 3 eq) are dissolved in a solvent (e. g. DCM; c = 0.2 M) and slowly allyloxycarbonyl chloride (2 eq) is added. Stirring is continued for 16 h and the reaction mixture is washed successively with HCI (5 %) and brine. After drying over Na2S04, filtration and removal of the solvent the product is isolated by column chromatography or crystallisation.
Protection of phenols with acid labile protecting groups:
Figure imgf000329_0003
BF OEt?
R-OH H3PQ4 , R J<
solvent υ
The phenol (1 eq) is dissolved in a solvent (e. g. DCM; c = 0.2 M) and cooled to -75<C. H3P04 and BF3 *OEt2 and isobutylene (excess) are added and the mixture is stirred 16 h at room temperature. After quenching the reaction by the addition of NH4OH (2 N) and extraction with organic solvent (e. g. DCM) the product is isolated by column chromatography or crystallisation.
Protection of phenols with the methoxybenzyl protecting group: PMB-CI
Figure imgf000330_0001
so ven
The phenol (1 eq), para-methoxybenzyl chloride (PMB-CI; 1 .1 eq) l~ (e. g. Bu4N-l, 1 .1 eq) and a base (e. g. K2C03, 1 .5 eq) are dissolved in a solvent (e. g. acetone; c = 0.2 M) and heated to 55 °C for 6-12h. The solvent is removed under reduced pressure and the residue diluted with EtOAc. The organic phase is washed successively with saturated NaHC03, HCI (5 %) and brine. After drying over Na2S04 and filtration the organic solvent is removed under reduced pressure. The product is isolated by column chromatography or crystallisation.
Protection of phenols with Pd-labile protecting groups:
Figure imgf000330_0002
solvent
The phenol (1 eq) is dissolved in a solvent (e. g. DMF, c = 0.2 M) and a base (e. g. K2C03, 3 eq) is added. Allylhalogenide (1 .5 eq) is added via a syringe pump and stirring is continued at room temperature for 12 h. The solvent is removed under reduced pressure and the product is isolated by column chromatography or crystallisation.
Protection of carboxylic acids with acid labile protecting groups:
Figure imgf000330_0003
O BF3OEt2 0
U H3PQ4 , M
R OH solvent R Ο""^-
The carboxylic acid (1 eq) is dissolved in a solvent (e. g. DCM; c = 0.2 M) and cooled to -75^. H3PO4 and BF3 *OEt2 and isobutylene (excess) are added and the mixture is stirred 16 h at room temperature. After quenching the reaction by the addition of NH4OH (2 N) and extraction with organic solvent (e. g. DCM) the product is isolated by column chromatography or crystallisation.
Protection of carboxylic acids with 4-methoxybenzyl protecting groups:
R
Figure imgf000330_0004
The carboxylic acid (1 eq) and a base (e. g. NEt3, 1 eq) are dissolved in a solvent (e. g. DCM c = 0.2 M) and cooled to O 'C. PMB-Br (1 eq) is added and the mixture is stirred 24 h at room temperature. The solution is washed successively with water, saturated NaHC03, water and brine. After drying over Na2S04 and filtration the organic solvent is removed under reduced pressure. The product is isolated by column chromatography or crystallisation.
Deprotection
Deprotection of acid labile protecting groups of the /V-terminus, of phenols and of carboxylic acids
Figure imgf000331_0001
The protected amine, phenol or acid is dissolved in an acid (e. g. TFA - 5-95 % in DCM) and scavenger (e. g. triethylsilane, 3 eq) is added. Stirring is continued for 12 h (TLC control) and the solvent is removed under reduced pressure. Purification is performed by column chromatography or crystallisation.
Deprotection of Pd-labile protecting groups of the /V-terminus of phenols and f the carboxylic acids
Figure imgf000331_0002
Pd°
ssecaavenger » OH
solvent
Figure imgf000331_0003
The protected amine (carbamate), phenol (ether) or carboxylic acid (ester) (1 eq) is dissolved in a solvent (e. g. THF), then scavenger (e. g. phenylsilane, 1 .5 eq) and Pd° (e. g. Pd[P(Ph)3]4, 0.1 eq) are added under argon or nitrogen atmosphere and the exclusion of light. Stirring is continued for 12 h at room temperature and the solvent is removed under reduced pressure. Column chromatography or crystallisation yields the pure product.
While the method illustrated above using acid or Palladium labile protecting groups, a person having ordinary skill in the art will recognize that other protecting groups may be employed. Groups suitable for protecting a wide variety of different functionalities, as well as conditions for their removal, are well known and will be apparent to those of ordinary skill in the art. Specific guidance for selectively protecting a wide variety of functionalities may be found, for example, in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd edition, 1999 ("Greene & Wuts"). Preferred protecting groups are those that may be easily removed. Preferred groups for protecting primary amines and aryl amines are tert-butyloxycarbonyl ("t- Boc"), allyloxycarbonyl (Alloc), 9-fluorenylmethoxycarbonyl ("Fmoc"), para-methoxybenzyl carbamate (Moz) and benzyloxycarbonyl ("Z").
Preferred groups for protecting carboxylic acids are tert-butyl ("t-Bu"), allyl (All), 9- fluorenylmethyl ("Fm"), para-methoxybenzyl (PMB) and benzyl ("Bzl").
Preferred groups for protecting phenols are tert-butyl ("t-Bu"), allyl (All), para-methoxybenzyl (PMB) and benzyl ("Bzl").
Preferred groups for protecting amides are 9-xanthenyl ("Xan"), Trityl (Trt), 4-Methyltrityl (Mtt) and benzyl ("Bzl").
General methods for peptide coupling
Coupling reaction with Bis-(trichloromethyl)carbonate (BTC)
Figure imgf000332_0001
Bis-(trichloromethyl)carbonate (1 .2 eq) and carboxylic acid (3.5 eq) are dissolved in dry organic solvent (e. g. THF) under argon atmosphere. 2,4,6-Collidine (8.0 eq) is added slowly via syringe. The resulting suspension is stirred at room temperature for 20 min and a solution of the amine (1 .0 eq), DIPEA (10.0 eq) in dry THF is added. Stirring is continued for 3 h at room temperature and the reaction is quenched by addition of water. The organic solvent is removed under reduced pressure and EtOAc is added. The mixture is washed successively with saturated NaHC03, water and brine. The organic solvent is dried over Na2S04, filtered and removed under reduced pressure. The product is purified by column chromatography or crystallisation.
Coupling reaction with (0-(7-azabenzotriazol-1 -yl)-/V,/V,/V,/V-tetramethyluronium
hexafluorophosphate) (HATU)
Figure imgf000333_0001
Carboxylic acid (1 .1 eq) is dissolved in dry organic solvent (e. g. DMF) and cooled to O'C. DIPEA (3 eq) and HATU (2 eq) is added. After five minutes the amine (1 eq) is added and stirring was continued for 12 h at room temperature. EtOAc is added and the mixture is washed successively with brine (3 x), saturated NaHC03, 5% HCI, water and brine. After drying over Na2S04 and filtration the solvent is removed under reduced pressure. The product is purified by column chromatography or crystallisation.
While the method illustrated above using a peptide coupling in the presence of BTC or HATU, a person having ordinary skill in the art will recognize that other coupling methods may be employed. Peptide coupling methods are well known and will be apparent to those of ordinary skill in the art.
In some embodiments, masked functional group M is NO2 or N3. The reduction of the masked functional group M is carried out under conditions which are state of the art and can be performed by a chemist experienced in the state of the art. The reduction of the nitro group and of the azide group is not limited to the use of hydrogen gas in combination with a catalyst.
The azide or the nitro-group containing compound is dissolved in appropriate solvents as ethyl acetate, acetonitrile, alcohols. A catalyst (Pd, Pt02, 10%Pd/C) is added under 1 atm hydrogen gas (H2). The reaction stirred preferably at room temperature may be performed between 1 h and 20h. The application of higher or lower reaction temperatures as well as elevated pressure of hydrogen gas may be applied.
It is understood that other methods exist which are state of the art for reduction: Applying Fe/CaCI2 enables the reduction of nitroarenes by catalytic transfer hydrogenation (S. Chandrappa, T. Vinaya, T. Ramakrishnappa, K. S. Rangappa, Synlett, 2010, 3019-3022).
GENERAL METHODS
Materials:
Commercially available reagents were used throughout the syntheses, without further purification unless otherwise stated; solvents were dried using standard procedures. Unless otherwise specified, reactions were performed under an inert atmosphere of dry nitrogen or argon using absolute solvents purchased from Acros or freshly taken over the PureSolv (Innovative Technologies, USA).. Amino acids and coupling reagents were obtained from either IRIS (Marktredwitz, Germany), Novabiochem (Darmstadt, Germany) or Bachem (Basel, Switzerland). Analytical thin layer chromatography was carried out using aluminium- backed plate coated with Merck Kieselgel 60 GF254. Plates were visualized under UV light (at □ = 254 and /or 360 nm) and stained with KMn04 solution or ninhydrin solution. Flash chromatography was carried out using silica gel 60 (Merck, Darmstadt, Germany). Column chromatography was performed on silica gel (0.04 - 0.063 mm) purchased from MACHERY- NAGEL GmbH & Co. KG.
Instrumentation and methods:
1H and 13C NMR spectra were recorded using Bruker Avance 400, DPX 500, 700 MHz instruments (Bruker, Karlsruhe, Germany) (corresponding 3C frequencies are 100, 125, 175 MHz); J values are in Hz. The 3C signals assigned from APT, HSQC and HMBC. Data are reported as parts per million (ppm) downfield shift from tetramethylsilane (TMS) using residual solvent peaks of chloroform (CDCI3, 7.26 ppm and 77.2 ppm) or dimethyl sulfoxide (DMSO-c 6, 2.50 ppm and 39.5 ppm) as internal references. Chemical shifts (δ, ppm), multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant (J Hz), relative integrals and assignment are quoted where possible.
LCMS/high-resolution mass spectra were recorded on a Orbitrap high resolution mass spectrometer using electrospray ionization (ESI) in positive mode unless otherwise specified.
Analytical Thin Layer Chromatography (TLC) was performed using pre-prepared plates (Merck Kieselgel 60, 0.25 mm F254) using UV light (□ = 254 nm) or ninhydrin stain for visualization. Flash column chromatography was performed using 230-400 mesh Kieselgel 60 silica gel using a mobile phase of the indicated solvents expressed as volume/volume ratios (v/v).
HPLC measurements were performed on a Agilent 1 100-HPLC with diode array detection (Agilent, Waldbronn, Germany). Unless otherwise noted the following parameters have been used; Coulmn: Luna C18, 100 A, 100x4.6 mm, 5 urn. Gradient: H20/ACN (A/B) + 0.1 % HCOOH, starting with 5% B to 100% B in 10 min, holding 2 min 100% B, reconditioning zo 5% B in 3 min, with a constant flow rate of 1 mL/min
HPLC-MS/high-resolution mass spectra were recorded on a Exactive Orbitrap high resolution mass spectrometer (Thermo Scientific, Bremen, Germany) using electrospray ionization (ESI) in positive mode unless otherwise specified. Column: Thermo Hypersil-Gold, 50 x 2.1 mm, 5 urn. Gradient: H20/MeOH (A B) + 0.1 % HCOOH, starting with 5 %B to 100%B in 6 min, holding for 4 min at 100% B, with a constant flow rate of 0.25 mL/min.
MS/MS experiments were performed on a ESI-Triple-Quadrupol-MS, 6460 series (Agilent Technologies, Waldbronn, Germany). HPLC-ESI-MS was performed on a LTQ Orbitrap XL (Thermo Fisher Scientific, Waltham, USA) mass spectrometer and an using a Grom-Sil-120-ODS-4-HE column (Grace, Maryland, USA), length 50 mm, i.d. 2 mm, particle size 3 μηι.
Gradient:
Eluent 1 : H20 + 0.1 % HC02H
Eluent 2: MeCN + 0.1 % HC02H
0 - 1 0 min : Eluent 2: 20% to 100%
10 - 13 min: Eluent 2: 100 %
13 - 17 min: Eluent 2: 20 %
flow: 0.3 ml_ / min
Circular dichroism (CD) spectra were recorded on a JASCO J-815 CD spectrometer (JASCO, Tokyo, Japan). The parameters are the following: constant temperature at 20 °C, cell length 10 mm, range of measurement 700-200 nm, data intervall 0.1 mm, scanning speed 1 00 nm/min. Each CD-spectrum was accumulated four times. Unless otherwise noted all spectra presented were recorded in DMSO as a solvent. CD-spectra of the albicidins were obtained after subtraction of the blank spectrum (DMSO).
Preparative/sem /preparative HPLC for purification was performed with a system from Agilent 1260 Infinity (Agilent, Santa Clara, USA) using a Ci8 - P - Column (Agilent, Santa Clara, USA), length 250 mm, i. d. 21 .2 mm, particle size 1 0 μηι.
Isolation protocol
Isolation protocol was established, testing bioactive fractions by the agar diffusion assay with E. coll. To the fermentation broth of X. axonopodis pv. vesicatoria XAD-7 was added to absorb metabolites from the liquid media. Albicidins were purified from XAD-7 with a MeOH-step- gradient (20%), separating undesirable crude material. The elution of albicidins was achieved with 100% MeOH. The eluted fraction was concentrated in a Genevac Speedvac (Great Britain, Ipswich) and dissolved in MeOH. After centrifugation, the supernatant was used for further purification by preparative HPLC-DAD (at λ = 310 nm) on a C18 reversed phase column using a linear MeOH-gradient. Albicidins eluted at the Rt = 33 min. The freeze-dried material was dissolved in 44 % THF + 1 % CH3COOH and further purified with HPLC-DAD (at 31 0 nm) using isocratic conditions and H20/THF as the solvent system on a polymeric reversed phase (PRP) column. Six albicidins eluted under this conditions (Figure 10). After a last third step albicidins were obtained as white solids. The conditions are shown in Table 1 .
Figure imgf000336_0001
Table 1 : Chromatographic conditions for purification of albicidins with HPLC-DAD.
Liquid cultures of heterologous host Xanthomonas axonopodis pv. vesicatoria were prepared in plastic falcon tubes of 500 mL, to avoid adsorption sticking of albicidins to the glass surfaces. Cultures were grown under agitation at 28 'C, for 5 days, in 72 tubes each containing 200 mL of a modified XaBMM (used for wild-type)/XVM2B (previously used for heterologous host) medium, now called XVM3B medium (see table 2).
Figure imgf000337_0001
Table 2: Medium composition per liter for the production of albicidins in X. axonopodis pv. vesicatoria
Unless otherwise specified, reactions were performed under an inert atmosphere of dry nitrogen using absolute solvents, freshly taken over the PureSolv (Innovative Technologies, USA) or purchased from Acros. Amino acids, coupling reagents were obtained from either IRIS (Marktredwitz, Germany), Novabiochem (Darmstadt, Germany) or Bachem (Basel, Switzerland).
Preparation of the test substrate
The dry compounds were dissolved in DMSO (1 mg/ml) and the so obtained stock solution was diluted with sterilized Millipore water 1 :10 and 1 :100
Reference agents:
Apramycin 1 mg/ml
Chloramphenicol 1 mg/ml DMSO 100%
H20
Preparation of the inoculum
20 μΙ of cryo stock of each strain were inoculated to 20 ml of Mueller-Hinton medium and grown overnight at 30 'Ό or 37<Ό on a vertical shaker with 160 rpm . The inoculum for the test was adjusted by the 0.5 McFarland Standard (OD625 from 0.08 to 0.1 )
Strains:
Staphylococcus aureus DSM 2569 [gram. Pos.] Medium: MHB / 37<Ό
Pseudomonas aeruginosa DSM1 1 17 [gram. Neg.] Medium: MHB / 37<Ό
Bacillus subtilis DSM10 [gram. Pos.] Medium: MHB / 30 <€
Micrococcus luteus DSM1790 [gram. Pos.] Medium: MHB / 37<€
Escherichia coli DH5a [gram. Neg.] Medium: MHB / 37<€
Escherichia coli albi-res (Montpellier) [gram. Neg.] Medium: MHB / 37<€
Bacillus megaterium [gram. Pos.] Medium: MHB / 30°C
Mycobacterium phlei DSM 750 [gram. Pos.] Medium: MHB / 30°C
Escherichia coli K12 (W1130) [gram. Neg.] Medium: MHB / 37°C
DSM 10, 1 1 17 1790 2569 are the order numbers of the "Leibniz-lnstitut DSMZ- Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH", one of the largest biological resource centres worldwide (www.dsmz.de)
Preparation of the test agar plates
Every plate is prepared by pouring 10ml Mueller-Hinton agar into standard petri dishes (diam 94mm). The so obtained Mueller-Hinton plates are overlayed with 4ml Mueller-Hinton soft agar containing 100μΙ suspension of the test strain.
After the soft agar turned solid, sterile susceptibility test discs were circular placed on the agar and on every test disc 10μΙ compound was added. Each concentration is tested in triplicate. The agar dishes were incubated for 18 hours at a temperature of 30 'Ό or 37 °C. Results are obtained by measuring the diameter of inhibition area around each test disc.
EN-ISO standard test:
Furthermore, compounds were tested against the following bacteria Escherichia coli (ATCC 25922, 100-2-49 and 100-2-56 ),
Salmonella enteritidis (PEG-10-3-58),
Pseudomonas aeruginosa (ATCC 27853 and PEG-10-2-61 )
Staphylococcus aureus (ATCC 29213 and PEG 10-38-22)
according to EN-ISO standard (ISO 20776-1 : 2006. Clinical laboratory testing and in vitro diagnostic test systems ~ Susceptibility testing of infectious agents and evaluation of performance of antimicrobial susceptibility test devices - Part 1 :Reference method for testing the in vitro activity of antimicrobial agents against rapidly growing aerobic bacteria involved in infectious diseases; German version EN ISO 20776-1 :2006. Beuth-Verlag, Berlin).
ATCC 25922, 27853, 29213 are the order numbers of the "American Type Culture
Collection", a biological resource centre.
RESULTS
Characterisation of the natural occurring L-albicidin of the general formula (1 L):
The natural occurring L-albicidin of the general formula (1 L) were characterised by mass spectrometry (MS and MS2), CD spectroscopy and NMR spectroscopy (1 H, 13C) and the molecular formulas of the respective albicidin was determined (see e.g. Figure 2).
Purification of the albicidin compounds
The albicidin compounds were purified by column chromatography or crystallization.
Activity of the albicidin compounds
Results are obtained by determining the diameter of inhibition area around each test disc, which could be seen in table 1 .
Table: Antibacterial activity against selected strains. A = Albicidin; EA = Enantio-Albicidin ("-" no activity detected).
Figure imgf000339_0001
Figure imgf000340_0001
Test agar plates (active substance 1 mg/ml)
Control substance:
Natural albicidin showed in the same tests a diameter of inhibition of more than 1 cm.
Staphylococcus aureus DSM 2569:
Compounds 1 to 5, 7 to 12, 15, 16, 30 and 34 to 36 show a diameter of inhibition of more than 1 cm and more than 2 cm.
Micrococcus luteus DSM1790:
Compounds 1 to 5, 9 to 13, 16, 30, 36 and 44 show a diameter of inhibition of more than 1 cm and more than 2 cm.
Pseudomonas aeruginosa DSM1 1 17:
Compounds 1 to 5, 7„ 10 to 13, 26, 29, 30, 34, 35, 36, 43 and 44 show a diameter of inhibition of more than 1 cm or more than 2 cm.
Bacillus subtilis DSM10
Compounds 1 to 5, 7 to 16, 26, 29, 30, 34, 35, 36, 38 to 41 , 43 and 44 show a diameter of inhibition of more than 1 cm or more than 3,9 cm
Escherichia coli albi-res (Montpellier):
Compounds 1 to 5, 7 to 16, 26, 29, 30, 34, 35, 36, 38 to 41 , 43, 44 and 49 show a diameter of inhibition of more than 1 cm or more than 2 cm.
Escherichia coli DH5a:
Compounds 1 to 5, 8 to 13, 16, 30, 34, 35, 36 and 44 show a diameter of inhibition of more than 1 cm or more than 2 cm.
EN-ISO standard test:
Escherichia coli ATCC 25922, 100-2-49 and 100-2-56J;
Compounds 1 , 5, 16, 30, 35, 36 and 43 show an activity with good to very good MIC values (minimal inhibitory concentration).
Salmonella enteritidis (PEG-10-3-58): Compounds 1 , 5, 16, 30, 35, 36 and 43 show an activity with good to very good MIC values. Pseudomonas aeruginosa (ATCC 27853):
Compounds 1 , 5, 30, 35 and 36 show an activity with good to very good MIC values.
Pseudomonas aeruginosa (PEG-10-2-61 ):
Compounds 1 , 5 and 36 show an activity with good to very good MIC values.
Staphylococcus aureus (ATCC 29213)
Compounds 1 , 5, 30 and 36 show an activity with good to very good MIC values.
Staphylococcus aureus (PEG 10-38-22)
Compounds 1 , 5 and 36 show an activity with good to very good MIC values.
Several of the herein tested strains are of importance for development of antibacterial therapy, particularly due to their resistance breaking potential against ciprofloxacin.
The Infectious Diseases Society of America in the January 2009 highlighted the impact of the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species) as a group of particularly troublesome bacteria having the ability to "escape" the effects of current antimicrobial agents [Boucher HW, Talbot GH, Bradley JS, et al Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis
2009;48:1 -12.]. The bacterium E coli is the predominant etiologic pathogen for gram- negative infections and it represents a great total burden of disease. Livermore et al
[Livermore DM, Hope R, Brick G, Lillie M, Reynolds R. BSAC Working Parties on Resistance Surveillance. Non-susceptibility trends among Enterobacteriaceae from bacteraemias in the UK and Ireland, 2001-06. J Antimicrob Chemother 2008;62(Suppl 2):ii41 -54.] point out that E coli infections currently account for -20% of all cases of bacteraemia in the United Kingdom. This rivals the incidence of S. aureus infection and is nearly double that associated with any other pathogen. Ciprofloxacin is commonly used for urinary tract and intestinal infections (traveler's diarrhea), used to treat especially tenacious infections. Many bacteria have developed resistance to this drug in recent years, leaving it significantly less effective than it would have been otherwise. Numerous pathogens, including Staphylococcus aureus, enterococci, Streptococcus pyogenes and Klebsiella pneumoniae (quinolone-resistant) now exhibit resistance worldwide. SYNTHESIS AND CHARACTERIZATION
Compound 1
Figure imgf000342_0001
Chemical Formula: C^HsyFNgO-i -i
Exact Mass: 844,2504
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. (E)-3-(4-fluorophenyl)-2-methylacrylic acid (3.5 eq, 0.305 mmol, 55 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (76 mg, 91 %). The oil (1 eq, 0.069 mmol, 67 mg) and phenylsilane (8 eq, 0.556 mmol, 0.069 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.035 mmol, 40 mg) was added and the mixture was stirred 12 h at room
temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (18 mg, 31 %). H-NMR (DMSO-ds, 500 MHz): δ [ppm] 2.10 (s, 3H), 3.06 (dd, Ji = 16.84 Hz, J2 = 8.72 Hz, 1 H), 3.15 (m, 1 H), 3.77 (s, 1 H), 3.90 (s, 1 H), 4.98 (m, 1 H), 7.28 (t, J = 8.82 Hz, 2H), 7.33 (s, 1 H), 7.55 (m, 4H), 7.79 (m, 3H), 7.84 (d, J = 8.72 Hz, 2H), 7.93 (d, J = 8.72 Hz, 2H), 8.00 (m, 3H), 9.02 (d, J = 7.53 Hz, 1 H), 9.68 (s, 1 H), 10.19 (s, 1 H), 10.56 (s, 1 H), 1 1 .13 (s, 1 H), 1 1 .52 (bs, 1 H).
HRMS (ESI): [M-H]" calculated: 843.2421
found: 843.2441 Compound 2
Chemical Formula: C44H38N60-i i
Exact Mass: 826,2599
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. (E)-2-methyl-3-phenylacrylic acid (3.5 eq, 0.305 mmol, 49 mg) was added, syn- Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (65 mg, 79 %). The oil (1 eq, 0.055 mmol, 52 mg) and phenylsilane (8 eq, 0.430 mmol, 0.054 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.027 mmol, 32 mg) was added and the mixture was stirred 12 h at room
temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (16 mg, 35 %).
H-NMR (DMSO-ds, 500 MHz): δ [ppm] 2.12 (s, 3H), 3.07 (dd, Ji = 16.84 Hz, J2 = 8.72 Hz, 1 H), 3.15 (m, 1 H), 3.77 (s, 3H), 3.91 (s, 3H), 4.98 (m, 1 H), 7.36 (m, 2H), 7.46 (m, 4H), 7.57 (m, 2H), 7.79 (m, 3H), 7.86 (d, J = 8.72 Hz, 2H), 7.93 (m, 2H), 7.98 (d, J = 8.52 Hz, 2H), 8.04 (d, J = 8.92 Hz, 1 H), 9.02 (d, J = 7.73 Hz, 1 H), 10.19 (s, 1 H), 10.57 (s, 1 H), 1 1 .16 (s, 1 H), 1 1 .52 (s, 1 H).
HRMS (ESI): [M-H]" calculated: 825.2515
found: 825.2533 Compound 3
Figure imgf000344_0001
Chemical Formula: C 3H36N60-| -i
Exact Mass: 812,2442
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. Cinnamic acid (3.5 eq, 0.305 mmol, 45 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (80 mg, 99 %). The oil (1 eq, 0.049 mmol, 46 mg) and phenylsilane (8 eq, 0.395 mmol, 0.049 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.025 mmol, 29 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (7 mg, 18 %). H-NMR (DMSO-ds, 500 MHz): δ [ppm] 3.06 (dd, Ji = 16.84 Hz, J2 = 8.72 Hz, 1 H), 3.15 (m, 1 H), 4.98 (m, 1 H), 6.85 (d, J = 15.66 Hz, 1 H), 7.43 (m, 3H), 7.60 (m, 5H), 7.80 (m, 5H), 7.93 (d, J = 8.72 Hz, 2H), 7.98 (d, J = 8.72 Hz, 2H), 8.05 (d, J = 8.92 Hz, 1 H), 9.02 (d, J = 7.73
Hz, 1 H), 9.68 (s, 1 H), 10.48 (s, 1 H), 10.55 (s, 1 H), 1 1 .16 (s, 1 H), 1 1 .51 (s, 1 H), 1 1 .58 (bs,
1 H).
HRMS (ESI): [M-H] calculated: 81 1 .2358
found: 81 1 .2373 Compound 4
Figure imgf000345_0001
Chemical Formula: 045^7^31^0! -!
Exact Mass: 894,2472
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. (E)-2-methyl-3-(4-(trifluoromethyl)phenyl)acrylic acid (3.5 eq, 0.305 mmol, 70 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (86 mg, 97 %). The oil (1 eq, 0.077 mmol, 78 mg) and phenylsilane (8 eq, 0.614 mmol, 0.076 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.038 mmol, 44 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (20 mg, 29 %). H-NMR (DMSO-ds, 400 MHz): δ [ppm] 2.12 (s, 3H), 3.06 (dd, Ji = 16.79 Hz, J2 = 8.73 Hz, 1 H), 3.15 (m, 1 H), 3.76 (s, 3H), 3.90 (s, 3H), 4.97 (m, 1 H), 7.39 (s, 1 H), 7.55 (m, 2H), 7.68 (d, J = 8.06 Hz, 2H), 7.79 (m, 5H), 7.85 (d, J = 8.60 Hz, 2H), 7.93 (m, 2H), 7.98 (d, J = 8.60 Hz, 2H), 8.03 (d, J = 8.87 Hz, 1 H), 9.04 (d, J = 7.52 Hz, 1 H), 9.70 (s, 1 H), 10.28 (s, 1 H), 10.58 (s, 1 H), 1 1 .16 (s, 1 H), 1 1 .54 (s, 1 H).
HRMS (ESI): [M-H]" calculated: 893.2389
found: 893.2410 Compound 5
Figure imgf000346_0001
Chemical Formula: C4 H36N6013
Exact Mass: 856,2340
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. (E)-3-(1 ,3-dihydroisobenzofuran-5-yl)acrylic acid (3.5 eq, 0.305 mmol, 59 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (56 mg, 66 %). The oil (1 eq, 0.057 mmol, 56 mg) and phenylsilane (8 eq, 0.460 mmol, 0.057 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.029 mmol, 33 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (10 mg, 20 %).
H-NMR (DMSO-ds, 700 MHz): δ [ppm] 3.05 (dd, Ji = 16.75 Hz, J2 = 8.82 Hz, 1 H), 3.14 (m,
1 H), 3.76 (s, 3H), 3.90 (s, 3H), 4.97 (m, 1 H), 6.08 (s, 2H), 6.67 (d, J= 15.66 Hz, 1 H), 6.98 (d, J = 7.93 Hz, 1 H), 7.15 (D, J = 7.93 Hz, 1 H), 7.19 (s, 1 H), 7.55 (m, 3H), 7.79 (m, 5H), 7.92 (d, J = 8.52 Hz, 2H), 7.97 (d, J = 8.72 Hz, 2H), 8.03 (d, J = 8.92 Hz, 1 H), 9.00 (d, J = 7.53 Hz, 1 H), 9.67 (s, 1 H), 10.37 (s, 1 H), 10.54 (s, 1 H), 1 1 .15 (s, 1 H), 1 1 .50 (s, 1 H), 1 1 .57 (bs, 1 H).
HRMS (ESI): [M+H]+ calculated 857.2413
found: 857.2422
[M+Na]+ calculated 879.2233
found: 879.2242 Compound 6
Figure imgf000347_0001
Chemical Formula: C 3H36N6012
Exact Mass: 828,2391
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. (E)-3-(4-(Allyloxy)phenyl)acrylic acid (3.5 eq, 0.305 mmol, 62 mg) was added, syn- Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (55 mg, 64 %). The oil (1 eq, 0.058 mmol, 57 mg) and phenylsilane (8 eq, 0.462 mmol, 0.057 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.029 mmol, 33 mg) was added and the mixture was stirred 12 h at room
temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (10 mg, 20 %). H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.07 (dd, Ji = 16.79 Hz, J2 = 8.73 Hz, 1 H), 3.16 (s, 1 H), 3.78 (s, 3H), 3.92 (s, 3H), 4.99 (m, 1 H), 6.64 (d, J = 15.58 Hz, 1 H), 6.84 (d, J = 8.33 Hz, 2H), 7.54 (m, 5H), 7.80 (m, 5H), 7.93 (d, J = 8.87 Hz, 2H), 7.99 (d, J = 8.87 Hz, 2H), 8.06 (d, J = 8.87 Hz, 1 H), 9.03 (d, J = 7.52 Hz, 1 H), 9.71 (s, 1 H), 9.98 (bs, 1 H), 10.37 (s, 1 H), 10.57 (s, 1 H), 1 1 .18 (s, 1 H), 1 1 .54 (s, 1 H), 1 1 .60 (bs, 1 H).
HRMS (ESI): [M-H]" calculated: 827.2307 found: 827.2331 Compound 7
Figure imgf000348_0001
Chemical Formula: C4iH34N60i2
Exact Mass: 802,2235
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. 4-(Allyloxy)benzoic acid (3.5 eq, 0.305 mmol, 67 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (58 mg, 69 %). The oil (1 eq, 0.058 mmol, 56 mg) and phenylsilane (8 eq, 0.466 mmol, 0.057 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.029 mmol, 34 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (19 mg, 41 %). H-NMR (DMSO-ds, 500 MHz): δ [ppm] 3.07 (dd, Ji = 16.65 Hz, J2 = 8.72 Hz, 1 H), 3.16 (m, 1 H), 3.77 (s, 3H), 3.90 (s, 3H), 4.98 (m, 1 H), 6.87 (d, J = 8.52 Hz, 2H), 7.57 (dd, Ji = 8.92 Hz, J2 = 4.56 Hz, 2H), 7.80 (m, 3H), 7.94 (m, 10H), 9.02 (d, J = 7.53 Hz, 1 H), 9.68 (s, 1 H), 10.16 (s, 1 H), 10.23 (s, 1 H), 10.59 (s, 1 H), 1 1 .14 (s, 1 H), 1 1 .52 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 803.2308 found: 803.2323
[M+Na]+ calculated: 825.2127 found: 825.2141 Compound 8
Figure imgf000349_0001
Chemical Formula: C 5H41 N7012
Exact Mass: 871 ,2813
BTC (1 .15 eq, 0.100 mmol, 29 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. 4-Morpholinobenzoic acid (3.5 eq, 0.305 mmol, 63 mg) was added. syn-Collidine (8 eq, 0.697 mmol, 91 μΙ) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (72 mg, 84 %). The oil (1 eq, 0.069 mmol, 68 mg) and phenylsilane (8 eq, 0.552 mmol, 68 μΙ) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.035 mmol, 40 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (6 mg, 10 %). H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.07 (dd, Ji = 16.12, J2 = 8.87 Hz, 1 H), 3.16 (dd, Ji =
16.12, J2= 5.10 Hz, 1 H), 3.27 (m, 4H), 3.76 (m, 4H), 3.79 (s, 3H), 3.85 (s, 3H), 4.99 (dd, Ji = 13.43, J2= 7.79 Hz, 1 H), 7.05 (d, J = 9.40 Hz, 2H), 7.42 (m, 2H), 7.56 (m, 2H), 7.63 (m, 2H), 7.78 (d, J = 8.87 Hz, 2H), 7.93 (m, 6H), 8.93 (s, 1 H), 9.04 (d, J = 7.79 Hz, 1 H), 10.22 (s, 1 H), 10.58 (s, 1 H), 10.64 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 872.2886
found: 872.2882 Compound 9
Figure imgf000350_0001
Chemical Formula: C47H38N601 1
Exact Mass: 862,2599
BTC (1 .15 eq, 0.100 mmol, 29 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. Biphenyl-4-carboxylic acid (3.5 eq, 0.305 mmol, 60 mg) was added. syn-Collidine (8 eq, 0.697 mmol, 91 μΙ) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (60 mg, 70 %). The oil (1 eq, 0.055 mmol, 54 mg) and phenylsilane (8 eq, 0.440 mmol, 54 μΙ) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.028 mmol, 32 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (7 mg, 15 %).
HRMS (ESI): [M+H]+ calculated: 863.2671
found: 863.2666 Compound 10
Figure imgf000351_0001
Chemical Formula: C42H36N6012
Exact Mass: 816,2391
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. 4-Methoxybenzoic acid (3.5 eq, 0.305 mmol, 46 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (43 mg, 53 %). The oil (1 eq, 0.046 mmol, 43 mg) and phenylsilane (8 eq, 0.367 mmol, 0.045 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.023 mmol, 26 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (5 mg, 13 %).
H-NMR (DMSO-ds, 700 MHz): δ [ppm]3.08 (m, 1 H), 3.17 (m, 1 H), 3.78 (s, 3H), 3.83 (s, 1 H),
3.86 (s, 3H), 5.00 (s, 1 H), 6.55 (bs, 1 H), 7.10 (d, J = 8.37 Hz, 2H), 7.56 (m, 2H), 7.81 (m, 3H), 7.97 (m, 9H), 9.05 (d, J = 7.18 Hz, 1 H), 9.68 (s, 1 H), 10.35 (s, 1 H), 10.58 (s, 1 H), 1 1 . (s, 1 H), 1 1 .54 (s, 1 H).
HRMS (ESI): [M-H] calculated: 815.2307
found: 815.2310 Compound 1 1
Figure imgf000352_0001
Chemical Formula: C^HssNyOn
Exact Mass: 81 1 ,2238
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. 4-Cyanobenzoic acid (3.5 eq, 0.305 mmol, 45 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (59 mg, 73 %). The oil (1 eq, 0.064 mmol, 59 mg) and phenylsilane (8 eq, 0.509 mmol, 0.063 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.032 mmol, 37 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (1 1 mg, 21 %). H-NMR (DMSO-ds, 500 MHz): δ [ppm] 3.09 (dd, Ji = 16.84 Hz, J2 = 8.92 Hz, 1 H), 3.18 (dd,
J, = 17.14 Hz, J2 = 5.85 Hz, 1 H), 3.79 (s, 3H), 3.91 (s, 3H), 5.01 (m, 1 H), 7.02 (s, 1 H), 7.12 (s, 1 H), 7.22 (s, 2H), 7.57 (d, J = 8.72 Hz, 2H), 7.81 (m, 4H), 7.93 (d, J = 8.52 Hz, 3H), 7.99 (m, 5 H), 8.96 (d, J = 8.13 Hz, 2H), 8.14 (d, J = 8.32 Hz, 2H), 9.08 (d, J =7.93 Hz, 1 H), 9.68 (s, 1 H), 10.59 (s, 1 H), 10.74 (s, 1 H), 1 1 .07 (bs, 1 H), 1 1 .55 (bs, 1 H). Compound 12
Figure imgf000353_0001
Chemical Formula: C^HssFsNgO-n
Exact Mass: 854,2159
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. 3-(Trifluoromethyl)benzoic acid (3.5 eq, 0.305 mmol, 61 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (86 mg, 99 %). The oil (1 eq, 0.077 mmol, 75 mg) and phenylsilane (8 eq, 0.617 mmol, 0.076 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.039 mmol, 45 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (43 mg, 65 %).
H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.08 (dd, Ji = 16.79 Hz, J2 = 9.00 Hz, 1 H), m (3.17, 1 H), 3.78 (s, 3H), 3.91 (s, 3H), 5.00 (m, 1 H), 7.58 (m, 2H), 7.81 (m, 4H), 7.99 (m, 8H), 8.31 (m, 2H), 9.09 (d, J = 8.09 Hz, 1 H), 9.72 (s, 1 H), 10.60 (s, 1 H), 10.73 (s, 1 H), 1 1 .18 (s, 1 H), 1 1 .55 (s, 1 H).
HRMS (ESI): [M-H]" calculated: 853.2076
found: 853.2095 Compound 13
Figure imgf000354_0001
Chemical Formula: C 7H38N601 1
Exact Mass: 862,2599
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. Biphenyl-2-carboxylic acid (3.5 eq, 0.305 mmol, 61 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (86 mg, 99 %). The oil (1 eq, 0.079 mmol, 78 mg) and phenylsilane (8 eq, 0.635 mmol, 0.078 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.040 mmol, 46 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (35 mg, 51 %). H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.06 (dd, Ji = 16.66 Hz, J2 = 8.60 Hz, 1 H), 3.15 (m,
1 H), 3.78 (s, 3H), 3.92 (s, 1 H), 4.98 (m, 1 H), 7.29 (m, 1 H), 7.37 (t, J = 7.52 Hz, 2H), 7.44 (m, 2H), 7.50 (m, 2H), 7.61 (m, 6H), 7.80 (m, 3H), 7.87 (d, J = 8.60 Hz, 2H), 7.99 (d, J = 8.60 Hz, 2H), 8.06 (d, J = 8.87 Hz, 1 H), 9.01 (d, J = 7.79 Hz, 1 H), 9.71 (s, 1 H), 10.50 (s, 1 H), 10.57 (s, 1 H), 1 1 .19 (s, 1 H), 1 1 .58 (m, 2H).
HRMS (ESI): [M-H] calculated: 861 .2593
found: 861 .2530 Compound 14
Figure imgf000355_0001
Chemical Formula: C39H33N7O-1 -1
Exact Mass: 775,2238
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon.1 H-pyrrole-2-carboxylic acid (3.5 eq, 0.305 mmol, 29 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .8 % MeOH) yielded the product as an orange solid (54 mg, 69 %). The solid (1 eq, 0.058 mmol, 56 mg) and phenylsilane (8 eq, 0.466 mmol, 0.057 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.029 mmol, 34 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (17 mg, 38 %).
H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.07 (m, 1 H), 3.16 (m, 1 H), 3.77 (s, 3H), 3.91 (s, 3H), 4.99 (m, 1 H), 6.18 (m, 1 H), 7.00 (m, 1 H), 7.12 (m, 1 H), 7.58 (t, J = 9.1 Hz, 2H), 7.80 (m, 3H), 7.88 (m, 4H), 7.99 (d, J = 8.9 Hz, 2H), 8.06 (d, J = 8.9 Hz, 1 H), 9.02 (d, J = 7.5 Hz, 1 H), 9.71 (s, 1 H), 9.99 (s, 1 H), 10.58 (s, 1 H), 1 1 .18 (s, 1 H), 1 1 .54 (s, 1 H).
HR-MS: [M-H]- calculated: 774.2154
[M-H]- found: 774.2153 Compound 15
Figure imgf000356_0001
Chemical Formula: C39H32N6012
Exact Mass: 776,2078
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. Furan-2-carboxylic acid (3.5 eq, 0.305 mmol, 29 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (72 mg, 89 %). The oil (1 eq, 0.078 mmol, 70 mg) and phenylsilane (8 eq, 0.625 mmol, 0.077 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.039 mmol, 45 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (16 mg, 27 %).
H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.07 (m, 1 H), 3.16 (m, 1 H), 3.77 (s, 3H), 3.91 (s, 3H), 4.99 (m, 1 H), 6.73 (s, 1 H), 7.39 (d, J = 3.0 Hz, 1 H), 7.57 (t, J = 8.3 Hz, 2H), 7.80 (m, 3H), 7.94 (m, 6H), 8.04 (d, J = 8.6 Hz, 1 H), 9.05 (d, J = 7.3 Hz, 1 H), 9.71 (s, 1 H), 10.44 (s, 1 H), 10.58 (s, 1 H), 1 1 .57 (s, 1 H), 1 1 .55 (s, 1 H).
HR-MS: [M-H]- calculated: 775.1994
[M-H] found: 775.1995 Compound 16
Figure imgf000357_0001
Chemical Formula: Cs^-i NyOnS
Exact Mass: 793,1802
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. Thiazole-4-carboxylic acid (3.5 eq, 0.305 mmol, 34 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an yellow solid (69 mg, 86 %). The solid (1 eq, 0.073 mmol, 67 mg) and phenylsilane (8 eq, 0.587 mmol, 0.072 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.037 mmol, 34 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (21 mg, 38 %).
H-NMR (DMSO-ds, 500 MHz): δ [ppm] 3.07 (dd, Ji = 16.79 Hz, J2 = 8.73 Hz, 1 H), 3.17 (m, 1 H), 3.78 (s, 3H), 3.92 (s, 3H), 4.99 (m, 1 H), 7.47 (m, 3H), 7.58 (m, 2H), 7.81 (m, 3H), 7.87 (d, J = 8.87 Hz, 2H), 7.94 (m, 2H), 8.00 (d, J = 8.60 Hz, 2H), 8.05 (d, J = 8.87 Hz, 1 H), 9.04 (d, J = 7.79 Hz, 1 H), 9.71 (s, 1 H), 10.22 (s, 1 H), 10.59 (s, 1 H), 1 1 .17 (s, 1 H), 1 1 .54 (s, 1 H).
HRMS (ESI): [M-H]+ calculated: 792.1718
found: 792.1717 Compound 17
Figure imgf000358_0001
Chemical Formula: C3gH32N80ii
Exact Mass: 788,2191
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. Pyrazine-2-carboxylic acid (3.5 eq, 0.305 mmol, 33 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange solid (70 mg, 88 %). The solid (1 eq, 0.073 mmol, 67 mg) and phenylsilane (8 eq, 0.590 mmol, 0.073 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.037 mmol, 34 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (19 mg, 33 %).
H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.07 (m, 1 H), 3.17 (m, 1 H), 3.77 (s, 3H), 3.91 (s, 1 H), 4.99 (m, 1 H), 7.58 (t, J = 8.9 Hz, 2H), 7.80 (m, 3H), 7.98 (m, 4H), 8.06 (m, 3H), 8.84 (m, 1 H), 8.94 (m, 1 H), 9.09 (d, J = 7.8 Hz, 1 H), 9.32 (s, 1 H), 9.71 (s, 1 H), 10.58 (s, 1 H), 1 1 .00 (s, 1 H), 1 1 .18 (s, 1 H), 1 1 .54 (s, 1 H).
HR-MS: [M+H]+ calculated: 789.2263
[M+H]+ found: 789.2260 Compound 18
Figure imgf000359_0001
Chemical Formula: C39H32N80ii
Exact Mass: 788,2191
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argonPyridazine-3-carboxylic acid (3.5 eq, 0.305 mmol, 33 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (58 mg, 73 %). The oil (1 eq, 0.058 mmol, 56 mg) and phenylsilane (8 eq, 0.466 mmol, 0.057 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.029 mmol, 34 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (7 mg, 15 %).
H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.08 (m, 1 H), 3.17 (m, 1 H), 3.77 (s, 3H), 3.91 (s, 3H), 5.00 (m, 1 H), 7.57 (t, J = 9.0 Hz, 1 H), 7.80 (m, 4H), 7.99 (m, 5H), 8.04 (m, 1 H), 8.1 1 (d, J = 8.9 Hz), 8.35 (dd, J = 1 .6 Hz), 9.10 (d, J = 7.0 Hz), 9.49 (dd, Ji = 5.0 Hz, J2 = 1 .5 Hz), 9.71 (s, 1 H), 10.59 (s, 1 H), 1 1 .18 (s, 1 H), 1 1 .34 (s, 1 H), 1 1 .54 (s, 1 H).
HR-MS: [M-H]- calculated: 787.2106
[M-H]- found: 787.21 1 1 Compound 19
Figure imgf000360_0001
Chemical Formula: C4oH32CIN7Oii
Exact Mass: 821 ,1848
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. 6-chloronicotinic acid (3.5 eq, 0.305 mmol, 42 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange solid (73 mg, 89 %). The solid (1 eq, 0.075 mmol, 71 mg) and phenylsilane (8 eq, 0.600 mmol, 0.074 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.038 mmol, 44 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (4 mg, 7 %).
H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.07 (m, 1 H), 3.16 (m, 1 H), 3.77 (s, 3H), 3.91 (s, 3H), 4.99 (m, 1 H), 6.18 (m, 1 H), 7.00 (m, 1 H), 7.12 (m, 1 H), 7.58 (t, J = 9.1 Hz, 2H), 7.80 (m, 3H), 7.88 (m, 4H), 7.99 (d, J = 8.9 Hz, 2H), 8.06 (d, J = 8.9 Hz, 1 H), 9.02 (d, J = 7.5 Hz, 1 H), 9.71 (s, 1 H), 9.99 (s, 1 H), 10.58 (s, 1 H), 1 1 .18 (s, 1 H), 1 1 .54 (s, 1 H).
HR-MS: [M-H]- calculated: 774.2154
[M-H]- found: 774.2153 Compound 20
Figure imgf000361_0001
Chemical Formula: C3gH32N60i2
Exact Mass: 776,2078
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. Furan-3-carboxylic acid (3.5 eq, 0.305 mmol, 29 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (72 mg, 92 %). The oil (1 eq, 0.078 mmol, 70 mg) and phenylsilane (8 eq, 0.625 mmol, 0.077 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.039 mmol, 45 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (6 mg, 10 %).
H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.08 (dd, J = 8,6 Hz, 1 H), 3.16 (dd, J = 5.4 Hz), 3.77 (s, 3H), 3.91 (s, 3H), 4.99 (m, 1 H), 7.02 (d, J = 1 .3 Hz, 1 H), 7.57 (m, 1 H), 7.82 (m, 6H), 7.97 (m, 5H), 8.05 (d, J = 8.9 Hz, 1 H), 8.43 (s, 1 H), 9.05 (d, J = 7.3 Hz, 1 H), 9.71 (s, 1 H), 10.17 (s, 1 H), 10.58 (s, 1 H), 1 1 .18 (s, 1 H), 1 1 .54 (s, 1 H).
HR-MS: [M-H]- calculated: 775.1994
[M-H]- found: 775.2000 Compound 21
Figure imgf000362_0001
Chemical Formula: C39H32N60i iS
Exact Mass: 792,1850
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. Thiophene-3-carboxylic acid (3.5 eq, 0.305 mmol, 34 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange solid (79 mg, 98 %). The oil (1 eq, 0.087 mmol, 79 mg) and phenylsilane (8 eq, 0.693 mmol, 0.085 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (1 .0 eq, 0.087 mmol, 100 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (20 mg, 29 %).
H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.07 (m, 1 H), 3.17 (m,1 H), 3.77 (s, 3H), 3.91 (s, 1 H), 4.99 (m, 1 H), 7.25 (t, J = 1 .1 , 1 H), 7.57 (d, 1 H), 7.80 (m, 3H), 7.89 (m, 4H), 7.98 (m, 4H), 8.04 (m, 1 H), 8.07 (d, J = 2.7 Hz, 1 H) 9.06 (d, J = 7.8 Hz, 1 H), 9.70 (s, 1 H), 10.47 (s, 1 H), 10.58 (s,1 H), 1 1 .16 (s, 1 H), 1 1 .53 (s, 1 H).
HR-MS: [M-H]- calculated: 791 .17660
[M-H] found: 791 .17853 Compound 22
Figure imgf000363_0001
Chemical Formula: C4iH32Cl2N60n
Exact Mass: 854,1506
The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (7 eq, 0.61 1 mmol, 0.100ml) were dissolved in dry THF (5 ml) under an atmosphere of argon. 3,5-Dichlorobenzoyl chloride (5 eq, 0.436 mmol, 91 mg) was added an the reaction mixture was stirred for 12 hours and the reaction was quenched by the addition of water.After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over NagSC and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (82 mg, 99 %). The oil (1 eq, 0.075 mmol, 73 mg) and phenylsilane (8 eq, 0.375 mmol, 0.046 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.037 mmol, 43 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (18 mg, 28 %).
H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.08 (dd, Ji = 16.79 Hz, J2 = 8.73 Hz, 1 H), 3.17 (m, 1 H), 3.78 (s, 3H), 3.92 (s, 3H), 5.00 (m, 1 H), 7.58 (m, 2H), 7.81 (m, 3H), 7.91 (m, 3H), 8.01 (m, 7H), 9.09 (d, J = 7.79 Hz, 1 H), 9.70 (s, 1 H), 10.59 (s, 1 H), 10.67 (s, 1 H), 1 1 .17 (s, 1 H), 1 1 .54 (s, 1 H).
HRMS (ESI): [M-H]" calculated: 853.1422
found: 853.1459 Compound 23
Figure imgf000364_0001
Chemical Formula: C4iH33FN60ii
Exact Mass: 804,2191
The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (7 eq, 0.61 1 mmol, 0.100ml) were dissolved in dry THF (5 ml) under an atmosphere of argon. 4-Fluorobenzoyl chloride (5 eq, 0.436 mmol, 69 mg) was added an the reaction mixture was stirred for 12 hours and the reaction was quenched by the addition of water.After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (78 mg, 97 %). The oil (1 eq, 0.081 mmol, 75 mg) and phenylsilane (8 eq, 0.651 mmol, 0.080 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.041 mmol, 47 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (6 mg, 9 %).
H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.01 (dd, Ji = 16.79 Hz, J2 = 8.73 Hz, 1 H), 3.10 (m, 1 H), 4.93 (m, 1 H), 7.33 (m, 2H), 7.50 (d, J = 8.87 Hz, 2H), 7.73 (m, 3H), 7.93 (m, 9H), 9.00 (d, J = 7.79 Hz, 1 H), 9.63 (s, 1 H), 10.45 (s, 1 H), 10.52 (s, 1 H), 1 1 .06 (s, 1 H), 1 1 .47 (s, 1 H).
HRMS (ESI): [M-H]" calculated: 803.2108
found: 803.2130 Compound 24
Figure imgf000365_0001
Chemical Formula: C40H33N7O11
Exact Mass: 787,2238
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. Nicotinic acid (3.5 eq, 0.305 mmol, 66 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an yellow solid (64 mg, 80 %). The solid (1 eq, 0.068 mmol, 62 mg) and phenylsilane (8 eq, 0.546 mmol, 0.066 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.034 mmol, 39 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (6 mg, 12 %).
H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.08 (m, 1 H), 3.17 (m, 1 H), 3.78 (s, 3H), 3.92 (s, 3H), 5.00 (m, 1 H), 7.58 (m, 4H), 7.80 (dd, Ji = 8.60 Hz, J2 = 6.18 Hz, 3H), 7.92 (m, 2H), 7.99 (m, 5H), 8.06 (d, J = 8.9 Hz, 1 H), 8.33 (d, J = 7.8 Hz, 1 H) 9.08 (d, J = 7.3 Hz, 1 H), 9.71 (s, 1 H), 10.59 (s, 1 H), 10.70 (s, 1 H), 1 1 .18 (s, 1 H), 1 1 .54 (s, 1 H).
HR-MS: [M-H]- calculated: 786.21543
[M-H]- found: 786.21777 Compound 25
Figure imgf000366_0001
Chemical Formula: C3gH32N80ii
Exact Mass: 788,2191
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. Pyrimidine-5-carboxylic acid (3.5 eq, 0.305 mmol, 67 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an yellow solid (55 mg, 65 %). The solid (1 eq, 0.058 mmol, 53 mg) and phenylsilane (8 eq, 0.467 mmol, 0.057 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.029 mmol, 34 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (9 mg, 20 %).
H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.08 (m, 1 H), 3.17 (dd, Ji = 17.1 Hz, J2 = 5.2 Hz, 1 H), 3.77 (s, 3H), 3.92 (s, 3H), 4.99 (m, 1 H), 7.56 (d, J = 8.9 Hz, 1 H), 7.81 (m, 3H), 7.91 (d, J = 8.9 Hz, 2H), 7.99 (d, J= 8.4 Hz, 5H) 8.32 (d, J = 9.4 Hz, 1 H), 9.1 1 (d, J = 7.5 Hz, 1 H), 9.32 (s, 2H), 9.39 (s, 1 H), 9.70 (s, 1 H), 10.61 (s, 1 H), 10.87 (s, 1 H), 1 1 .15 (s, 1 H), 1 1 .57 (s, 1 H).
HR-MS: [M-H]- calculated: 787.21068
[M-H]- found: 787.21283 Compound 26
Figure imgf000367_0001
Chemical Formula: C42H35CIN601 1
Exact Mass: 834,2052
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. 2-(4-Chlorophenyl)acetic acid (3.5 eq, 0.305 mmol, 52 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (35 mg, 42 %). The oil (1 eq, 0.037 mmol, 35 mg) and phenylsilane (8 eq, 0.293 mmol, 0.036 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.018 mmol, 21 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (7 mg, 23 %).
H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.05 (m, 1 H), 3.15 (m, 1 H), 3.70 (s, 2H), 3.77 (s, 3H), 3.91 (s, 3H), 4.97 (m, 1 H), 7.38 (m, 4H), 7.57 (d, J = 8.33 Hz, 2H), 7.76 (m, 5H), 7.96 (m, 5H), 9.02 (d, J = 5.91 Hz, 1 H), 9.69 (s, 1 H), 10.46 (s, 1 H), 10.57 (s, 1 H), 1 1 .15 (s, 1 H), 1 1 .54
(bs, 1 H).
HRMS (ESI): [M-H] calculated: 833.1969
found: 833.1962 Compound 27
Figure imgf000368_0001
Chemical Formula: C42H36N6Oi2
Exact Mass: 816,2391
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. 2-(4-(Allyloxy)phenyl)acetic acid (3.5 eq, 0.305 mmol, 59 mg) was added, syn- Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (68 mg, 80 %). The oil (1 eq, 0.072 mmol, 70 mg) and phenylsilane (8 eq, 0.576 mmol, 0.071 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.036 mmol, 42 mg) was added and the mixture was stirred 12 h at room
temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (30 mg, 51 %). H-NMR (DMSO-ds, 700 MHz): δ [ppm] 3.05 (dd, Ji = 16.79 Hz, J2 = 8.73 Hz, 1 H), 3.15 (m, 1 H), 3.54 (s, 2H), 3.78 (s, 3H), 3.92 (s, 3H), 4.97 (m, 1 H), 6.71 (d, J= 8.60 Hz, 2H), 7.13 (d, J = 8.60 Hz, 2H), 7.58 (m, 2H), 7.71 (d, J= 8.87 Hz, 2H), 7.80 (m, 3H), 7.90 (d, J = 8.87 Hz, 2H), 7.99 (d, J = 8.87 Hz, 2H), 8.05 (d, J= 8.87 Hz, 1 H), 9.01 (d, J= 7.79 Hz, 1 H), 9.28 (s, 1 H), 9.70 (s, 1 H), 10.35 (s, 1 H), 10.57 (s, 1 H), 1 1 .18 (s, 1 H), 1 1 .53 (s, 1 H).
HRMS (ESI): [M-H]" calculated: 815.2307
found: 815.2321 Compound 28
Figure imgf000369_0001
Chemical Formula: C42H35FN60i i
Exact Mass: 818,2348
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. 2-(4-Fluorophenyl)acetic acid (3.5 eq, 0.305 mmol, 47 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (60 mg, 74 %). The oil (1 eq, 0.057 mmol, 54 mg) and phenylsilane (8 eq, 0.456 mmol, 0.056 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.029 mmol, 33 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (23 mg, 49 %). H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.06 (dd, Ji = 16.79 Hz, J2= 8.73 Hz, 1 H), 3.15 (m, 1 H), 3.69 (s, 2H), 3.78 (s, 3H), 3.92 (s, 3H), 4.97 (m, 1 H), 7.16 (m, 2H), 7.37 (m, 2H), 7.58 (m, 2H), 7.72 (d, J = 8.06 Hz, 2H), 7.80 (m, 3H), 7.91 (d, J = 8.60 Hz, 2H), 7.99 (d, J = 8.60 Hz, 2H), 8.06 (d, J = 8.87 Hz, 1 H), 9.02 (d, J = 7.79 Hz, 1 H), 9.70 (s, 1 H), 10.45 (s, 1 H), 10.57 (s, 1 H), 1 1 .18 (s, 1 H), 1 1 .53 (s, 1 H), 1 1 .60 (bs, 1 H).
HRMS (ESI): [M-H]" calculated: 817.2264
found: 817.2283 Compound 29
Figure imgf000370_0001
Chemical Formula:
Figure imgf000370_0002
-1
Exact Mass: 815,2551
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. 3-(Pyridin-2-yl)propanoic acid (3.5 eq, 0.305 mmol, 46 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (47 mg, 58 %). The oil (1 eq, 0.047 mmol, 44 mg) and phenylsilane (8 eq, 0.377 mmol, 0.046 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.024 mmol, 27 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (8 mg, 21 %).
H-NMR (DMSO-ds, 400 MHz): δ [ppm] 2.74 (s, 2H), 3.10 (m, 4H), 3.77 (s, 3H), 3.91 (s, 3H), 4.97 (m, 1 H), 7.63 (m, 6H), 7.84 (m, 6H), 8.02 (m, 4H), 9.01 (d, J = 7.25 Hz, 1 H), 9.70 (s, 1 H), 10.24 (s, 1 H), 10.57 (s, 1 H), 1 1 .18 (s, 1 H), 1 1 .55 (s, 1 H).
HRMS (ESI): [M-H]" calculated: 814.2467
found: 814.2487 Compound 30
Figure imgf000371_0001
Chemical Formula: C42H36N6012
Exact Mass: 816,2391
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. 2-Phenoxyacetic acid (3.5 eq, 0.305 mmol, 46 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (73 mg, 90 %). The oil (1 eq, 0.070 mmol, 66 mg) and phenylsilane (8 eq, 0.561 mmol, 0.069 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.024 mmol, 27 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (1 1 mg, 19 %). H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.06 (m, 1 H), 3.16 (m, 1 H), 3.77 (s, 3H), 3.91 (s, 3H), 4.74 (s, 2H), 4.98 (m, 1 H), 6.99 (m, 3H), 7.32 (m, 3H), 7.79 (m, 4H), 7.93 (d, J = 8.06 Hz, 2H), 7.99 (d, J = 8.60 Hz, 2H), 8.05 (d, J = 8.60 Hz, 1 H), 9.05 (d, J = 6.98 Hz, 1 H), 9.70 (s, 1 H), 10.37 (s, 1 H), 10.58 (s, 1 H), 1 1 .17 (s, 1 H), 1 1 .54 (s, 1 H). Compound 31
Figure imgf000372_0001
Chemical Formula: C43H38N6
Exact Mass: 830,2548
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. 3-(4-(Allyloxy)phenyl)propanoic acid (3.5 eq, 0.305 mmol, 63 mg) was added, syn- Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (84 mg, 97 %). The oil (1 eq, 0.080 mmol, 79 mg) and phenylsilane (8 eq, 0.640 mmol, 0.079 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.040 mmol, 46 mg) was added and the mixture was stirred 12 h at room
temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (13 mg, 20 %).
H-NMR (DMSO-ds, 400 MHz): δ [ppm] 2.59 (t, J = 7.79 Hz, 2H), 2.80 (t, J = 7.52 Hz, 2H), 3.06 (dd, J, = 16.92 Hz, J2 = 8.60 Hz, 1 H), 3.15 (m, 1 H), 3.77 (s, 3H), 3.92 (s, 3H), 4.97 (m, 1 H), 6.66 (d, J = 8.33 Hz, 2H), 7.03 (d, J = 8.33 Hz, 2H), 7.58 (m, 2H), 7.70 (d, J = 8.60 Hz, 2H), 7.80 (m, 3H), 7.90 (d, J = 8.87 Hz, 2H), 7.99 (d, J = 8.87 Hz, 2H), 8.06 (d, J = 8.87 Hz, 1 H), 9.01 (d, J = 8.06 Hz, 1 H), 9.17 (bs, 1 H), 9.71 (s, 1 H), 10.17 (s, 1 H), 10.57 (s, 1 H), 1 1 .19 (s, 1 H), 1 1 .54 (s, 1 H), 1 1 .61 (bs, 1 H).
HRMS (ESI): [M-H]" calculated: 829.2464
found: 829.2483 Compound 32
Figure imgf000373_0001
Chemical Formula: C43H37FN60H
Exact Mass: 832,2504
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. 3-(4-Fluorophenyl)propanoic acid (3.5 eq, 0.305 mmol, 51 mg) was added, syn- Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (72 mg, 87 %). The oil (1 eq, 0.071 mmol, 67 mg) and phenylsilane (8 eq, 0.566 mmol, 0.070 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.035 mmol, 41 mg) was added and the mixture was stirred 12 h at room
temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (29 mg, 49 %). H-NMR (DMSO-ds, 400 MHz): δ [ppm] 2.66 (d, J = 7.66 Hz, 2H), 2.91 (d, J = 7.52 Hz, 2H), 3.06 (dd, J, = 16.79 Hz, J2 = 8.73 Hz, 1 H), 3.15 (m, 1 H), 3.78 (s, 3H), 3.92 (s, 3H), 4.97 (m, 1 H), 7.1 1 (m, 2H), 7.29 (m, 2H), 7.58 (m, 2H), 7.70 (d, J = 8.87 Hz, 2H), 7.80 (m, 3H), 7.90 (d, J = 8.60 Hz, 2H), 7.99 (d, J = 8.60 Hz, 2H), 8.06 (d, J = 8.87 Hz, 1 H), 9.01 (d, J = 7.79 Hz, 1 H), 9.71 (s, 1 H), 10.20 (s, 1 H), 10.57 (s, 1 H), 1 1 .18 (s, 1 H), 1 1 .54 (s, 1 H), 1 1 .65 (bs, 1 H).
HRMS (ESI): [M-H]" calculated: 831 .2421
found: 831 .2437 Compound 34
Figure imgf000374_0001
Chemical Formula: C40H40N6O
Exact Mass: 780,2755
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. Hexanoic acid (3.5 eq, 0.305 mmol, 35 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (39 mg, 50 %). The oil (1 eq, 0.039 mmol, 35 mg) and phenylsilane (8 eq, 0.31 1 mmol, 0.038 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.019 mmol, 22 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (4 mg, 13 %). H-NMR (DMSO-d6, 400 MHz): δ [ppm] 0.85 (m, 4H), 1 .20 (m, 7H), 3.05 (m, 1 H), 3.12 (m, 1 H), 3.75 (s, 3H), 3.84 (s, 3H), 4.95 (m, 1 H), 7.51 (d, J = 8.60 Hz, 2H), 7.68 (d, J = 8.87 Hz, 3H), 7.76 (m, 3H), 7.87 (d, J = 8.87 Hz, 2H), 7.96 (d, J = 8.60 Hz, 2H), 8.97 (d, J = 7.79 Hz, 1 H), 9.63 (s, 1 H), 10.12 (s, 1 H), 10.55 (s, 1 H), 10.82 (bs, 1 H).
HRMS (ESI): [M+H]+ calculated: 781 .2828
found: 781 .2837
[M+Na]+ calculated 803.2647
found: 803.2654 Compound 35
Figure imgf000375_0001
Chemical Formula: C41 H40N6O1 1
Exact Mass: 792,2755
BTC (1 .15 eq, 0.100 mmol, 30 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. Cyclohexanecarboxylic acid (3.5 eq, 0.305 mmol, 40 mg) was added. syn-Collidine (8 eq, 0.700 mmol, 0.092 ml) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (61 mg, 77 %). The oil (1 eq, 0.062 mmol, 57 mg) and phenylsilane (8 eq, 0.500 mmol, 0.062 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.031 mmol, 36 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (9 mg, 18 %). H-NMR (DMSO-de, 400 MHz): δ [ppm] 1 .10 (m, 2H), 1 .20 (m, 2H), 1 .34 (m, 2H), 1 .59 (m, 1 H), 1 .72 (m, 4H), 2.99 (dd, Ji = 16.66 Hz, J2 = 8.87 Hz, 1 H), 3.08 (m, 1 H), 3.71 (s, 3H), 3.84
(s, 1 H), 4.90 (m, 1 H), 7.50 (d, J = 8.87 Hz, 2H), 7.66 (d, J = 8.60 Hz, 2H), 7.73 (m, 3H), 7.82 (d, J = 8.87 Hz, 2H), 7.92 (m, 3H), 8.93 (d, J = 7.79 Hz, 1 H), 9.63 (s, 1 H), 10.03 (s, 1 H), 10.51 (s, 1 H), 1 1 .06 (s, 1 H), 1 1 .47 (bs, 1 H).
HRMS (ESI): [M+H]+ calculated 793.2822
found: 793.2836
[M+Na]+ calculated 815.2647
found: 815.2654 Compound 36
Figure imgf000376_0001
Chemical Formula: C45H44N60H
Exact Mass: 844,3068
The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (7 eq, 0.61 1 mmol, 0.100ml) were dissolved in dry THF (5 ml) under an atmosphere of argon. AdCOCI (5 eq, 0.436 mmol, 87 mg) was added an the reaction mixture was stirred for 12 hours and the reaction was quenched by the addition of water.After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (73 mg, 87 %). The oil (1 eq, 0.071 mmol, 69 mg) and phenylsilane (8 eq, 0.568 mmol, 0.070 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.036 mmol, 41 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (33 mg, 55 %). H-NMR (DMSO-ds, 700 MHz): δ [ppm] 1 .72 (s, 6H), 1 .94 (s, 6H), 2.04 (s, 3H), 3.07 (m, 1 H), 3.16 (m, 1 H), 3.79 (s, 3H), 3.92 (s, 3H), 4.99 (m, 1 H), 7.59 (m, 2H), 7.81 (m, 5H), 7.91 (d, J = 8.37 Hz, 2H), 8.00 (d, J= 8.37 Hz, 2H), 8.05 (d, J = 8.67 Hz, 1 H), 9.00 (d, J = 7.78 Hz, 1 H), 9.39 (s, 1 H), 9.70 (s, 1 H), 10.58 (s, 1 H), 1 1 .70 (s, 1 H), 1 1 .54 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 845.3141
found: 845.3134
[M+Na]+ calculated: 867.2960
found: 867.2954 Compound 37
Figure imgf000377_0001
Chemical Formula: C36H32N6011
Exact Mass: 724,2129
The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (7 eq, 0.61 1 mmol, 0.100ml) were dissolved in dry THF (5 ml) under an atmosphere of argon. Acetyl chloride (5 eq, 0.436 mmol, 34 mg) was added an the reaction mixture was stirred for 12 hours and the reaction was quenched by the addition of water.After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (40 mg, 54 %). The oil (1 eq, 0.057 mmol, 48 mg) and phenylsilane (8 eq, 0.455 mmol, 0.056 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.028 mmol, 33 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (2 mg, 5 %). H-NMR (DMSO-ds, 800 MHz): δ [ppm] 2.09 (s, 3H), 3.07 (dd, = 16.17 Hz, J2 = 8.40 Hz, 1 H), 3.16 (m, 1 H), 3.78 (s, 3H), 3.93 (s, 3H), 4.98 (m, 1 H), 7.58 (d, J= 8.68 Hz, 1 H), 7.60 (d, J = 8.68 Hz, 1 H), 7.70 (d, J = 8.68 Hz, 2H), 7.81 (m, 3H), 7.91 (d, J= 9.59 Hz, 2H), 8.00 (d, J = 8.98 Hz, 2H), 8.06 (d, J = 8.96 Hz, 1 H), 9.00 (d, J = 8.40 Hz, 1 H), 9.70 (s, 1 H), 10.22 (s, 1 H), 10.57 (s, 1 H), 1 1 .17 (s, 1 H), 1 1 .54 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 725.2202
found: 725.2209
[M+Na]+ calculated: 747.2021
found: 747.2027 Compound 38
Figure imgf000378_0001
Chemical Formula: C38H34N601 1
Exact Mass: 750,2286
Cyclopropanecarbonyl chloride (5 eq, 0.436 mmol, 39.5 μΙ) was added via syringe to a solution of amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (5 eq, 0.436 mmol, 76 μΙ) under an atmosphere of argon. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (64 mg, 84 %). The oil (1 eq, 0.069 mmol, 60 mg) and phenylsilane (8 eq, 0.552 mmol, 68 μΙ) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.035 mmol, 40 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (15 mg, 29 %). H-NMR (DMSO-ds, 500 MHz): δ [ppm] 0.83 (m, 4H), 1 .83 (m, 1 H), 3.07 (dd, Ji = 17.24, J2 = 9.12 Hz, 1 H), 3.16 (dd, Ji = 16.84, J2 = 6.14 Hz, 1 H), 3.78 (s, 3H), 3.91 (s, 3H), 4.97 (dd, Ji = 14.27, J2 = 8.32 Hz, 1 H), 7.58 (t, J = 8.82 Hz, 2H), 7.72 (d, J = 8,72 Hz, 2H), 7.80 (t, J = 8.50 Hz, 3H), 7.90 (d, J = 8.72 Hz, 2H), 7.98 (d, J = 8.52 Hz, 2H), 8.04 (d, J = 8.92 Hz, 1 H), 9.00 (d, J = 7.73 Hz, 1 H), 9.68 (s, 1 H), 10.51 (s, 1 H), 10.61 (s, 1 H), 1 1 .16 (s, 1 H), 1 1 .52 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 751 .2358
found: 751 .2358
[M+Na]+ calculated: 773.2178
found: 773.2178 Compound 39
Figure imgf000379_0001
Chemical Formula: C40H40N6O1 1
Exact Mass: 780,2755
2-Ethylbutanoyl chloride (5 eq, 0.436 mmol, 59.7 μΙ) was added via syringe to a solution of amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (5 eq, 0.436 mmol, 76 μΙ) under an atmosphere of argon. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (75 mg, 96 %). The oil (1 eq, 0.078 mmol, 70 mg) and phenylsilane (8 eq, 0.624 mmol, 77 μΙ) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.039 mmol, 45 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (32 mg, 53 %). H-NMR (DMSO-ds, 500 MHz): δ [ppm] 0.86 (t, J = 7.43 Hz, 6H), 1 .46 (m, 2H), 1 .57 (m, 2H), 2.26 (m, 1 H), 3.06 (dd, Ji = 17.04, J2 = 8.72 Hz, 1 H), 3.15 (dd, Ji = 16.64, J2 = 5.35 Hz, 1 H), 3.78 (s, 3H), 3.91 (s, 3H), 4.98 (dd, Ji = 13.67, J2 = 8.13 Hz, 1 H), 7.57 (d, J = 8.72 Hz, 1 H), 7.75 (d, J = 8.72 Hz, 2H), 7.79 (d, J = 8.72 Hz, 1 H), 7.81 (d, J = 9.12 Hz, 1 H), 7.90 (d, J = 8.72 Hz, 2H), 7.98 (d, J = 8.52 Hz, 2H), 8.04 (d, J = 8.52 Hz, 1 H), 8.98 (d, J = 7.53 Hz, 1 H), 9.68 (s, 1 H), 10.13 (s, 1 H), 10.55 (s, 1 H), 1 1 .15 (s, 1 H), 1 1 .52 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 781 .2826
found: 781 .2828
[M+Na]+ calculated: 803.2647
found: 803.2645 Compound 40
Figure imgf000380_0001
Chemical Formula: C39H38N60i i
Exact Mass: 766,2599
Trimethylacetyl chloride (5 eq, 0.436 mmol, 53.7 μΙ) was added via syringe to a solution of amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (5 eq, 0.436 mmol, 76 μΙ) under an atmosphere of argon. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (52 mg, 67 %). The oil (1 eq, 0.054 mmol, 48 mg) and phenylsilane (8 eq, 0.432 mmol, 53 μΙ) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.027 mmol, 31 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (15 mg, 36 %). H-NMR (DMSO-ds, 400 MHz): δ [ppm] 1 .24 (s, 9H), 3.06 (dd, Ji = 16.39, J2 = 8.33 Hz, 1 H), 3.13 (dd, Ji = 16.79, J2 = 5.24 Hz, 1 H), 3.77 (s, 3H), 3.91 (s, 3H), 4.97 (dd, Ji = 13.70, J2= 7.52 Hz, 1 H), 7.56 (d, J= 8.87 Hz, 2H), 7.79 (m, 5H), 7.90 (d, J = 8.60 Hz, 2H), 7.99 (d, J = 8.33 Hz, 2H), 8.04 (d, J= 8.60 Hz, 1 H), 9.01 (d, J = 7.52 Hz, 1 H), 9.46 (s, 1 H), 9.71 (s, 1 H), 10.59 (s, 1 H), 1 1 .17 (s, 1 H), 1 1 .55 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 767.2671
found: 767.2670
[M+Na]+ calculated: 789.2491
found: 789.2490 Compound 41
Figure imgf000381_0001
Chemical Formula: C40H38N6O1 1
Exact Mass: 778,2599
Cyclopentanecarbonyl chloride (5 eq, 0.436 mmol, 53 μΙ) was added via syringe to a solution of amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (5 eq, 0.436 mmol, 76 μΙ) under an atmosphere of argon. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (67 mg, 86 %). The oil (1 eq, 0.069 mmol, 62 mg) and phenylsilane (8 eq, 0.552 mmol, 68 μΙ) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.035 mmol, 40 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (2 mg, 4 %).
Ή-NMR (DMSO-d6, 400 MHz): δ [ppm] 1 .56 (m, 2H), 1 .70 (m, 4H), 1 .86 (m, 2H), 2.80 (m, 1 H), 3.06 (dd, Ji = 16.92, J2 = 8.87 Hz, 1 H), 3.15 (dd, Ji = 16.79, J2 = 4.70 Hz, 1 H), 3.77 (s, 3H), 3.89 (s, 3H), 4.97 (dd, Ji = 14.24, J2= 7.79 Hz, 1 H), 7.55 (d, J = 8.60 Hz, 2H), 7.63 (m, 1 H), 7.73 (d, J = 8.60 Hz, 2H), 7.79 (t, J = 7.80 Hz, 3H), 7.89 (d, J = 8.60 Hz, 2H), 7.98 (d, J
= 8.87 Hz, 2H), 9.01 (d, J = 7.25 Hz, 1 H), 9.69 (s, 1 H), 10.16 (s, 1 H), 10.58 (s, 1 H), 1 1 .03 (s, 1 H), 1 1 .56 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 779.2671
found: 779.2672
[M+Na]+ calculated: 801 .2491
found: 801 .2487 Compound 42
Figure imgf000382_0001
Chemical Formula: C42H42N60ii
Exact Mass: 806,2912
BTC (2.9 eq, 0.253 mmol, 75 mg) was dissolved in dry THF (5 ml) under an atmosphere of argon. Cycloheptanecarboxylic acid (9 eq, 0.785 mmol, 1 12 mg) was added. syn-Collidine (8 eq, 0.697 mmol, 91 μΙ) was slowly added via syringe and the white suspension was stirred at room temperature for 10 min. The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (10 eq, 0.872 mmol, 0.150 ml) were added via syrringe. The reaction mixture was stirred for 12 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (48 mg, 60 %). The oil (1 eq, 0.049 mmol, 45 mg) and phenylsilane (8 eq, 0.392 mmol, 48 μΙ) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.025 mmol, 28 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (10 mg, 25 %). H-NMR (DMSO-d6, 400 MHz): δ [ppm] 1 .54 (m, 4H), 1 .72 (m, 4H), 1 .84 (m, 4H), 2.54 (m, 1 H), 3.06 (dd, Ji = 17.19, J2 = 9.13 Hz, 1 H), 3.13 (dd, Ji = 16.92, J2 = 5.37 Hz, 1 H), 3.77 (s, 3H), 3.90 (s, 3H), 4.97 (dd, Ji = 13.97, J2 = 8.06 Hz, 1 H), 7.56 (d, J = 8.87 Hz, 2H), 7.71 (d, J = 8.87 Hz, 2H), 7.79 (m, 4H), 7.89 (d, J = 8.60 Hz, 2H), 7.98 (d, J = 8.60 Hz, 2H), 9.00 (d, J = 7.79 Hz, 1 H), 9.70 (s, 1 H), 10.08 (s, 1 H), 10.58 (s, 1 H), 1 1 .1 1 (s, 1 H), 1 1 .55 (s, 1 H).
HRMS (ESI): [M-H]" calculated: 805.2839
found: 805.2826 Compound 43
Figure imgf000383_0001
Chemical Formula: C4iH35N7
Exact Mass: 801 ,2395
The amine (1 eq, 0.087 mmol, 70 mg) and phenyl isocyanate (5 eq, 0.435 mmol, 0.047ml) were dissolved in dry THF (5 ml) under an atmosphere of argon. The reaction mixture was stirred at room temperature for 12 h and another portion of phenyl isocyanate (5 eq, 0.435 mmol, 0.047ml) was added. The solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (78 mg, 97 %). The oil (1 eq, 0.073 mmol, 67 mg) and phenylsilane (8 eq, 0.584 mmol, 0.072 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.036 mmol, 42 mg) was added and the mixture was stirred 12 h at room
temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (8 mg, 14 %). H-NMR (DMSO-ds, 500 MHz): δ [ppm] 3.08 (dd, J, = 16.84, J2 = 8.72 Hz, 1 H), 3.16 (m, 1 H), 3.79 (s, 3H), 3.93 (s, 3H), 4.99 (m, 1 H), 7.00 (t, J= 7.43 Hz, 1 H), 7.30 (t, J = 7.83 Hz, 2H), 7.48 (d, J= 7.93 Hz, 2H), 7.59 (m, 4H), 7.81 (m, 3H), 7.91 (d, J = 8.52 Hz, 2H), 8.00 (d, J = 8.72 Hz, 2H), 8.06 (d, J= 8.92 Hz, 1 H), 8.79 (s, 1 H), 8.97 (d, J= 7.73 Hz, 1 H), 9.02 (s, 1 H), 9.69 (s, 1 H), 10.56 (s, 1 H), 1 1 .17 (s, 1 H), 1 1 .53 (s, 1 H), 1 1 .60 (bs, 1 H).
HRMS (ESI): [M+H]+ calculated: 802.2461
found: 802.2467
[M+Na]+ calculated 824.2287
found: 824.2279 Compound 44
Figure imgf000384_0001
Chemical Formula: C47H 0N6O10
Exact Mass: 848,2806
Amino derivative (1 .0 eq, 0.062 mmol, 50 mg) and biphenyl-4-carbaldehyde (1 eq, 0.062 mmol, 1 1 mg) were dissolved in dry THF under argon atmosphere and a catalytic amount of acetic acid was added. After stirring this solution for 60 min NaBH3CN (1 .3 eq, 0.081 mmol, 5 mg) was added. After 3 h of stirring at room temperature another 1 .3 eq of NaBH3CN was added and the Mixture was stirred for 16 h. The reaction was quenched by addition of 1 N HCI and extracted three times with EtOAc. The organic solvent was dried over Na2S04, filtered and removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (55 mg, 62 %). The oil (1 eq, 0.059 mmol, 50 mg) and phenylsilane (8 eq, 0.472 mmol, 58 μΙ) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.030 mmol, 35 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (8 mg, 16 %).
H-NMR (DMSO-ds, 400 MHz): δ [ppm] 3.02 (dd, Ji = 17.19, J2 = 9.13 Hz, 1 H), 3.1 1 (dd, Ji = 16.79, J2 = 5.51 Hz, 1 H), 3.77 (s, 3H), 3.90 (s, 3H), 4.40 (d, J = 5.37 Hz, 2H), 4.92 (dd, Ji = 13.97, J2= 8.06 Hz, 1 H), 6.65 (d, J = 8.87 Hz, 2H), 7.44 (d, J = 8.06 Hz, 4H), 7.63 (d, J = 6.72 Hz, 2H), 7.65 (d, J = 5.91 Hz, 2H), 7.70 (d, J = 8.87 Hz, 2H), 7.78 (m, 4H), 7.92 (d, J = 8.33 Hz, 2H), 7.97 (d, J = 8.87 Hz, 2H), 8.01 (d, J = 8.33 Hz, 1 H), 8.64 (d, J = 7.52 Hz, 1 H), 9.69 (s, 1 H), 10.51 (s, 1 H), 1 1 .07 (s, 1 H), 1 1 .57 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 849.2879
found: 849.2878 Compound 48
Figure imgf000385_0001
Chemical Formula: C40H33FN6O12S
Exact Mass: 840,1861
The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (7 eq, 0.61 1 mmol, 0.100ml) were dissolved in dry THF (5 ml) under an atmosphere of argon. 4-Fluorobenzene-1 -sulfonyl chloride (5 eq, 0.435 mmol, 84 mg) was added and the reaction mixture was stirred for 12 hours and the reaction was quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (62 mg, 89 %). The oil (1 eq, 0.072 mmol, 58 mg) and phenylsilane (8 eq, 0.576 mmol, 71 μΙ) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.036 mmol, 42 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (23 mg, 38 %).
H-NMR (DMSO-ds, 700 MHz): δ [ppm] 3.02 (dd, Ji = 16.75, J2= 8.68 Hz, 1 H), 3.12 (dd, Ji = 16.75, J2 = 5.39 Hz, 1 H), 3.78 (s, 3H), 3.92 (s,3H), 4.94 (dd, Ji = 13.76, J2= 8.08 Hz, 1 H), 7.21 (d, J = 8.68 Hz, 2H), 7.41 (t, J = 8.68 Hz, 2H), 7.58 (t, J = 8.40 Hz, 2H), 7.76 (d, J = 8.38 Hz, 2H), 7.81 (m, 3H), 7.88 (dd, Ji = 8.68, J2 = 5.09 Hz, 2H), 7.97 (d, J = 8.68 Hz, 2H), 8.03 (d, J = 8.68 Hz, 1 H), 8.95 (d, J = 7.78 Hz, 1 H), 9.63 (s, 1 H), 10.47 (s, 1 H), 10.68 (s, 1 H), 1 1 .12 (s, 1 H), 1 1 .47 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 841 .1934
found: 841 .1929
[M+Na]+ calculated: 863.1753
found: 863.1746 Compound 49
Figure imgf000386_0001
Chemical Formula: C41 H36N60 3S
Exact Mass: 852,2061
The amine (1 eq, 0.087 mmol, 70 mg) and DIPEA (7 eq, 0.61 1 mmol, 0.100ml) were dissolved in dry THF (5 ml) under an atmosphere of argon. 4-Methoxy-sulfonic carbonyl chloride (3 eq, 0.262 mmol, 54 mg) was added an the reaction mixture was stirred for 12 hours and the reaction was quenched by the addition of water.After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 50 ml). The organic phase was washed with saturated NaHC03 solution (2 x 50 ml), aqueous HCI solution (5 %, 2 x 50 ml), water (1 x 50 ml) and brine (1 x 50 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (23 mg, 26 %). The oil (1 eq, 0.022 mmol, 22 mg) and phenylsilane (8 eq, 0.181 mmol, 0.022 ml) were dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.01 1 mmol, 13 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated after preparative HPLC purification as a white powder (9 mg, 46 %). H-NMR (DMSO-ds, 700 MHz): δ [ppm] 3.02 (dd, Ji = 16.75, J2= 8.68 Hz, 1 H), 3.12 (dd, Ji = 16.75, J2 = 5.39 Hz, 1 H), 3.78 (s, 3H), 3.92 (s,3H), 4.94 (dd, Ji = 13.76, J2 = 8.08 Hz, 1 H), 7.21 (d, J = 8.68 Hz, 2H), 7.41 (t, J = 8.68 Hz, 2H), 7.58 (t, J = 8.40 Hz, 2H), 7.76 (d, J = 8.38 Hz, 2H), 7.81 (m, 3H), 7.88 (dd, J, = 8.68, J2 = 5.09 Hz, 2H), 7.97 (d, J = 8.68 Hz, 2H), 8.03 (d, J = 8.68 Hz, 1 H), 8.95 (d, J = 7.78 Hz, 1 H), 9.63 (s, 1 H), 10.47 (s, 1 H), 10.68 (s, 1 H), 1 1 .12 (s, 1 H), 1 1 .47 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 841 .1934
found: 841 .1929
[M+Na]+ calculated: 863.1753
found: 863.1746 Compound 50
Figure imgf000387_0001
General deprotection of compound 53
H-NMR (DMSO-ds, 500 MHz): δ [ppm]3.08 (dd, Ji = 16.84 Hz, J2 = 8.72 Hz, 1 H), 3.18 (m, 1 H), 3.77 (s, 3H), 3.90 (s, 3H), 5.02 (m, 1 H), 7.55 (d, J= 8.92 Hz, 2H), 7.79 (m, 3H), 7.97 (m, 3H), 8.17 (d, J = 8.72 Hz, 2H), 8.37 (d, J = 8.72 Hz, 2H), 9.53 (d, J= 7.53 Hz, 1 H), 9.68 (s, 1 H), 10.62 (s, 1 H), 1 1 .09 (s, 1 H), 1 1 .54 (bs, 1 H).
HRMS (ESI): [M+H]+ calculated: 713.1838
found: 713.1862
Compound 51
Figure imgf000387_0002
General deprotection of compound 54 H-NMR (DMSO-ds, 500 MHz): δ [ppm] 3.03 (d, J, = 16.84 Hz, J2 = 8.72 Hz, 1 H), 3.1 1 (m, 1 H), 3.77 (s, 3H), 3.91 (s, 3H), 4.92 (m, 1 H), 6.63 (d, J= 8.52 Hz, 2H), 7.33 (m, 1 H), 7.58 (m, 3H), 7.68 (d, J = 8.52 Hz, 2H), 7.79 (m, 3H), 7.97 (d, J = 8.52 Hz, 2H), 8.05 (d, J = 8.92 Hz, 1 H), 8.64 (d, J = 7.73 Hz, 1 H), 9.68 (s, 1 H), 10.51 (s, 1 H), 1 1 .17 (s, 1 H), 1 1 .53 (bs, 1 H).
HRMS (ESI): [M+H]+ calculated: 683.2096
found: 683.2123
[M+Na]+ calculated: 705.1916
found: 705.1940 Compound 52
(S)-4-(3-Cyano-2-(4-nitrobenzamido)propanamido)benzoic acid
Figure imgf000388_0001
{S)-tert- Butyl 4-(2-(te/t-butoxycarbonylamino)-3-cyanopropanamido)benzoate (56) (1 .0 eq, 0.81 mmol, 314 mg) was dissolved in HCI/dioxane (4 M, 5 mL) and the reaction mixture was stirred at room temperature until cleavage of the Boc group and te/t-butyl ester was completed (LC/MS monitoring, approximately 6 hours). The solvent was removed under reduced pressure and the residue resolved in dry DMF (10 mL) under argon atmosphere. Triethylamine (3.0 eq, 2.42 mmol, 0.73 mL) and 2,5-dioxopyrrolidin-1 -yl 4-nitrobenzoate (1 .1 eq, 0.89 mmol, 234 mg) were added and the mixture was stirred at room temperature for 16 h. EtOAc (50 mL) was added and the mixture was washed successively with brine (3 x 25 mL), saturated NaHC03 solution (2 x 25 mL), HCI (5 %, 2 x 25 mL) and brine (1 x 25 mL). The organic phase was dried over Na2S04, filtered and the solvent was removed under reduced pressure. Column chromatography (CHCI3:CH3OI-l - 9:0.5) yielded the product as a white solid (1 19 mg, 39 %)
Compound 53
Allyl 2-(allyloxy)-4-(2-(allyloxy)-4-amino-3-methoxybenzamido)-3-methoxybenzoate
Figure imgf000388_0002
Allyl 2-(allyloxy)-4-(2-(allyloxy)-3-methoxy-4-nitrobenzamido)-3-methoxybenzoate (63) (1 .0 eq, 2.41 mmol, 1 .2 g) and SnCI2 *2H20 (7.0 eq, 16.86 mmol, 3.8 g) were dissolved in EtOH (40 mL) and stirred at 60 'C for 1 h. The solution was concentrated under reduced pressure and diluted with water (100 mL). The pH was adjusted to 8-9 by adding saturated NaHC03 solution and the aqueous suspension was extracted with EtOAc (3 x 250 mL). The phases were separated and the organic phase was washed with brine (1 x 250 mL), dried over Na2S04 and filtered. After removing the solvent under reduced pressure, column chromatography (H:EA - 3:1 ) yielded the product as an orange oil (892 mg, 79 %).
Compound 54
(S)-Allyl 2-(allyloxy)-4-(2-(allyloxy)-4-(4-(3-cyano-2-(4-nitrobenzamido)propanamido) benzamido)-3-methoxybenzamido)-3-methoxybenzoate
Figure imgf000389_0001
Bis-(trichloromethyl)carbonate (0.5 eq, 0.13 mmol, 37 mg) and (S)-4-(3-Cyano-2-(4- nitrobenzamido)propanamido)benzoic acid (52) (1 .5 eq, 0.38 mmol, 146 mg) were dissolved in dry THF (3 mL) under argon atmosphere. 2,4,6-Collidine (8.0 eq, 2.04 mmol, 270 DL) was added slowly via syringe. The resulting suspension was stirred at room temperature for 1 h and a solution of (53) (1 .0 eq, 0.26 mmol, 1 19 mg), DIPEA (10.0 eq, 2.55 mmol, 430 DL) in dry THF (2 mL) was added. Stirring was continued for 20 h at room temperature and the reaction was quenched by addition of MeOH (2 mL). The organic solvent was removed under reduced pressure and EtOAc (20 mL) was added. The mixture was washed successively with saturated NaHC03 (2 x 10 mL), HCI (5 %, 2 x 10 mL), water (1 x 10 mL) and brine (1 x 10 mL). The organic solvent was dried over Na2S04, filtered and removed under reduced pressure. Purification by column chromatography (H:EA - 1 :1 ) yielded the product as a white solid (1 15 mg, 54 %).
Compound 55
(S)-Allyl 2-(allyloxy)-4-(2-(allyloxy)-4-(4-(2-(4-aminobenzamido)-3-cyanopropanamido) benzamido)-3-methoxybenzamido)-3-methoxybenzoate
Figure imgf000389_0002
(S)-Allyl 2- (allyloxy) -4- (2- (allyloxy) -4- (4- (3-cyano -2- (4-nitrobenzamido) propanamido) benzamido)-3-methoxybenzamido)-3-methoxybenzoate (54) (1 .0 eq, 0.13 mmol, 106 mg) and SnCI2 *2H20 (5.0 eq, 0.63 mmol, 143 mg) were dissolved in EtOH (10 mL) and stirred at 60 'Ό for 6 h. The solution was concentrated under reduced pressure and diluted with water (10 mL). The pH was adjusted to 8-9 by adding saturated NaHC03 solution and the aqueous suspension was extracted with EtOAc (3 x 50 mL). The phases were separated and the organic phase was washed with brine (1 x 25 mL), dried over Na2S04 and filtered. After removing the solvent under reduced pressure, column chromatography (CHCI3:CH3OI-l - 9:0.3) yielded the product as a slightly yellow solid (69 mg, 67 %). Compound 56
(S)-te/?-Butyl 4-(2-(te/t-butoxycarbonylamino)-3-cyanopropanamido)benzoate
Figure imgf000390_0001
Method A:
Boc-L-Asn-OH (1 .0 eq, 4.31 mmol, 1 .0 g), DIPEA (5.0 eq, 21 .53 mmol, 3.7 ml_) and HATU (2.0 eq, 8.61 mmol, 3.3 g) were dissolved in dry DMF (40 ml_) under argon atmosphere. After stirring for 10 min at room temperature te/t-butyl 4-aminobenzoate (1 .0 eq, 4.31 mmol, 0.8 g) was added and stirring was continued for 19 h. EtOAc (200 ml_) was added and the mixture was washed successively with brine (3 x 80 ml_), saturated NaHC03 solution (2 x 80 ml_), HCI (5 %, 2 x 80 ml_) and brine (1 x 80 ml_). The organic phase was dried over MgS04, filtered and the solvent was removed under reduced pressure. Column chromatography (H:EA - 4:1 ) yielded the product as a white solid (1 .4 g, 84 %).
Method B:
Boc-L-Asn-OH (1 .0 eq, 4.31 mmol, 1 .0 g), DIPEA (5.0 eq, 21 .53 mmol, 3.7 ml_) and HATU (2.0 eq, 8.61 mmol, 3.3 g) were dissolved in dry DMF (40 ml_) under argon atmosphere. After stirring for 10 min at room temperature te/t-butyl 4-aminobenzoate (1 .0 eq, 4.31 mmol, 0.8 g) was added and stirring was continued for 19 h. EtOAc (200 ml_) was added and the mixture was washed successively with brine (3 x 80 ml_), saturated NaHC03 solution (2 x 80 ml_), HCI (5 %, 2 x 80 ml_) and brine (1 x 80 ml_). The organic phase was dried over MgS04, filtered and the solvent was removed under reduced pressure. Column chromatography (H:EA - 4:1 ) yielded the product as a white solid (1 .4 g, 84 %).
Boc-L-Asn-OH (2.0 eq, 2.07 mmol, 481 mg) and DCC (4.0 eq, 4.14 mmol, 854 mg) are dissolved in dry DMF (10 ml_) under an atmosphere of argon, te/t-butyl 4-aminobenzoate (1 .0 eq, 1 .04 mmol, 200 mg) is added and the reaction mixture is stirred at room temperature for 12 h. EtOAc (50 ml_) is added and the mixture is washed with brine (3 x 20 ml_). The mixture was washed successively with brine (3 x 80 ml_), saturated NaHC03 solution (2 x 20 ml_), HCI (5 %, 2 x 20 ml_) and brine (1 x 20 ml_). The organic phase was dried over MgS04, filtered and the solvent was removed under reduced pressure. Column chromatography (H:EA - 4:1 ) yielded the product as a white solid (331 mg, 65 %). Compound 63
Allyl 2-(allyloxy)-4-(2-(allyloxy)-3-methoxy-4-nitrobenzamido)-3-methoxybenzoate
Figure imgf000391_0001
Bis-(trichloromethyl)carbonate (0.5 eq, 1 .31 mmol, 388 mg) and 2-(allyloxy)-3-methoxy-4- nitrobenzoic acid (1 .5 eq, 4.01 mmol, 1014 mg) were dissolved in dry THF (25 ml_) under argon atmosphere. 2,4,6-Collidine (8.0 eq, 21 .38 mmol, 2.8 ml_) was added slowly via syringe. The resulting suspension was stirred at room temperature for 15 min and a solution of allyl 2-(allyloxy)-4-amino-3-methoxybenzoate (1 .0 eq, 2.67 mmol, 703 mg), DIPEA (10.0 eq, 26.72 mmol, 4.5 ml_) in dry THF (25 ml_) was added. Stirring was continued for 1 1 h at room temperature and the reaction was quenched by addition of water (10 ml_). The organic solvent was removed under reduced pressure and EtOAc (70 ml_) was added. The mixture was washed successively with saturated NaHC03 (2 x 25 ml_), HCI (5 %, 2 x 25 ml_), water (1 x 25 ml_) and brine (1 x 25 ml_). The organic solvent was dried over Na2S04, filtered and removed under reduced pressure. Purification by column chromatography (heaxane (H): ethyl acetate (EA); H:EA - 8:1 ) yielded the product as a slightly yellow oil (1 .2 g, 91 %).
Compound 64
Figure imgf000391_0002
Free amine (1 .0 eq) and aldehyde (1 .0 eq) were dissolved in MeOH and acetic acid (3.5 eq) was added. To this solution NaBH3CN (1 .2 eq) was added and the mixture was stirred for 16 h at room temperature. The reaction mixture was quenched with saturated NaHC03 solution and extracted with EtOAc. The organic solvent was dried over Na2S04, filtered and removed under reduced pressure. The residue was dissolved in 4 N HCI in dioxane. After 5 h of stirring at room temperature the organic solvent was removed under reduced pressure. The residue was dissolved in 10% NaHC03 and filtrated. Acidification with cone. HCI precipitated the pure carboxylic acid which was isolated by filtration Compound 66
Figure imgf000392_0001
66
Boc-Gly-OH (2.0 eq, 20.8 mmol, 3.64 g), DIPEA (5.0 eq, 52.0 mmol, 8.8 mL) and HATU (1 .9 eq, 19.8 mmol, 7.51 g) were dissolved in dry DMF (200 mL) under argon atmosphere. After stirring for 10 min at room temperature te/t-butyl 4-aminobenzoate (1 .0 eq, 10.4 mmol, 2.00 g) was added and stirring was continued for 18 h. EtOAc (400 mL) was added and the mixture was washed successively with brine (3 x 160 mL), saturated NaHC03 solution (2 x 160 mL), HCI (5 %, 2 x 160 mL) and brine (1 x 160 mL). The organic phase was dried over Na2S04, filtered and the solvent was removed under reduced pressure. Column
chromatography (H:EA - 5:2) yielded the product as a white solid (3.15 g, 86 %).
H-NMR (dmso-ds, 400 MHz): δ [ppm] 1 .38 (s, 3H), 1 .52 (s, 3H), 3.73 (d, J = 6.18 Hz, 2H), 7.07 (t, J = 6.04 Hz, 1 H), 7.68 (d, J = 8.60 Hz, 2H), 7.84 (d, J = 8.87 Hz, 2H), 10.23 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 351 .1914
found: 351 .191 1
[M+Na]+ calculated: 373.1734
found: 373.1729
Compound 68
Figure imgf000392_0002
68
Compound (66) (1 .0 eq, 8.57 mmol, 3.0 g) was dissolved in HCI/dioxane (4 M, 20 mL) and the reaction mixture was stirred at room temperature until cleavage of the boc group and tert- butyl ester was completed (LC/MS monitoring, approximately 6 hours). The solvent was removed under reduced pressure and the residue resolved in dry DMF (25 mL) under argon atmosphere. Triethylamine (2.0 eq, 17.14 mmol, 2.4 mL) and 2,5-dioxopyrrolidin-1 -yl 4- nitrobenzoate (1 .1 eq, 9.43 mmol, 2.5 g) were added and the mixture was stirred at room temperature for 16 h. EtOAc (300 mL) was added and the mixture was washed successively with HCI (5 %, 1 x 100 mL) and brine (3 x 100 mL). The product was filtered and lyophilized and obtained as a white solid (1 .6 g, 54 %, two steps). H-NMR (dmso-ds, 400 MHz): δ [ppm] 4.14 (d, J = 5.64 Hz, 2H), 7.73 (d, J = 8.87 Hz, 2H), 7.90 (d, J = 8.60 Hz, 2H), 8.14 (d, J = 9.13 Hz, 2H), 8.35 (d, J = 8.87 Hz, 2H), 9.27 (t, J = 5.78 Hz, 1 H), 10.48 (s, 1 H), 12.56 (bs, 1 H).
HRMS (ESI): [M+H]" calculated: 342.0721
found: 342.0718
Compound 69
Figure imgf000393_0001
Bis-(trichloromethyl)carbonate (1 .15 eq, 0.61 mmol, 182 mg) and (68) (3.5 eq, 1 .87 mmol, 641 mg) were dissolved in dry THF (15 mL) under argon atmosphere. 2,4,6-Collidine (8.0 eq, 4.27 mmol, 0.6 mL) was added slowly via syringe. The resulting suspension was stirred at room temperature for 1 h and a solution of (53) (1 .0 eq, 0.53 mmol, 250 mg), DIPEA (10.0 eq, 5.34 mmol, 0.9 mL) in dry THF (10 mL) was added. Stirring was continued for 20 h at room temperature and the reaction was quenched by addition of water (10 mL). The organic solvent was removed under reduced pressure and EtOAc (50 mL) was added. The mixture was washed successively with saturated NaHC03 (2 x 20 mL), HCI (5 %, 2 x 20 mL), water (1 x 20 mL) and brine (1 x 20 mL). The organic solvent was dried over NagSC , filtered and removed under reduced pressure. Purification by column chromatography (C:M - 18:1 ) yielded the product as a white solid (228 mg, 54 %). H-NMR (dmso-ds, 400 MHz): δ [ppm] 3.92 (s, 3H), 3.93 (s, 3H), 4.16 (d, J = 5.91 Hz, 2H), 4.45 (d, J = 5.64 Hz, 2H), 4.78 (d, J = 5.64 Hz, 2H), 4.80 (d, J = 6.18, 2H), 5.27 (m, 3H), 5.40 (m, 3H), 6.08 (m, 3H), 7.57 (d, J = 8.87 Hz, 1 H), 7.80 (m, 3H), 7.93 (d, J = 8.87 Hz, 1 H), 7.98 (d, J = 8.87 Hz, 2H), 8.15 (d, J = 8.87 Hz, 2H), 8.33 (d, J = 8.87 Hz, 1 H), 8.37 (d, J = 8.87 Hz, 2H), 9.27 (t, J = 5.78 Hz, 1 H), 10.46 (s, 1 H), 10.66 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 794.2668
found: 794.2678
[M+Na]+ calculated: 816.2487
found: 816.2497 Compound 70
Figure imgf000394_0001
Compound (69) (1 .0 eq, 0.26 mmol, 200 mg) and SnCI2 *2H20 (7.0 eq, 1 .80 mmol, 400 mg) were dissolved in EtOH (10 ml_) and stirred at 60 'C for 3 h when another portion of
SnCI2 *2H20 (3.5 eq, 0.90 mmol, 200 mg) and the stirring continued for another 3 h. The solution was concentrated under reduced pressure and diluted with EtOAc (200 ml_).
Saturated NaHC03 solution (400 ml_) was added and extracted with EtOAc (2 x 300 ml_). The phases were separated and the organic phase was washed with brine (1 x 400 ml_), dried over Na2S04 and filtered. After removing the solvent under reduced pressure, column chromatography (CHCI3:CH3OH - 1 .5 % MeOH) yielded the product as a slightly yellow solid (140 mg, 71 %). H-NMR (dmso-ds, 400 MHz): δ [ppm] 3.92 (s, 3H), 3.93 (s, 3H), 4.04 (d, J = 5.91 Hz, 2H), 4.54 (d, J = 5.91 Hz, 2H), 4.79 (m, 4H), 5.33 (m, 6H), 5.67 (s, 2H), 6.08 (m, 3H), 6.57 (d, J = 8.60 Hz, 2H), 7.57 (d, J = 8.87 Hz, 1 H), 7.63 (d, J = 8.60 Hz, 2H), 7.79 (m, 3H), 7.95 (m, 3H), 8.34 (d, J = 8.87 Hz, 1 H), 8.40 (t, J = 5.78 Hz, 1 H), 9.66 (s, 1 H), 10.35 (s, 1 H), 10.66 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 764.2926
found: 764.2941
Compound 70
Figure imgf000394_0002
BTC (2.0 eq, 0.19 mmol, 56 mg) was dissolved in dry THF (5 ml) under an atmospher of argon. (E)-3-(4-(allyloxy)phenyl)-2-methylacrylic acid (6.0 eq, 0.56 mmol, 123 mg) was added. syn-Collidine (8.0 eq, 0.94 mmol, 0.1 ml) was slowly added via syrringe and the white suspension was stirred at room temperature for 20 min. 18 (1 eq, 0.09 mmol, 72 mg) and DIPEA (10 eq, 1 .13 mmol, 0.19 ml) dissolved in dry THF (5 ml_) were added via syrringe. The reaction mixture was stirred for 4 h at room temperature and quenched by the addition of water. After removing the organic solvent under reduced pressure the aqueous phase was extracted with EtOAc (3 x 40 ml). The organic phase was washed with saturated NaHC03 solution (2 x 25 ml), aqueous HCI solution (5 %, 2 x 25 ml), water (1 x 25 ml) and brine (1 x 25 ml). After drying over Na2S04 and filtration, the solvent was removed under reduced pressure. Column chromatography (CHCI3:MeOH; 1 .5 % MeOH) yielded the product as an orange oil (61 mg, 67 %). The oil (1 eq, 0.06 mmol, 56 mg) and phenylsilane (8 eq, 0.47 mmol, 0.057 ml_) were dissolved in dry THF (5 ml_) under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (0.5 eq, 0.03 mmol, 34 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The product was isolated by preparative HPLC purification as a white powder (8 mg, 17 %). H-NMR (DMSO-ds, 700 MHz): δ [ppm] 2.12 (s, 3H), 3.78 (s, 3H), 3.92 (s, 3H), 4.1 1 (d, J = 5.31 Hz, 2H), 6.85 (d, J = 8.47, 2H), 7.27 (s, 1 H), 7.36 (d, J = 8.47 Hz, 2H), 7.59 (t, J = 9.28 Hz, 2H), 7.81 (m, 5H), 7.89 (d, J = 9.59 Hz, 2H), 7.98 (d, J = 7.77 Hz, 2H), 8.07 (d, J = 9.03 Hz, 1 H), 8.81 (t, J = 5.39 Hz, 1 H), 9.71 (s, 1 H), 9.80 (s, 1 H), 8.81 (s, 1 H), 10.42 (s, 1 H), 1 1 .20 (s, 1 H), 1 1 .56 (s, 1 H), 1 1 .63 (bs, 1 H).
HRMS (ESI): [M-H]" calculated: 802.2355
found: 802.2362
Compound 71
Figure imgf000395_0001
Chemical Formula: C43H37N70 2
Exact Mass: 843,2500
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[4-[[(2S)-2-[[5-[[(E)-3-(4-allyloxyphenyl)-2-methyl-prop-2- enoyl]amino]pyridine-2-carbonyl]amino]-3-cyano-propanoyl]amino]benzoyl]amino]-3- methoxy-benzoyl]amino]-3-methoxy-benzoate (65 mg, 0.065 mmol, 1 .00 eq), was dissolved in THF (5 ml). Phenylsilane (56 mg, 64 μΙ, 0.518 mmol, 8.00 eq) and [Pd(PPh3)4] (38 mg, 0.032 mmol, 0.50 eq) were added and the mixture was stirred for 16 h. After adding 3 drops of acetic acid the solvent was removed and the crude product was purified via HPLC chromatography to give the product as a white solid (42 %).
H-NMR (400 MHz, DMSO-d6): 3.21 - 3.27 (m, 2H), 3.77 (s, 3H), 3.91 (s, 3H), 5.02- 5.07 (m, 1 H), 6.85 (d, J = 8.6 Hz, 2H), 7.34 (s, 1 H), 7.38 (d, J = 8.6 Hz, 2H), 7.55 - 7.60 (m, 3H), 7.76 - 7.82 (m, 2H), 7.99 (d, J = 8.6 Hz, 2H), 8.04 - 8.09 (m, 2H), 8.36 - 8.39 (m, 1 H), 9.02 (s, 1 H), 9.18 (d, J= 8.1 Hz, 1 H), 9.73 (s, 1 H), 10.40 (s, 1 H), 1 1 .19 (s, 1 H), 1 1 .55 (s, 1 H)
HR-MS: calc.: [M+H]+: 844.2549
found: [M+H]+: 844.2573
Compound 72
Figure imgf000396_0001
Chemical Formula: C43H37N7012
Exact Mass: 843,2500
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[5-[[(2S)-2-[[4-[[(E)-3-(4-allyloxyphenyl)-2-methyl-prop-2- enoyl]amino]benzoyl]amino]-3-cyano-propanoyl]amino]pyridine-2-carbonyl]amino]-3- methoxy-benzoyl]amino]-3-methoxy-benzoate (1 .00 eq) was dissolved in THF. Phenylsilane (8.00 eq) and [Pd(PPh3)4] (0.50 eq) were added and the mixture was stirred for 16 h. After adding 3 drops of acetic acid the solvent was removed and the crude product was purified via HPLC chromatography to give the product as a solid.
Compound 73
Figure imgf000396_0002
Chemical Formula: C42H36N8012
Exact Mass: 844,2453
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[5-[[(2S)-2-[[5-[[(E)-3-(4-allyloxyphenyl)-2-methyl-prop-2- enoyl]amino]pyridine-2-carbonyl]amino]-3-cyano-propanoyl]amino]pyridine-2- carbonyl]amino]-3-methoxy-benzoyl]amino]-3-methoxy-benzoate (1 .00 eq) was dissolved in THF. Phenylsilane (8.00 eq) and [Pd(PPh3)4] (0.50 eq) were added and the mixture was stirred for 16 h. After adding 3 drops of acetic acid the solvent was removed and the crude product was purified via HPLC chromatography to give the product as a solid.
Compound 74
Figure imgf000397_0001
Chemical Formula: C43H38N6013S
Exact Mass: 878,2218
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[4-[[(2S)-2-[[4-[[(E)-3-(4-allyloxyphenyl)-2-methyl-prop-2- enoyl]amino]benzoyl]amino]-3-cyano-propanoyl (1 .00 eq) was dissolved in THF. Phenylsilane (8.00 eq) and [Pd(PPh3)4] (0.50 eq) were added and the mixture was stirred for 16 h. After adding 3 drops of acetic acid the solvent was removed and the crude product was purified via HPLC chromatography to give the product as a solid.
Compound 75
Figure imgf000397_0002
Chemical Formula: C43H38N60 3S
Exact Mass: 878,2218
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[4-[[(2S)-2-[[4-[[(E)-3-(4-allyloxyphenyl)-2-methyl-prop-2- enoyl]amino]phenyl]sulfonylamino]-3-cyano-propanoyl]amino]benzoyl]amino]-3-methoxy- benzoyl]amino]-3-methoxy-benzoate (1 .00 eq) was dissolved in THF. Phenylsilane (8.00 eq) and [Pd(PPh3)4] (0.50 eq) were added and the mixture was stirred for 16 h. After adding 3 drops of acetic acid the solvent was removed and the crude product was purified via HPLC chromatography to give the product as a solid.
Compound 76
Figure imgf000398_0001
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[4-[[(2S)-3-cyano-2-[[4-[[(E)-3-(4-diallyloxyphosphoryloxy phenyl)-2-methyl-prop-2-enoyl]amino]benzoyl]amino]propanoyl]amino]benzoyl]am
methoxy-benzoyl]amino]-3-methoxy-benzoate (1 eq, 0.0534 mmol, 60 mg) with phenylsilane (20 eq, 1 .07 mmol, 132 μΙ) dissolved in dry THF under an atmosphere of argon and exclusion of light. Pd[P(Ph)3]4 (1 eq, 0.0534 mmol, 62 mg) was added and the mixture was stirred 12 h at room temperature. After adding 3 drops of acetic acid the solvent was removed under reduced pressure. The final product was isolated after preparative HPCL purification as a white powder
Starting materials:
Allyl 2-(allyloxy)-4-nitrobenzoate
OAllyl
Figure imgf000398_0002
2-Hydroxy-4-nitrobenzoic acid (1 .0 eq, 27.32 mmol, 5.0 g) was dissolved in DMF (150 ml_) and K2CO3 (4.0 eq, 109.28 mmol, 15.1 g) were added. Allyl-Br (3.0 eq, 81 .96 mmol, 7.1 ml_) were slowly added via syringe and the reaction mixture was stirred 12 h at room
temperature. It was diluted with EtOAc (200 ml_) and washed with brine (3 x 100 ml_). The organic solvent was dried over Na2S04, filtered and purified by column chromatography (H:EE - 10:1 ). The product was isolated as an orange oil (6.5 g, 90 %).
Ή-NMR (dmso-d6, 400 MHz): δ [ppm] 4.80 (m, 4H), 5.27 (m, 2H), 5.42 (m, 2H), 6.01 (m, 2H), 7.87 (m, 3H).
HRMS (ESI): [M+H]+ calculated: 264.0866
found: 264.0869 2-(Allyloxy)-4-nitrobenzoic acid
Figure imgf000399_0001
Allyl 2-(allyloxy)-4-nitrobenzoate (1 .0 eq, 3.72 mmol, 1 .0 g) was dissolved in THF (50 mL) and MeOH (75 mL). KOH (5.0 eq, 18.58 mmol, 1 .0 g) dissolved in H20 (50 mL) was added and the reaction mixture was stirred at room temperature for 23 h. The organic solvents were removed and the aqueous phase acidified with HCI (5%) and the product was filtered and freeze dried. The product was isolated as a white solid (775 mg, 94%).
H-NMR (dmso-ds, 500 MHz): δ [ppm] 4.81 (d, J= 4.76 Hz, 2H), 5.30 (m, 1 H), 5.49 (m, 1 H), 6.05 (m, 1 H), 7.84 (m, 3H).
HRMS (ESI): [M-H]" calculated: 222.0397
found: 222.0400
Allyl 2-(allyloxy)-4-aminobenzoate
OAllyl
Figure imgf000399_0002
Allyl 2-(allyloxy)-4-nitrobenzoate (1 .0 eq, 3.80 mmol, 1 .0 g) was dissolved in EtOH (20 mL), SnCI2 *2H20 (5.0 eq, 19.0 mmol, 4.3 g) was added and the reaction mixture was stirred at 60 °C for 4 h. The solvent was removed under reduced pressure and the residue diluted with EtOAc (100 mL). Saturated NaHC03-solution (300 mL) was added and after phase separation the aqueous phase was extracted with EtOAc (2 x 200 mL). The organic solvent was washed with brine (1 x 400 mL), dried over NagSC , filtered and removed under reduced pressure. The product was obtained after column chromatography (H:EE - 3:1 ) as a yellow oil (779 mg, 88%).
Ή-NMR (dmso-d6, 400 MHz): δ [ppm] 4.49 (m, 2H), 4.63 (m, 2H), 5.22 (m, 2H), 5.35 (m, 1 H), 5.53 (m, 1 H), 6.01 (m, 4H), 6.18 (m, 2H), 7.55 (d, J = 8.33 Hz, 1 H).
HRMS (ESI): [M+H]+ calculated: 234.1 125
found: 234.1 1 15 Allyl 3-methoxy-4-nitrobenzoate
Figure imgf000400_0001
3-Methoxy-4-nitrobenzoic acid (1 .0 eq, 5.07 mmol, 1 .0 g) and K2C03 (2.0 eq, 10.15 mmol, 1 .4 g) were dissolved in DMF (20 mL) and Allyl-Br (1 .2 eq, 6.09 mmol, 0.5 mL) was added. The reaction mixture was stirred at room temperature for 20 h and diluted with EtOAc (100 mL). Water (100 mL) was added and the phases were separated. The organic phase was washed with brine (3 x 100 mL), dried over Na2S04, filtered and removed under reduced pressure. The product was obtained after column chromatography (H:EE - 10:1 ) as a colorless oil (1 .2 g, 98%). H-NMR (dmso-ds, 400 MHz): δ [ppm] 4.00 (s, 3H), 4.86 (m, 2H), 5.31 (m, 1 H), 5.43 (m, 1 H), 6.06 (m, 1 H), 7.69 (dd, Ji = 8.33 Hz, J2 = 1 .61 Hz, 1 H), 7.78 (d, J = 1 .34 Hz, 1 H), 8.00 (d, J = 8.33 Hz, 1 H).
HRMS (ESI): [M+Na]+ calculated: 260.0529
found: 260.0236
Allyl 4-amino-3-methoxybenzoate
Figure imgf000400_0002
Allyl 3-methoxy-4-nitrobenzoate (1 .0 eq, 4.64 mmol, 1 .1 g) and SnCI2 *2H20 (5.0 eq, 23.20 mmol, 5.2 g) were dissolved in EtOH (50 mL). The reaction mixture was stirred for 6 h at 60 'Ό and the solvent was removed under reduced pressure. The residue was diluted with EtOAc (100 mL) and saturated NaHC03 (50 mL) was added. After separating the phases, the aqueous phase was extracted with EtOAc (100 mL). The combined organic layers were washed with brine (1 x 200 mL), dried over Na2S04 and filtered. After removing the solvent under reduced pressure the product was obtained after column chromatography (H:EE - 3:1 ) as a brown oil (720 mg, 75%).
H-NMR (dmso-ds, 400 MHz): δ [ppm] 3.81 (s, 3H), 4.71 (m, 2H), 5.23 (m, 1 H), 5.36 (m, 1 H), 5.67 (s, 2H), 6.02 (s, 1 H), 6.66 (d, J = 8.33 Hz, 1 H), 7.31 (d, J = 1 .61 Hz, 1 H), 7.42 (dd, Ji = 8.19 Hz, J2 = 1 .75 Hz, 1 H).
HRMS (ESI): [M+H]+ calculated: 208.0968
found: 208.0965 2-(Allyloxy)-3-methoxy-4-nitrobenzaldehyde
Figure imgf000401_0001
2-Hydroxy-3-methoxy-4-nitrobenzaldehyde (1 .0 eq, 72 mmol, 14.25 g) was dissolved in DMF (400 mL) and K2C03 (2.0 eq, 145 mmol, 20.00 g) was added. Allyl bromide (1 .5 eq, 108 mmol, 9.4 mL) was added via syringe and the mixture was stirred at room temperature for 12 h. EtOAc (500 mL) was added and the mixture was washed with brine (3 x 200 mL). After drying over Na2S04 and filtration the solvent was removed under reduced pressure.
Purification by column chromatography (H:EA - 10:1 ) yielded the product as an orange oil (14.0 g, 82 %).
H-NMR (dmso-ds, 400 MHz): δ [ppm] 3.95 (s, 3H), 4.71 (s, 2H), 5.29 (dd, Ji = 10.48 Hz, J2 = 1 .61 Hz, 1 H), 5.41 (dd, Ji = 17.19 Hz, J2 = 1 .34 Hz, 1 H), 6.12 (m, 1 H), 7.61 (d, J = 8.60 Hz, 1 H), 7.74 (d, J = 8.33 Hz, 1 H), 10.28 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 238.0710
found: 238.0750
2-(Allyloxy)-3-methoxy-4-nitrobenzoic acid
Figure imgf000401_0002
2-(Allyloxy)-3-methoxy-4-nitrobenzaldehyde (1 .0 eq, 5.87 mmol, 1 .39 g) was dissolved in fBuOH (44 mL) and 2-methylbut-2-ene (1 .2 mlJmmol) and NaCI02 (1 .2 eq, 7.04 mmol, 0.8 g - 80 %) in NaH2P04 (0.5 M in water, 7 mL) was added. The mixture was stirred at room temperature for 3 h and the solvent was removed under reduced pressure. After diluting with water the pH was adjusted to 2 (5 % HCI). After cooling the precipitate was filtered and dried. The product was obtained as a white solid (1 .4 g, 92 %).
H-NMR (dmso-ds, 400 MHz): δ [ppm] 3.90 (s, 3H), 4.57 (s, 2H), 5.24 (dd, 1 H, J, = 10.34 Hz, J2 = 1 .48 Hz, 1 H), 5.37 (dd, Ji = 17.19 Hz, J2 = 1 .61 Hz, 1 H), 6.03 (m, 1 H), 7.52 (d, J = 8.60 Hz, 1 H), 7.67 (d, J = 8.60 Hz, 1 H).
HRMS (ESI): [M+H]+ calculated: 254.0659
found: 254.0662 Allyl 2-(allyloxy)-3-methoxy-4-nitrobenzoate
Figure imgf000402_0001
2-(Allyloxy)-3-methoxy-4-nitrobenzoic acid (1 .0 eq, 1 .76 mmol, 445 mg) was dissolved in DMF (10 mL) and K2C03 (2.0 eq, 3.52 mmol, 486 mg) was added. Allyl iodide (1 .5 eq, 2.66 mmol, 0.24 mL) was added via syringe and the mixture was stirred at room temperature for 12 h. EtOAc (100 mL) was added and the mixture was washed with brine (3 x 30 mL). After drying over Na2S04 and filtration the solvent was removed under reduced pressure.
Purification by column chromatography (H:EA - 12:1 ) yielded the product as an orange oil (471 mg, 87 %). H-NMR (dmso-ds, 400 MHz): δ [ppm] 3.92 (s, 3H), 4.56 (d, J = 5.91 Hz, 1 H), 4.80 (d, J = 5.37 Hz, 1 H), 5.32 (m, 4H), 6.02 (m, 2H), 7.58 (d, J = 8.60 Hz, 1 H), 7.71 (d, J = 8.60 Hz, 1 H).
HRMS (ESI): [M+H]+ calculated: 294.0972
found: 294.0990
Allyl 2-(allyloxy)-4-amino-3-methoxybenzoate
Figure imgf000402_0002
Allyl 2-(allyloxy)-3-methoxy-4-nitrobenzoate (1 .0 eq, 1 .61 mmol, 471 mg) and SnCI2 *2H20 (5.0 eq, 8.04 mmol, 1 .81 g) were dissolved in EtOH (20 mL) and stirred at 60 °C for 1 h. The solution was concentrated under reduced pressure and diluted with water (50 mL). The pH was adjusted to 8-9 by adding saturated NaHC03 solution and the aqueous suspension was extracted with EtOAc (3 x 100 mL). The phases were separated and the organic phase was washed with brine (1 x 100 mL), dried over Na2S04 and filtered. After removing the solvent under reduced pressure, column chromatography (H:EA - 8:1 ) yielded the product as an orange oil (355 mg, 84 %). H-NMR (dmso-ds, 400 MHz): δ [ppm] 3.67 (s, 3H), 4.43 (m, 2H), 4.64 (m, 2H), 5.19 (m, 2H), 5.34 (m, 2H), 5.77 (s, 2H), 6.01 (m, 2H), 6.44 (d, J = 8.60 Hz, 1 H), 7.33 (d, J = 8.60 Hz, 1 H).
HRMS (ESI): [M+H]+ calculated: 264.1230
found: 264.1233 (E)-Allyl 3-(4-(allyloxy)phenyl)-2-methylacrylate
AllylO
Figure imgf000403_0001
(E)-3-(4-hydroxyphenyl)-2-methyl-prop-2-enoic acid (1 .0 eq, 5.60 mmol, 1 .0 g), which can be synthesised according to Yamamoto, A., Nakamura, K., Furukawa, K., Konishi, Y., Ogino, T., Higashiura, K., Yago, H., Okamoto, K., Otsuka, M., Chem. Pharm. Bull., 2002, 50, 47-52, was dissolved in DMF (50 mL) and K2C03 (3.0 eq, 16.8 mmol, 2.32 g) was added. Allyl iodide (3.0 eq, 16.8 mmol, 1 .53 mL was added via syringe and the mixture was stirred at room temperature for 12 h. EtOAc (150 mL) was added and the mixture was washed with brine (3 x 50 mL). After drying over Na2S04 and filtration the solvent was removed under reduced pressure. Purification by column chromatography (H:EA - 12:1 --> 4:1 )) yielded the product as an orange oil (1 .3 g, 90 %). H-NMR (dmso-ds, 400 MHz): δ [ppm] 2.08 (s, 3H), 4.62 (d, J = 4.61 Hz, 2H), 4.68 (d, J = 5.37 Hz, 2H), 5.32 (m, 4H), 6.03 (m, 2H), 7.02 (d, J = 8.87 Hz, 1 H), 7.47 (d, J = 8.87 Hz, 1 H), 7.60 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 259.1329
found: 259.1335
(E)-3-(4-(Allyloxy)phenyl)-2-methylacrylic acid
Figure imgf000403_0002
(E)-Allyl 3-(4-(allyloxy)phenyl)-2-methylacrylate (1 .0 eq, 1 .93 mmol, 500 mg) and KOH (2.0 eq, 3.86 mmol, 217 mg) were dissolved in MeOH (10 mL) and stirred for 16 h at room temperature. The solvent was removed under reduced pressure and the residue suspended in HCI (1 M, 10 mL). The aqueous phase was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (1 x 25 mL), dried over Na2S04 and filtered. The product was obtained as a slightly brown - white solid (384 mg, 87 %).
H-NMR (dmso-ds, 400 MHz): δ [ppm] 2.03 (s, 3H), 4.61 (m, 2H), 5.27 (m, 1 H), 5.41 (m, 1 H), 6.06 (m, 1 H), 7.01 (d, J = 8.87 Hz, 1 H), 7.44 (d, J = 8.60 Hz, 1 H), 7.55 (s, 1 H), 12.38 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 219.1016
found: 219.1034 (E)-Allyl 3-(4-(allyloxy)phenyl)-2-methylacrylate
AllylO
Figure imgf000404_0001
E)-3-(4-(Allyloxy)phenyl)-2-methylacrylic acid (1 .0 eq, 5.60 mmol, 1 .0 g) was dissolved in DMF (50 mL) and K2C03 (3.0 eq, 16.8 mmol, 2.32 g) was added. Allyl iodide (3.0 eq, 16.8 mmol, 1 .53 mL was added via syringe and the mixture was stirred at room temperature for 12 h. EtOAc (150 mL) was added and the mixture was washed with brine (3 x 50 mL). After drying over Na2S04 and filtration the solvent was removed under reduced pressure.
Purification by column chromatography (H:EA - 12:1 --> 4:1 )) yielded the product as an orange oil (1 .3 g, 90 %). H-NMR (dmso-ds, 400 MHz): δ [ppm] 2.08 (s, 3H), 4.62 (d, J = 4.61 Hz, 2H), 4.68 (d, J = 5.37 Hz, 2H), 5.32 (m, 4H), 6.03 (m, 2H), 7.02 (d, J = 8.87 Hz, 1 H), 7.47 (d, J = 8.87 Hz, 1 H), 7.60 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 259.1329
found: 259.1335
2,5-dioxopyrrolidin-l-yl 4-nitrobenzoate
Figure imgf000404_0002
2,5-dioxopyrrolidin-1 -yl 4-nitrobenzoate can be synthesised according to Adamczyk, M., Fino, J., R., Org. Prep. Proced. Int., 2009, 28, 470-474.
Allyl 2-(allyloxy)-4-(2-(allyloxy)-3-methoxy-4-nitrobenzamido)-3-methoxybenzoate
Figure imgf000404_0003
Bis-(trichloromethyl)carbonate (0.5 eq, 1 .31 mmol, 388 mg) and 2-(allyloxy)-3-methoxy-4- nitrobenzoic acid (1 .5 eq, 4.01 mmol, 1014 mg) were dissolved in dry THF (25 mL) under argon atmosphere. 2,4,6-Collidine (8.0 eq, 21 .38 mmol, 2.8 mL) was added slowly via syringe. The resulting suspension was stirred at room temperature for 15 min and a solution of allyl 2-(allyloxy)-4-amino-3-methoxybenzoate (1 .0 eq, 2.67 mmol, 703 mg), DIPEA (10.0 eq, 26.72 mmol, 4.5 mL) in dry THF (25 mL) was added. Stirring was continued for 1 1 h at room temperature and the reaction was quenched by addition of water (10 mL). The organic solvent was removed under reduced pressure and EtOAc (70 mL) was added. The mixture was washed successively with saturated NaHC03 (2 x 25 mL), HCI (5 %, 2 x 25 mL), water (1 x 25 mL) and brine (1 x 25 mL). The organic solvent was dried over Na2S04, filtered and removed under reduced pressure. Purification by column chromatography (H:EA - 8:1 ) yielded the product as a slightly yellow oil (1 .2 g, 91 %).
H-NMR (dmso-ds, 500 MHz): δ [ppm] 3.90 (s, 3H), 3.99 (s, 3H), 4.53 (d, J = 4.53 Hz, 2H), 4.76 (d, J= 4.76 Hz, 2H), 4.78 (d, J= 5.35 Hz, 2H), 5.27 (m, 3H), 5.41 (m, 3H), 6.07 (m, 3H), 7.57 (d, J = 8.72 Hz, 1 H), 7.74 (d, J = 8.72 Hz, 1 H), 7.79 (d, J = 8.52 Hz, 1 H), 8.21 (d, J = 8.72, 1 H), 10.43 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 499.171 1
found: 499.1701
[M+Na]+ calculated: 521 .1530
found: 521 .1520
Allyl 2-(allyloxy)-4-(2-(allyloxy)-4-amino-3-methoxybenzamido)-3-methoxybenzoate
Figure imgf000405_0001
Allyl 2-(allyloxy)-4-(2-(allyloxy)-3-methoxy-4-nitrobenzamido)-3-methoxybenzoate (1 .0 eq, 2.41 mmol, 1 .2 g) and SnCI2 *2H20 (7.0 eq, 16.86 mmol, 3.8 g) were dissolved in EtOH (40 mL) and stirred at 60 'Ό for 1 h. The solution was concentrated under reduced pressure and diluted with water (100 mL). The pH was adjusted to 8-9 by adding saturated NaHC03 solution and the aqueous suspension was extracted with EtOAc (3 x 250 mL). The phases were separated and the organic phase was washed with brine (1 x 250 mL), dried over Na2S04 and filtered. After removing the solvent under reduced pressure, column
chromatography (H:EA - 3:1 ) yielded the product as an orange oil (892 mg, 79 %). H-NMR (dmso-ds, 400 MHz): δ [ppm] 3.76 (s, 3H), 3.91 (s, 3H), 4.54 (d, J = 5.75 Hz, 2H), 4.78 (m, 4H), 5.26 (dd, Ji = 17.54 Hz, J2 = 10.40, 3H), 5.41 (m, 3H), 5.87 (s, 2H), 6.08 (m, 3H), 6.58 (d, J= 8.72 Hz, 1 H), 7.54 (d, J= 8.92 Hz, 1 H), 7.59 (d, J= 8.92 Hz, 1 H), 8.36 (d, J = 8.92 Hz, 1 H), 10.64 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 469.1969 found: 469.1958
[M+Na]+ calculated: 491 .1789
found: 491 .1778
(S)-ferf-Butyl 4-(2-(ferf-butoxycarbonylamino)-3-cyanopropanamido)benzoate
Figure imgf000406_0001
Boc-L-Asn-OH (2.0 eq, 34.44 mmol, 8.0 g) and DCC (4.0 eq, 68.87 mmol, 14.2 g) were dissolved in dry DMF (150 mL) under argon atmosphere. After stirring for 10 min at room temperature te/t-butyl 4-aminobenzoate (1 .0 eq, 17.22 mmol, 3.9 g) was added and stirring was continued for 19 h. EtOAc (400 mL) was added and the mixture was washed
successively with brine (3 x 150 mL), saturated NaHC03 solution (2 x 150 mL), HCI (5 %, 2 x 150 mL) and brine (1 x 150 mL). The organic phase was dried over Na2S04, filtered and the solvent was removed under reduced pressure. Column chromatography (H:EA - 4:1 ) yielded the product as a white solid (4.2 g, 57 %). H-NMR (dmso-ds, 400 MHz): δ [ppm] 1 .40 (s, 9H), 1 .53 (s, 9H), 2.83 (dd, Ji = 16.92 Hz, 1 H), 2.99 (dd, Ji = 16.92 Hz, J2 = 5.10 Hz, 1 H), 4.46 (dd, Ji = 13.70 Hz, J2 = 8.86 Hz, 1 H), 7.58 (d, J = 7.79 Hz, 1 H), 7.71 (d, J = 8.60 Hz, 2H), 7.87 (d, J = 8.60 Hz, 2H), 10.48 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 390.2034
found: 390.2017
[M+Na]+ calculated: 412.1843
found: 412.1834
(S)-4-(3-Cyano-2-(4-nitrobenzamido)propanamido)benzoic acid
Figure imgf000406_0002
{S)-tert- Butyl 4-(2-(te/?-butoxycarbonylamino)-3-cyanopropanamido)benzoate (1 .0 eq, 0.81 mmol, 314 mg) was dissolved in HCI/dioxane (4 M, 5 mL) and the reaction mixture was stirred at room temperature until cleavage of the boc group and te/t-butyl ester was completed (LC/MS monitoring, approximately 6 hours). The solvent was removed under reduced pressure and the residue resolved in dry DMF (10 ml_) under argon atmosphere. Triethylamine (3.0 eq, 2.42 mmol, 0.73 ml_) and 2,5-dioxopyrrolidin-1 -yl 4-nitrobenzoate (1 .1 eq, 0.89 mmol, 234 mg) were added and the mixture was stirred at room temperature for 16 h. EtOAc (50 ml_) was added and the mixture was washed successively with brine (3 x 25 ml_), saturated NaHC03 solution (2 x 25 ml_), HCI (5 %, 2 x 25 ml_) and brine (1 x 25 ml_). The organic phase was dried over Na2S04, filtered and the solvent was removed under reduced pressure. Column chromatography (CHCI3:CH3OI-l - 9:0.5) yielded the product as a white solid (1 19 mg, 39 %).
H-NMR (dmso-ds, 400 MHz): δ [ppm] 3.06 (dd, Ji = 16.92 Hz, J2 = 8.60 Hz, 1 H), 3.17 (dd, Ji =16.92 Hz, J2 = 5.37 Hz, 1 H), 5.01 (m, 1 H), 7.74 (d, J = 8.87 Hz, 1 H), 7.92 (d, J = 8.87 Hz, 1 H), 8.16 (d, J = 9.13 Hz, 1 H), 8.38 (d, J = 8.87 Hz, 1 H), 9.53 (d, J = 7.79 Hz, 1 H), 10.61 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 383.0986
found: 390.0974
Methyl-6-amineonicotinate
Figure imgf000407_0001
Chemical Formula: C7H8N2C>2
Exact Mass: 152,0586
6-Amineonicotinic acid ( 1 .00 g, 7.246 mmol, 1 .00 eq) was dissolved in abs. MeOH (40 ml) and cooled to 0 °C. SOCI2 (2.587 g, 1 .70 ml, 21 .739 mmol, 3.00 eq) was added and the reaction mixture was allowed to warm up to room temperature. After stirring for 16 h the solvent was evaporated to give the product as a pale yellow solid (60 %).
H-NMR (400 MHz, DMSO-d6): 3.75 (s, 3H), 6.43 - 6.46 (dd, Ji = 8.7 Hz, J2 = 0.7 Hz, 1 H), 6.84 (s, 2H), 7.81 - 7.83 (dd, Ji = 8.9 Hz, J2 = 2.4 Hz, 1 H), 8.50 (d, J = 2.1 Hz, 1 H),
3C-NMR (100.6 MHz, DMSO-d6): 51 .36, 107.13, 1 13.19, 137.60, 151 .04, 162.52, 165.72
HR-MS: calc.: [M+H]+ 153.0659
found: [M+H]+ 153.0654 Methyl 6-[[(E)-3-(4-allyloxyphenyl)-2-methyl-prop-2-enoyl]amino]pyridine-3-carboxylate
Figure imgf000408_0001
Chemical Formula: C2oH2oN204
Exact Mass: 352, 1423
The Allyl protected cinnamic acid (200 mg, 0.917 mmol, 1 .00 eq) was dissolved in DCM (10 ml) and a catalytic amount of DMF (100 μΙ) was added. SOCI2 (545 mg, 0.36 ml, 4.579 mmol, 5.00 eq) was added dropwise and the mixture was stirred for 16 h. The solvents were removed and the residue redissolved in DMF. Methyl-6-amineonicotinate (139 mg, 0.917 mmol, 1 .00 eq) was dissolved in DMF and added. After stirring for another 16 h the mixture was diluted with EE and the organic layer was washed 3 x with 1 N HCI, sat. NaHC03 and brine. The organic layer was dried over Na2S04 and the solvent was evaporated. The crude product was chromatographically purified to give the product as a pale yellow solid.
6-[[(E)-3-(4-allyloxyphenyl)-2-methyl-prop-2-enoyl]amino]pyridine-3-carboxylic acid
Figure imgf000408_0002
Chemical Formula: C19H18N204
Exact Mass: 338, 1267
Methyl 6-[[(E)-3-(4-allyloxyphenyl)-2-methyl-prop-2-enoyl]amino]pyridine-3-carboxylate (1 .00 eq) was dissolved in Dioxane/H20 (1 :1 ) and LiOH (3.00 eq) was added. The mixture was stirred for 4 h. The Dioxane was removed and the aqueous layer acidified with cone. HCI. The aqueous layer was extracted 3 x with EE and the combined organic layers were dried over Na2S04. The solvent was evaporated to give the product. Allyl 2-allyloxy-4-[[2-allyloxy-4-[[4-[[(2S)-2-[[6-[[(E)-3-(4-allyloxyphenyl)-2-methyl-prop-2- enoyl]amino]pyridine-3-carbonyl]amino]-3-cyano-propanoyl]amino]benzoyl]
Figure imgf000409_0001
Chemical Formula: C55H53N70-|2
Exact Mass: 1003,3752
6-[[(E)-3-(4-allyloxyphenyl)-2-methyl-prop-2-enoyl]amino]pyridine-3-carboxylic acid (1 .50 eq) was dissolved in THF. Triphosgen (0.50 eq) and Collidin (8.00 eq) were added and stirred for 20 min. The aminee (1 .00 eq) and DIPEA (10.00 eq) were dissolved in THF and added to mixture. After stirring for 16 h the mixture was diluted with EE and the organic layer was washed 3 x with 1 N HCI, sat. NaHC03 and brine. After drying the organic layer over Na2S04 the solvent was removed and the crude product was chromatographically purified to give the product.
4-[[(2S)-3-cyano-2-[(5-nitropyridine-2-carbonyl)amino]propanoyl]amino]benzoic acid
Figure imgf000409_0002
Chemical Formula: C17H13N506
Exact Mass: 383,0866
(S)-1 -((4-carboxyphenyl)amineo)-3-cyano-1 -oxopropan-2-amineium chloride (424 mg, 1 .58 mmol, 1 .00 eq) was dissolved in abs. DMF (10 ml) and TEA (479 mg, 665 μΙ, 4.74 mmol, 3.00 eq) was slowly added. 2,5-dioxopyrrolidin-1 -yl 5-nitropicolinate (440 mg, 1 .66 mmol, 1 .05 eq) was dissolved in DMF (10 ml) and added to the reaction mixture. After stirring for 16 h at room temperature the mixture was diluted with EE (50 ml) and the organic layer was washed 4 x with 1 N HCI and brine. The solvent was evaporated and the crude product was chromatographically purified (Hex:EE 1 :1 ) to give the product as a pale yellow solid (78 %). H-NMR (400 MHz, DMSO-d6): 3.19 - 3.28 (m, 2H), 5.04 - 5.10 (m, 1 H), 7.72 (d, J = 8.9 Hz, 2H), 7.92 (d, J = 8.6 Hz, 2H), 8.32 (d, J = 8.6 Hz, 1 H), 8.79 - 8.82 (dd, Ji = 8.6 Hz, J2 = 2.4 Hz, 1 H), 9.46 (d, J = 2.4 Hz, 1 H), 9.55 (d, J = 8.3 Hz, 1 H), 10.53 (s, 1 H), 12.73 (br, 1 H) 3C-NMR (100.6 MHz, DMSO-d6): 20.30, 50.08, 1 17.96, 1 18.99, 123.12, 125.78, 130.35, 133.54, 142.31 , 144.04, 145.92, 152.98, 162.54, 166.80, 167.37
HR-MS: calc: [M-H]" 382.0782
found: [M-H]" 382.0789
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[4-[[(2S)-3-cyano-2-[(5-nitropyridine-2-carbonyl)
amino]propanoyl]amino]benzoyl]amino]-3-methoxy-benzoyl]amino]-3-methoxy-benzoate
Figure imgf000410_0001
Chemical Formula: C42H39N70-|2
Exact Mass: 833,2657
(S)-4-(3-cyano-2-(5-nitropicolinamido)propanamido)benzoic acid (404 mg, 1 .05 mmol, 2.00 eq) was dissolved in THF (20 ml), BTC (104 mg, 0.35 mmol, 0.66 eq) and Collidin (510 mg, 558 μΙ, 4.22 mmol, 8.00 eq) was added and stirred 20 min at room temperature. Allyl 2- (allyloxy)-4-(2-(allyloxy)-4-amineo-3-methoxybenzamido)-3-methoxybenzoate (246 mg, 0.52 mmol, 1 .00 eq) and DIPEA (679 mg, 940 μΙ, 5.27 mmol, 10.00 eq) were dissolved in THF (10 ml) and added to the reaction mixture. After stirring for 16 h the mixture was diluted with EE (50 ml) and washed 3 x with 1 N HCI, sat. NaHC03 and brine. After drying over Na2S04 the solvent was evaporated. The crude product was chromatographically purified (Hex:EE 1 :1 ) to give the product as a yellow solid (69 %).
H-NMR (400 MHz, DMSO-d6): 3.24 - 3.29 (m, 2H), 3.91 (s, 3H), 3.93 (s, 3H), 4.53 - 4.55 (m, 2H), 4.76 - 4.81 (m, 4H), 5.06 - 5.12 (m, 1 H), 5.23 - 5.31 (m, 3H), 5.36 - 5.44 (m, 3H), 5.99 - 6.16 (m, 3H), 7.57 (d, J= 8.6 Hz, 1 H), 7.77 (d, J= 8.6 Hz, 2H), 7.80 (d, J= 8.9 Hz, 1 H), 7.90 - 7.92 (m, 1 H), 7.99 (d, J = 8.9 Hz, 2H), 8.32 - 8.35 (m, 2H), 8.80 - 8.83 (m, 1 H), 9.48 (dd, Ji = 2.6 Hz, J2 = 0.7 Hz, 1 H), 9.57 (d, J = 8.6 Hz, 1 H), 9.70 (s, 1 H), 10.55 (s, 1 H), 10.65 (s, 1 H)
HR-MS: calc: [M+H]+ 834.2729
found: [M+H]+ 804.2900 Allyl 2-allyloxy-4-[[2-allyloxy-4-[[4-[[(2S)-2-[(5-aminopyridine-2-carbonyl)amino]-3-cyano- propanoyl]amino]benzoyl]amino]-3-methoxy-benzoyl]amino]-3-methoxy-benzoate
Figure imgf000411_0001
Chemical Formula: C42H4 N7O 0
Exact Mass: 803,2915
(S)-allyl2-(allyloxy)-4-(2-(allyloxy)-4-(4-(3-cyano-2-(5-nitropicolinamido)propanamido)benz- amido)-3-methoxybenzamido)-3-methoxybenzoate (335 mg, .402 mmol, 1 .00 eq) was dissolved in EtOH (30 ml) and SnCI2-H20 was added. The mixture was stirred at 60 'Ό for 6 h. The solvent was evaporated and the residue was redissolved in EE. The organic layer was washed with sat. NaHC03 and the aqueous layer extracted twice with EE. The organic layer was washed with brine, dried over Na2S04 and evaporated. The crude product was chromatographically purified (CHCI3:MeOH 9:0.1 ) to give the product as a yellow solid (60 %). H-NMR (400 MHz, DMSO-d6): 3.18 - 3.23 (m, 1 H), 3.27 - 3.32 (m, 1 H), 3.91 (s, 3H), 3.93 (s, 3H), 4.53 - 4.55 (m, 2H), 4.77 - 4.81 (m, 4H), 4.99 - 5.04 (m, 1 H), 5.23 - 5.31 (m, 3H), 5.36 - 5.44 (m, 3H), 5.99 - 6.16 (m, 3H), 7.29 (dd, Ji = 7.72 Hz, J2 = 2.6 Hz, 1 H), 7.57 (d, J = 8.6 Hz, 1 H), 7.76 - 7.81 (m, 3H), 7.91 (dd, Ji = 8.7 Hz, J2 = 2.8 Hz, 2H), 7.99 (d, J = 8.6 Hz, 2H), 8.18 (d, J = 2.4 Hz, 1 H), 8.33 (d, J = 8.9 Hz, 1 H), 8.85 (d, J = 1 .6 Hz, 1 H), 8.93 (d, J = 8.3 Hz, 1 H), 9.14 (s, 1 H), 9.69 (s, 1 H), 10.56 (s, 1 H), 10.65 (s, 1 H)
HR-MS: calc.: [M+H]+ 804.2988
found: [M+H]+ 804.2900
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[4-[[(2S)-2-[[5-[[(E)-3-(4-allyloxyphenyl)-2-methyl-prop-2- enoyl]amino]pyridine-2-carbonyl]amino]-3-cyano-propanoyl]amino]benzoyl]amino]-3-methoxy- benzoyl]amino]-3-methoxy-benzoate
Figure imgf000412_0001
Chemical Formula: CssHssNyO^
Exact Mass: 1003,3752
(E)-3-(4-(allyloxy)phenyl)-2-methylacrylic acid (42 mg, 0.194 mmol, 3.00 eq) was dissolved in THF. BTC (19 mg, 0.065 mmol, 1 .00 eq) and Collidin (63 mg, 69 μΙ, 0.518 mmol, 8.00 eq) were added and the mixture was stirred at room temperature. After 20 min (S)-allyl 2-(allyloxy)-4-(2- (allyloxy)-4-(4-(2-(5-amineopicolinamido)-3-cyanopropanamido)benzamido)-3- methoxybenzamido)-3-methoxybenzoate (52 mg, 0.065 mmol, 1 .00 eq) and DIPEA ( 83 mg, 1 16 μΙ, 0.647 mmol, 10.00 eq) were dissolved in THF, added to the reaction mixture and stirred for an additional 16 h. The reaction mixture was diluted with EE and washed 3 x with 1 N HCI, sat. NaHC03 and brine. After drying over Na2S04 the solvent was removed. The crude product was chromatographically purified (CHCI3:MeOH 9:0.2) to give the product as a yellow solid (95 %).
H-NMR (400 MHz, DMSO-d6): 2.15 (s, 3H), 3.91 (s, 3H), 3.93 (s, 3H), 4.53 - 4.55 (m, 2H), 4.60 - 4.63 (m, 2H), 4.76 - 4.81 (m, 4H), 5.01 - 5.08 (m, 1 H), 5.26 - 5.29 (m, 4H), 5.38 - 5.44 (m, 4H), 6.00 - 6.10 (m, 4H), 7.04 - 7.06 (m, 2H), 7.46 - 7.49 (m, 2H), 7.56 - 7.58 (m, 1 H), 7.77 - 7.82 (m, 3H), 7.91 - 7.93 (m, 1 H), 7.98 - 8.01 (m, 2H), 8.07 - 8.09 (m, 1 H), 8.33 (d, J = 8.9 Hz, 1 H), 8.36 - 8.39 (dd, Ji = 8.6 Hz, J2 = 2.1 Hz, 1 H), 9.03 (d, J = 2.6 Hz, 1 H), 9.18 (d, J = 9.1 Hz, 1 H), 9.71 (s, 1 H), 10.43 (s, 1 H), 10.58 (s, 1 H), 10.66 (s, 1 H)
HR-MS: calc.: [M+H]+: 1004.3825
found: [M+H]+: 1004.3842 tert-butyl 5-nitropyridine-2-carboxylate
Figure imgf000413_0001
Chemical Formula: C10H 2N2O4
Exact Mass: 224,0797
DIC (3.00 eq), fBuOH (4.00 eq) and CuCI (0.02 eq) were stirred under an Argon-athmosphere at room temperature for 5 d. The mixture was filtered through a pad of celite and diluted with DCM (4:1 ). 5-Nitropicolinic acid (1 .00 g, 5.952 mmol, 1 .00 eq) was dissolved in DMF (20 ml) and the activated fBuOH was added via a dropping funnel. After stirring for 4 h at room temperature the mixture was cooled to 0 'Ό. Hexane (40 ml) was added and it was stirring for an additional 30 min. The mixture was filtered through celite and the filtrate was washed 3 x with H20. The solvent was removed and the crude product was chromatographically purified (Hex/EE 5:1 ) to give the product as a white solid (70 %).
H-NMR (400 MHz, DMSO-d6): 1 .58 (s, 9H), 8.21 - 8.23 (dd, Ji = 8.6 Hz, J2 = 0.8 Hz, 1 H), 8.72 - 8.75 (dd, Ji = 8.6 Hz, J2 = 2.7 Hz, 1 H), 9.44 - 9.45 (d, J = 2.6 Hz, 1 H)
3C-NMR (100.6 MHz, DMSO-d6): 27.62, 82.75, 125.17, 133.07, 144.73, 152.81 , 160.74, 174.17
HR-MS: calc: [M+H]+: 225.0870
found: [M+H]+: 255.0872 tert-butyl 5-aminopyridine-2-carboxylate
Figure imgf000413_0002
Chemical Formula: C10H 4N2O2
Exact Mass: 194, 1055 reri-Butyl-5-nitro-picolinate (822 mg, 3.67 mmol) was dissolved in EE/MeOH (9:1 ) (20 ml) and Pd/C 10 % (82 mg) was added. The mixture was stirred at room temperature under a Hydrogen-atmosphere for 5 h. The mixture was filtrated through a pad of celite and the solvents were evaporated to give the product as an white solid (90 %).
H-NMR (400 MHz, DMSO-d6): 1 .50 (s, 9H), 6.08 (s, 2H), 6.89 (dd, Ji = 8.6 Hz, J2 = 2.7 Hz, 1 H), 7.68 (d, J = 8.6 Hz, 1 H), 7.95 (d, J = 2.7 Hz, 1 H)
3C-NMR (100.6 MHz, DMSO-d6): 27.95, 79.57, 1 18.07, 126.09, 135.55, 135.60, 147.72, 164.06 HR-MS: calc: [M+H]+: 195.1 128
found: [M+H]+: 195.1 128 tert-butyl 5-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyano-propanoyl]amino]pyridine-2-carboxylate
Figure imgf000414_0001
Chemical Formula: C19H26N405
Exact Mass: 390, 1903 reri-butyl-5-amineo-picolinate (727 mg, 3.747 mmol, 1 .00 eq) and Boc-Asn-OH (1 .739 g, 7.495 mmol, 2.00 eq) were dissolved in DMF (30 ml) and DCC (3.092 g, 14.989 mmol, 4.00 eq) was added. After stirring for 16 h at room temperature the mixture was filtrated and the filtrate diluted with EE (60 ml). The organic layer was washed 3 x with 1 N HCI, sat. NaHC03 and brine. The organic layer was dried over Na2S04 and the solvent was removed. The crude product was chromatographically purified (Hex/EE 1 :2) to give the product as a white solid (60 %).
H-NMR (400 MHz, DMSO-d6): 1 .41 (s, 9H), 1 .54 (s, 9H), 6.08 (s, 2H), 6.89 (dd, Ji = 8.6 Hz, J2 = 2.7 Hz, 1 H), 7.68 (d, J = 8.6 Hz, 1 H), 7.95 (d, J = 2.7 Hz, 1 H)
3C-NMR (100.6 MHz, DMSO-d6): 27.95, 79.57, 1 18.07, 126.09, 135.60, 147.72, 164.06
[(lS)-2-[(6-carboxy-3-pyridyl)amino]-l-(cyanomethyl)-2-oxo-ethyl]ammonium chloride
Figure imgf000414_0002
Chemical Formula: C-IQH-I -I ^OS
Exact Mass: 235,0826
Tert-butyl 5-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyano-propanoyl]amino]pyridine-2- carboxylate (900 mg, 2.310 mmol) was dissolved in 4 M HCI in Dioxane (20 ml). The solution was stirred at room temperature for 5 h. The solvent was evaporated and the product dried in vacuo (quant.). 5-[[(2S)-3-cyano-2-[(4-nitrobenzoyl)amino]propanoyl]amino]pyridine-2-carboxylic acid
Figure imgf000415_0001
Chemical Formula: C-|7H-|3N506
Exact Mass: 383,0866
[(1 S)-2-[(6-carboxy-3-pyridyl)amino]-1 -(cyanomethyl)-2-oxo-ethyl]ammonium chloride (1 .00 eq) was dissolved in DMF and TEA (3.00 eq) was added dropwise. 2,5-Dioxopyrrolidin-1 -yl-4- nitrobenzoate (1 .05 eq) was dissolved in DMF and added to the mixture. After stirring at room temperature for 16 h the mixture was diluted with EE and washed 4 x with 1 N HCI and brine. The organic layer was dried over Na2S04 and the solvent was removed. The crude product was chromatographically purified to give the product as a yellow solid.
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[5-[[(2S)-3-cyano-2-[(4-nitrobenzoyl)amino]propanoyl]
amino]pyridine-2-carbonyl]amino]-3-methoxy-benzoyl]amino]-3-methoxy-benzoate
Figure imgf000415_0002
Chemical Formula: C42H3gN7
Exact Mass: 833,2657
5-[[(2S)-3-cyano-2-[(4-nitrobenzoyl)amino]propanoyl]amino]pyridine-2-carboxylic acid (2.00 eq) was dissolved in THF and Triphosgen (0.66 eq) and Collidin (8.00 eq) were added. The mixture was stirred at room temperature for 40 min. The amine (1 .00 eq) and DIPEA (10.00 eq) were dissolved in THF, added to the mixture and it was stirred for an additional 16 h at room temperature. The reaction was diluted with EE and washed 3 x with 1 N HCI, sat. NaHC03 and brine. After drying over Na2S04 the solvent was removed. The crude product was chromatographically purified to give the product as a yellow solid. Allyl 2-allyloxy-4-[[2-allyloxy-4-[[5-[[(2S)-2-[(4-aminobenzoyl)amino]-3-cyano- propanoyl]amino]pyridine-2-carbonyl]amino]-3-methoxy-benzoyl]amino]-3-methoxy-benzoate
Figure imgf000416_0001
Chemical Formula: C42H4 N7O 0
Exact Mass: 803,2915
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[5-[[(2S)-3-cyano-2-[(4-nitrobenzoyl)amino]propanoyl] amino]pyridine-2-carbonyl]amino]-3-methoxy-benzoyl]amino]-3-methoxy-benzoate (1 .00 eq) was dissolved in EtOH and SnCI2-H20 (5.00 eq) was added. The mixture was stirred at 60 'Ό for 6 h. The solvent was removed and the residue uptaken in EE. Sat. NaHC03 was added and the aqueous layer was extracted 3 x with EE. The combined organic layers were dried over Na2S04 and the solvent was removed. The crude product was chromatographically purified to give the product as a yellow solid.
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[5-[[(2S)-2-[[4-[[(E)-3-(4-allyloxyphenyl)-2-methyl-prop-2- enoyl]amino]benzoyl]amino]-3-cyano-propanoyl]amino]pyridine-2-carbonyl]amino]-3-methoxy- benzoyl]amino]-3-methoxy-benzoate
Figure imgf000416_0002
Chemical Formula: C55H53N7012
Exact Mass: 1003,3752
The cinnamic acid (3.00 eq) was dissolved in THF. Triphosgen (1 .00 eq) and Collidin (8.00 eq) were added and it was stirred for 15 min. Allyl 2-allyloxy-4-[[2-allyloxy-4-[[5-[[(2S)-2-[(4- aminobenzoyl)amino]-3-cyano-propanoyl]amino]pyridine-2-carbonyl]amino]-3-methoxy- benzoyl]amino]-3-methoxy-benzoate (1 .00 eq) and DIPEA (10.00 eq) were dissolved in THF and added to the mixture. After stirring for 16 h the mixture was diluted with EE and the organic layer was washed 3 x with 1 N HCI, sat. NaHC03 and brine. After drying over Na2S04 the solvent was removed. The crude product was chromatographically purified to give the product as a yellow solid.
5-[[(2S)-3-cyano-2-[(5-nitropyridine-2-carbonyl)amino]propanoyl]amino]pyridine-2-carboxylic acid
Figure imgf000417_0001
Chemical Formula: C-|6H 2N606
Exact Mass: 384,0818
The amine (1 .00 eq) was dissolved in DMF and TEA (3.00 eq) was added dropwise. 2,5- Dioxopyrrolidin-1 -yl-5nitropicolinate (1 .05 eq) was dissolved in DMF and added to the mixture. . After stirring at room temperature for 16 h the mixture was diluted with EE and washed 4 x with 1 N HCI and brine. The organic layer was dried over Na2S04 and the solvent was removed. The crude product was chromatographically purified to give the product as a yellow solid.
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[5-[[(2S)-3-cyano-2-[(5-nitropyridine-2- carbonyl)amino]propanoyl]amino]pyridine-2-carbonyl]amino]-3-methoxy-benzoyl]amino]-3- methoxy-benzoate
Figure imgf000417_0002
Chemical Formula: C41 H38N80 2
Exact Mass: 834,2609
5-[[(2S)-3-cyano-2-[(5-nitropyridine-2-carbonyl)amino]propanoyl]amino]pyridine-2-carboxylic acid (2.00 eq) was dissolved in THF and Triphosgen (0.66 eq) and Collidin (8.00 eq) were added. The mixture was stirred at room temperature for 40 min. The amine (1 .00 eq) and DIPEA (10.00 eq) were dissolved in THF, added to the mixture and it was stirred for an additional 16 h at room temperature. The reaction was diluted with EE and washed 3 x with 1 N HCI, sat. NaHC03 and brine. After drying over Na2S04 the solvent was removed. The crude product was chromatographically purified to give the product as a yellow solid. Allyl 2-allyloxy-4-[[2-allyloxy-4-[[5-[[(2S)-2-[(5-aminopyridine-2-carbonyl)amino]-3-cyano- propanoyl]amino]pyridine-2-carbonyl]amino]-3-methoxy-benzoyl]amino]-3-methoxy-benzoate
Figure imgf000418_0001
Chemical Formula: C41 H40N8O10
Exact Mass: 804,2867
5-[[(2S)-3-cyano-2-[(5-nitropyridine-2-carbonyl)amino]propanoyl]amino]pyridine-2-carboxy^ acid (1 .00 eq) was dissolved in EtOH and SnCI2-H20 (5.00 eq) was added. The mixture was stirred at 60 'Ό for 6 h. The solvent was removed and the residue uptaken in EE. Sat. NaHC03 was added and the aqueous layer was extracted 3 x with EE. The combined organic layers were dried over Na2S04 and the solvent was removed. The crude product was chromatographically purified to give the product as a yellow solid.
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[5-[[(2S)-2-[[5-[[(E)-3-(4-allyloxyphenyl)-2-methyl-prop-2- enoyl]amino]pyridine-2-carbonyl]amino]-3-cyano-propanoyl]am
methoxy-benzoyl]amino]-3-methoxy-benzoate
Figure imgf000418_0002
Chemical Formula: C54H52N8012
Exact Mass: 1004,3705
The cinnamic acid (3.00 eq) was dissolved in THF. Triphosgen (1 .00 eq) and Collidin (8.00 eq) were added and it was stirred for 15 min. Allyl 2-allyloxy-4-[[2-allyloxy-4-[[5-[[(2S)-2-[(5- aminopyridine-2-carbonyl)amino]-3-cyano-propanoyl]amino]pyridine-2-carbonyl]amino]-3- methoxy-benzoyl]amino]-3-methoxy-benzoate (1 .00 eq) and DIPEA (10.00 eq) were dissolved in THF and added to the mixture. After stirring for 16 h the mixture was diluted with EE and the organic layer was washed 3 x with 1 N HCI, sat. NaHC03 and brine. After drying over Na2S04 the solvent was removed. The crude product was chromatographically purified to give the product as a yellow solid.
Allyl 2-allyloxy-4-[[2-allyloxy-3-methoxy-4-[(4-nitrophenyl)sulfonylamino]benzoyl]amino]-3- methoxy-benzoate
Figure imgf000419_0001
Chemical Formula: C31 H31 N3O1 -1 S
Exact Mass: 653, 1679
The amine (500 mg, 1 .068 mmol, 1 .00 eq) was dissolved in DCM and DMAP (100 mg, w/w 10 %) and Pyridin (2.5 ml) were added. 4-Nitrobenzene-1 -sulfonyl chloride (710 mg, 3.205 mmol, 3.00 eq) was added and it was stirred at room temperature for 72 h. The mixture was washed 3 x with 1 N HCI and brine. After drying over Na2S04 the solvent was removed. The crude product was chromathographically (Hex/EE 3:1 ) purified to give the product as a yellow solid. H-NMR (400 MHz, DMSO-d6): 3.59 (s, 3H), 3.87 (s, 3H), 4.50 - 4.52 (m, 2H), 4.63 - 4.65 (m, 2H), 4.75 - 4.76 (m, 2H), 5.24 - 5.28 (m, 2H), 5.34 - 5.42 (m, 2H), 5.92 - 6.12 (m, 3H), 7.29 (d, J= 8.9 Hz, 1 H), 7.54 (d, J= 8.9 Hz, 1 H), 7.69 (d, J= 8.9 Hz, 1 H), 8.09 (d, J= 8.9 Hz, 2H), 8.26 (d, J = 8.9 Hz, 1 H), 8.42 (d, J = 8.9 Hz, 2H), 10.51 (s, 1 H), 10.59 (s, 1 H)
3C-NMR (100.6 MHz, DMSO-d6): 59.76, 60.95, 65.1 1 , 1 14.87, 1 17.86, 1 18.14, 120.21 , 120.38, 124.70, 126.24, 128.30, 132.45, 132.61 , 133.93, 136.37, 142.52, 144.59, 149.74, 149.91 , 151 .06, 162.17, 164.44, 172.51
HR-MS: calc.: [M+H]+:
found: [M+H]+: Allyl 2-allyloxy-4-[[2-allyloxy-4-[(4-aminophenyl)sulfonylamino]-3-methoxy-benzoyl]amino]-3- methoxy-benzoate
Figure imgf000420_0001
Chemical Formula: C31 H33N3O9S
Exact Mass: 623, 1938
Allyl 2-allyloxy-4-[[2-allyloxy-3-methoxy-4-[(4-nitrophenyl)sulfonylamino]benzoyl]amino]-3- methoxy-benzoate (320 mg, 0.490 mmol, 1 .00 eq), was dissolved in EtOH (30 ml) and and SnCI2-H20 (554 mg, 2.45 mmol, 5.00 eq) was added. The mixture was stirred at 60 'Ό for 6 h. The solvent was removed and the residue uptaken in EE. Sat. NaHC03 was added and the aqueous layer was extracted 3 x with EE. The combined organic layers were dried over Na2S04 and the solvent was removed. The crude product was chromatographically (Hex/EE 1 :1 ) purified to give the product as a yellow solid (90 %).
H-NMR (400 MHz, DMSO-d6): 3.64 (s, 3H), 3.88 (s, 3H), 4.50 - 4.52 (m, 2H), 4.67 - 4.69 (m, 2H), 4.75 - 4.76 (m, 2H), 5.24 - 5.30 (m, 2H), 5.34 - 5.42 (m, 2H), 5.96 - 6.12 (m, 3H), 6.04 (s, 2H), 6.55 (d, J= 8.6 Hz, 2H), 7.32 (d, J= 9.1 Hz, 1 H), 7.48 (d, J= 8.6 Hz, 2H), 7.54 (d, J = 8.9 Hz, 1 H), 7.67 (d, J = 8.9 Hz, 1 H), 8.28 (d, J = 8.9 Hz, 1 H), 9.69 (s, 1 H), 10.54 (s, 1 H) 3C-NMR (100.6 MHz, DMSO-d6): 60.85, 60.98, 65.09, 74.54, 74.84, 1 12.51 , 1 14.75, 1 15.13, 1 17.85, 1 18.13, 120.18, 120.24, 121 .65, 124.20, 125.73, 126.27, 128.88, 132.51 , 132.63, 133.95, 136.39, 136.53, 142.42, 142.88, 149.70, 151 .07, 153.18, 162.27, 164.45
HR-MS: calc.: [M+H]+: 624.2010
found: [M+H]+: 624.2018 Allyl 2-allyloxy-4-[[2-allyloxy-4-[[4-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyano- propanoyl]amino] henyl]sulfon lamino]-3-methoxy-benzoyl]amino]-3-methoxy-benzoate
Figure imgf000421_0001
Chemical Formula: C40H 5N5O12S
Exact Mass: 819,2785
The amine (1 .00 eq) and Boc-Asn-OH (2.00 eq) were dissolved in DMF. DCC (4.00 eq) was added and the mixture was stirred at room temperature for 72 h. The mixture was diluted with EE and washed with 3 x with 1 N HCI, sat. NaHC03 and brine. After drying over NagSC the solvent was evaporated. The crude product was chromatographically purified to give the product as a yellow solid.
[(lS)-2-[4-[[3-allyloxy-4-[(3-allyloxy-4-allyloxycarbonyl-2-methoxy-phenyl)carbamoyl]-2-methoxy- phenyl]sulfamoyl]anilino]-l-(cyanomethyl)-2-oxo-ethyl]ammonium chloride
Figure imgf000421_0002
Chemical Formula: C35H38N5O10S+
Exact Mass: 720,2334
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[4-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyano- propanoyl]amino]phenyl]sulfonylamino]-3-methoxy-benzoyl]amino]-3-methoxy-benzoate was dissolved in 4 M HCI in Dioxane and stirred for 1 h. The solvent was removed and the product dried in vacuo. Allyl 2-allyloxy-4-[[2-allyloxy-4-[[4-[[(2S)-3-cyano-2-[(4-nitrobenzoyl)amino]
propanoyl]amino]phenyl]sulfonylamino]-3-methoxy-benzoyl]amino]-3-methoxy-benzoate
Figure imgf000422_0001
Chemical Formula: C 2H40N6O13S
Exact Mass: 868,2374
The amine (1 .00 eq) was dissolved in DMF and TEA (3.00 eq) was added dropwise. 2,5- Dioxopyrrolidin-1 -yl-4-nitrobenzoate (1 .05 eq) was dissolved in DMF and added to the mixture. After stirring at room temperature for 16 h the mixture was diluted with EE and washed 4 x with 1 N HCI and brine. The organic layer was dried over Na2S04 and the solvent was removed. The crude product was chromatographically purified to give the product as a yellow solid.
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[4-[[(2S)-2-[(4-aminobenzoyl)amino]-3-cyano- propanoyl]amino]phenyl]sulfonylamino]-3-methoxy-benzoyl]amino]-3-methoxy-benzoate
Figure imgf000422_0002
Chemical Formula: C42H42N60iiS
Exact Mass: 838,2632
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[4-[[(2S)-3-cyano-2-[(4-nitrobenzoyl)amino] propanoyl]amino]phenyl]sulfonylamino]-3-methoxy-benzoyl]amino]-3-methoxy-benzoate (1 .00 eq), was dissolved in EtOH and and SnCI2-H20 5.00 eq) was added. The mixture was stirred at 60 'Ό for 6 h. The solvent was removed and the residue uptaken in EE. Sat. NaHC03 was added and the aqueous layer was extracted 3 x with EE. The combined organic layers were dried over Na2S04 and the solvent was removed. The crude product was chromatographically purified to give the product as a yellow solid. Allyl 2-allyloxy-4-[[2-allyloxy-4-[[4-[[(2S)-2-[[4-[[(E)-3-(4-allyloxyphenyl)-2-methyl-prop-2- enoyl]amino]benzoyl]amino]-3-cyano-propanoyl
Figure imgf000423_0001
Chemical Formula: C55H5 N6013S
Exact Mass: 1038,3470
The cinnamic acid (3.00 eq) was dissolved in THF. Triphosgen (1 .00 eq) and Collidin (8.00 eq) were added and it was stirred for 15 min. Allyl 2-allyloxy-4-[[2-allyloxy-4-[[4-[[(2S)-2-[(4- aminobenzoyl)amino]-3-cyano-propanoyl]amino]phenyl]sulfonylamino]-3-methoxy- benzoyl]amino]-3-methoxy-benzoate (1 .00 eq) and DIPEA (10.00 eq) were dissolved in THF and added to the mixture. After stirring for 16 h the mixture was diluted with EE and the organic layer was washed 3 x with 1 N HCI, sat. NaHC03 and brine. After drying over Na2S04 the solvent was removed. The crude product was chromatographically purified to give the product as a yellow solid.
[(lS)-2-(4-benzyloxycarbonylanilino)-l-(cyanomethyl)-2-oxo-ethyl]ammonium
Figure imgf000423_0002
Chemical Formula: ΰ-ΐΒΗ-ιβΝβΟβ "
Exact Mass: 324,1343
The Boc-protected amine (1 .49 g, 3.45 mmol) was dissolved in 4 M HCI in Dioxane (20 ml). After stirring for 1 h at room temperature the solvent was evaporated and the product dried in vacuo (quant.). benzyl 4-[[(2S)-3-cyano-2-[(4-nitrophenyl)sulfonylamino]propanoyl]amino]benzoate
Figure imgf000424_0001
Chemical Formula: C24H2oN407S
Exact Mass: 508,1053
The amine (400 mg, 1 .1 1 mmol, 1 .00 eq) was dissolved in DCM (20 ml). DMAP (50 mg, 3.88 mmol, 3.50 eq) and Pyridine (2 ml), followed by 4-nitrobenzene-1 -sulfonyl chloride (741 mg, mmol, 3.00 eq). The reaction was stirred at room temperature for 72 h and subsequently washed 3 x with 1 N HCI and brine. After drying over Na2S04 the solvent was evaporated and the crude product chromatographically purified (Hex/EE 2:1 ) to give the desired product as a yellow solid (60 %).
4-[[(2S)-2-[(4-aminophenyl)sulfonylamino]-3-cyano-propanoyl]amino]benzoic acid
Figure imgf000424_0002
Chemical Formula: C 7H16N405S
Exact Mass: 388,0841
The peptide was dissolved in EE/MeOH 9:1 and Pd/C 10 % (w/w 10 %) was added. Under a Hydrogen-atmosphere it was stirred at room temperature for 2 h. The reaction mixture was filtered through a pad of celite. After drying over Na2S04 the solvent was evaporated to give the product.
4-[[(2S)-2-[[4-(tert-butoxycarbonylamino)phenyl]sulfonylamino]-3-cyano- propanoyl]amino]benzoic acid
Figure imgf000424_0003
Chemical Formula: C22H24N407S
Exact Mass: 488,1366 The amineoacid (1 .00 eq) was dissolved in dioxane/H20 and K2C03 (2.20 eq) and Boc20 (1 .10 eq) were added. After stirring at room temperature for 16 h the Dioxane was removed. The aqueous layer was extracted with MTBE. Subsequently the aqueous layer was acidified with 2 M HCI and extracted 3 x with EE. After drying the combined organic layers over Na2S04 the solvents was evaporated to give the product.
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[4-[[(2S)-2-[[4-(tert-butoxycarbonylamino)phenyl]sulfonylamino]- 3-cyano-propanoyl]amino]benzoyl]amino]-3-methoxy-benzoyl]amino]-3-methoxy-benzoate
Figure imgf000425_0001
Chemical Formula: C47H50Nf
Exact Mass: 938,3157
4-[[(2S)-2-[[4-(tert-butoxycarbonylamino)phenyl]sulfonylamino]-3-cyano- propanoyl]amino]benzoic acid (2.00 eq) was dissolved in THF and Triphosgen (0.66 eq) and Collidin (8.00 eq) were added. The mixture was stirred at room temperature for 40 min. The amine (1 .00 eq) and DIPEA (10.00 eq) were dissolved in THF, added to the mixture and it was stirred for an additional 16 h at room temperature. The reaction was diluted with EE and washed 3 x with 1 N HCI, sat. NaHC03 and brine. After drying over Na2S04 the solvent was removed. The crude product was chromatographically purified to give the product as a yellow solid.
[4-[[(lS)-2-[4-[[3-allyloxy-4-[(3-allyloxy-4-allyloxycarbonyl-2-methoxy-phenyl)carbamoyl]-2- methoxy-phenyl]carbamoyl]anilino]-l-(cyanomethyl)-2-oxo-ethyl]sulfamoyl]phenyl]ammonium
Figure imgf000425_0002
Chemical Formula: C42H43N601 1S+
Exact Mass: 839,2705 The Boc-protected amine was dissolved in 4 M HCI in Dioxane. After stirring for 1 h at room temperature the solvent was evaporated and the product dried in vacuo.
Allyl 2-allyloxy-4-[[2-allyloxy-4-[[4-[[(2S)-2-[[4-[[(E)-3-(4-allyloxyphenyl)-2-methyl-prop-2- enoyl]amino]phenyl]sulfonylamino]-3-cyano-propanoyl]amino]benzoyl]amino]-3-methoxy- benzoyl]amino]-3-methoxy-benzoate
Figure imgf000426_0001
Chemical Formula: Cssl-^NeO-i
Exact Mass: 1038,3470
The cinnamic acid (3.00 eq) was dissolved in THF. Triphosgen (1 .00 eq) and Collidin (8.00 eq) were added and it was stirred for 15 min. The amine (1 .00 eq) and DIPEA (10.00 eq) were dissolved in THF and added to the mixture. After stirring for 16 h the mixture was diluted with EE and the organic layer was washed 3 x with 1 N HCI, sat. NaHC03 and brine. After drying over Na2S04 the solvent was removed. The crude product was chromatographically purified to give the product as a yellow solid.
(S,E)-Allyl 2-(allyloxy)-4-(2-(allyloxy)-4-(4-(2-(4-(3-(4-(allyloxy)phenyl)-2-methylacrylamido) benzamido)-3-cyanopropanamido)benzamido)-3-methoxybenzamido)-3-methoxybenzoate
Figure imgf000426_0002
Bis-(trichloromethyl)carbonate (1 .2 eq, 0.10 mmol, 29 mg) and (£)-3-(4-(allyloxy)phenyl)-2- methylacrylic acid (3.5 eq, 0.30 mmol, 66 mg) were dissolved in dry THF (2 ml_) under argon atmosphere. 2,4,6-Collidine (8.0 eq, 0.69 mmol, 91 μΙ_) was added slowly via syringe. The resulting suspension was stirred at room temperature for 20 min and a solution of (S)-Allyl 2-
(allyloxy)- 4-(2-(allyloxy) -4-(4-(2-(4-aminobenzamido) -3-cyanopropanamido) benzamido)-3- methoxybenzamido)-3-methoxybenzoate (12) (12) (1 .0 eq, 0.09 mmol, 69 mg), DIPEA (10.0 eq, 0.86 mmol, 146 μΙ_) in dry THF (3 mL) was added. Stirring was continued for 3 h at room temperature and the reaction was quenched by addition of water (2 mL). The organic solvent was removed under reduced pressure and EtOAc (20 mL) was added. The mixture was washed successively with saturated NaHC03 (3 x 10 mL), water (1 x 10 mL) and brine (1 x 10 mL). The organic solvent was dried over Na2S04, filtered and removed under reduced pressure. Purification by column chromatography (CHCI3 - 2 % MeOH) yielded the product as a slightly yellow oil (64 mg, 75 %).
Rf (CHCI3:CH3OH - 9:0.5) = 0.15 H-NMR (dmso-ds, 500 MHz): δ [ppm] 2.14 (s, 3H), 3.08 (dd, Ji = 16.75 Hz, J2 = 8.82 Hz, 1 H), 3.17 (dd, Ji = 16.84 Hz, J2 = 5.35 Hz, 1 H), 3.93 (s, 3H), 3.94 (s, 3H), 4.55 (d, J = 5.55 Hz, 2H), 4.63 (d, J = 5.15 Hz, 2H), 4.78 (d, J = 5.35 Hz, 2H), 4.81 (d, J = 6.14 Hz, 2H), 5.00 (dd, Ji = 13.87 Hz, J2 = 8.13 Hz, 1 H), 5.28 (m, 4H), 5.41 (m, 4H), 6.09 (m, 4H), 7.05 (d, J = 8.72 Hz, 2H), 7.32 (s, 1 H), 7.46 (d, J = 8.72 Hz, 2H), 7.58 (d, J = 8.72 Hz, 1 H), 7.81 (m, 3H), 7.86 (d, J = 8.72 Hz, 2H), 7.94 (m, 3H), 8.00 (d, J = 8.72 Hz, 2H), 8.34 (d, J = 8.72 Hz, 1 H), 9.03 (d, J = 7.53 Hz, 1 H), 9.69 (s, 1 H), 10.15 (s, 1 H), 10.59 (s, 1 H), 10.66 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 1003.3873
found: 1003.3880
[M+Na]+ calculated: 1025.3692
found: 1025.3697
(S,E)-4-(4-(4-(3-cyano-2-(4-(3-(4-hydroxyphenyl)-2-methylacrylamido)benzamido)
propanamido)benzamido)-2-hydroxy-3-methoxybenzamido)-2-hydroxy-3-methoxybenzoic acid (albicidin)
Figure imgf000427_0001
(S,£)-Allyl 2-(allyloxy)-4-(2-(allyloxy)-4-(4-(2-(4-(3-(4-(allyloxy)phenyl)-2-methylacrylamido) benzamido)-3-cyanopropanamido)benzamido)-3-methoxybenzamido)-3-methoxybenzoate (14) (1 .0 eq, 30 μηιοΙ, 30 mg) was dissolved in dry THF (5 mL) under argon atmosphere and exclusion of light. Phenylsilane (8.0 eq, 239 μηιοΙ, 30 μΙ) and Pd[P(Ph)3]4 (0.5 eq, 15 μηιοΙ, 17 mg) were added and the reaction mixture was stirred for 10 hours at room temperature. AcOH (1 ml_) was added, the solvent was removed under reduced pressure and the sample was freeze dried. Purification was achieved by preparative HPLC and yielded the product as a white solid (12 mg, 48 %).
H-NMR (THF-ds, 500 MHz): δ 2.05 (s, 3H), 3.01 (dd, Ji = 16.84 Hz, J2 = 8.72 Hz, 1 H), 3.09 (m, 1 H), 3.71 (s, 3H), 3.84 (s, 3H), 4.92 (m, 1 H), 6.78 (d, J = 8.32 Hz, 2H), 7.21 (s, 1 H), 7.29 (d, J = 8.32 Hz, 2H), 7.50 (d, J = 8.92 Hz, 2H), 7.74 (m, 3H), 7.78 (d, J = 8.52 Hz, 2H), 7.86 (m, 2H), 7.94 (m, 3H), 8.96 (d, J= 7.53 Hz, 1 H), 9.63 (s, 1 H), 9.72 (s, 1 H), 10.04 (s, 1 H), 10.52 (s, 1 H), 1 1 .08 (s, 1 H), 1 1 .48 (s, 1 H).
HRMS (ESI): [M-H]" calculated: 841 .2460
found: 841 .2440
Allyl 2-(allyloxy)-4-((2-(allyloxy)-3-methoxy-4-(4-nitrobenzamido)benzoyl)oxy)-3-methoxybenzoate
Figure imgf000428_0001
Allyl 2-(allyloxy)-4-(2-(allyloxy)-4-amino-3-methoxybenzamido)-3-methoxybenzoate (4) (1 .0 eq, 0.49 mmol, 210 mg) was dissolved in dry THF and DIPEA (7.0 eq, 3.14 mmol, 533 μΙ) and p-nitro benzoic acid chloride (3.0 eq, 1 .34 mmol, 250 mg) was added under argon atmosphere. The solution was stirred for 18 h at room temperature. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (H:EA - 4:1 ) to yield the product as a yellow solid (84 mg, 30 %).
Rf (H:EA - 3:1 ) = 0.19
H-NMR (CDCIa, 400 MHz): δ [ppm] 3.99 (s, 3H), 4.06 (s, 3H), 4.57-4.60 (m, 2H), 4.77 (d, J = 6.42 Hz 2H), 4.81 (dt, = 5.73 Hz, J2 = 1 .34 Hz, 2H), 5.23-5.45 (m, 6 H), 6.00-6.21 (m, 3 H), 7.69 (d, J = 8.9 Hz, 1 H), 8.06-8.09 (m, 3 H), 8.38-8.41 (m, 2H), 8.45 (dd, Ji = 9.14 Hz, J2 = 3.15 Hz, 2H), 8.69 (s, 1 H) .
HRMS (ESI): [M+H]+ calculated: 618.2082
found: 618.2075
[M+Na]+ calculated: 640.1902
found: 640.1896 Allyl 2-(allyloxy)-4-(2-(allyloxy)-4-(4-aminobenzamido)-3-methoxybenzamido)-3-methoxybenzoate
OAllyl
Figure imgf000429_0001
Allyl 2-(allyloxy) -4-((2-(allyloxy) -3-methoxy -4-(4-nitrobenzamido) benzoyl) oxy)-3-methoxy benzoate (20) (1 .0 eq, 0.13 mmol, 82 mg) was dissolved in ethanol/dioxane (1 :1 ,1 .8 mL) and SnCI2'H20 (5.0 eq, 0.66 mmol, 150 mg) was added. The solution was stirred for 17 h at room temperature. 1 M KOH was added, the aqueous phase was extracted with EtOAc, the combined organic layers were washed with brine and dried over Na2S04. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (H:EA - 1 :1 ) to yield the product as a yellow solid (65 mg, 83 %).
Rf (H:EA - 1 :1 ) = 0.23
HRMS (ESI): [M+H]+ calculated: 588.2340
found: 588.2338
[M+Na]+ calculated: 610.2160
found: 610.2158
(S)-allyl 2-(allyloxy)-4-(2-(allyloxy)-4-(4-(2-((tert-butoxycarbonyl)amino)-3- cyanopropanamido)benzamido)-3-methoxybenzamido)-3-methoxybenzoate
OAllyl
Figure imgf000429_0002
Allyl 2-(allyloxy) -4-(2-(allyloxy) -4-(4-aminobenzamido) -3-methoxybenzamido) -3-methoxy benzoate (17) (1 .0 eq, 0.095 mmol, 56 mg) was dissolved in dry DMF under argon atmosphere. Boc-Asn-OH (3.0 eq, 0.29 mmol, 67 mg), HATU (6.1 eq, 0.58 mmol, 220 mg) and DIPEA (7 eq, 0.67 mmol, 1 13 μΙ) were added. The mixture was stirred at room temperature for 14 h. EtOAc was added and the organic layer was washed with saturated NH4CI solution, saturated NaHC03 solution, brine and dried over Na2S04. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (CHCI3:CH3OH - 9:0.2) to yield the product as a yellow, viscous oil. Since the product still contained impurities after chromatography the yield was determined after the last coupling step.
R, (C:M - 9:0.2) = 0.08
HRMS (ESI): [M+Na]+ calculated: 806.3008
found: 806.3007
(S)-allyl 2-(allyloxy)-4-(2-(allyloxy)-4-(4-(2-amino-3-cyanopropanamido)benzamido)-3- methoxybenzamido)-3-methoxybenzoate
Figure imgf000430_0001
(S)-allyl 2-(allyloxy)-4-(2-(allyloxy)-4-(4-(2-((tert-butoxycarbonyl)amino)-3-cyanopropanamido) benzamido)-3-methoxybenzamido)-3-methoxybenzoate (21 ) was dissolved in dioxane and 4 M HCI in dioxane was added. The mixture was stirred at room temperature for 1 .5 h. The solvent was removed under reduced pressure and the crude product was used for the next step without further purification. The yield was determined after the last coupling step.
R, (C:M - 9:1 ) = 0.34
HRMS (ESI): [M+H]+ calculated: 684.2664
found: 684.2674
[M+Na]+ calculated: 706.2484
found: 706.2492
(E)-Methyl 4-(3-(4-(allyloxy)phenyl)-2-methylacrylamido)benzoate
Figure imgf000430_0002
(E)-3-(4-allyloxyphenyl)-2-methyl-prop-2-enoic acid (13) (1 .0 eq, 0.72 mmol, 157 mg) was dissolved in dry DCM under argon atmosphere and thionyl chloride (10.0 eq, 7.20 mmol, 522 μΙ_) was added The solution was stirred at room temperature for 20 h. The solvent and thionyl chloride were removed under reduced pressure. The residue was dissolved in dry THF and methyl 4-aminobenzoate (0.7 eq, 0.48 mmol, 73 mg) and DIPEA (8.0 eq, 5.76 mmol, 976 μΙ_) were added. The mixture was stirred at room temperature for 20 h, DCM was added and the organic layer was washed with saturated NH4CI solution and brine and dried over MgS04. The solvent vas evaporated and the crude product was purified using reversed phase flash chromatography (water/MeOH) to yield the product as a white solid (121 mg, 71 %).
Rf (CHCI3:CH3OH - 100:1 ) = 0.71 H-NMR (dmso-ds, 400 MHz): δ [ppm] 2.12 (d, Λ = 0.9 Hz, 3H), 3.83 (s, 3H), 4.60-4.63 (m, 2H), 5.25-5.30 (m, 1 H), 5.38-5.45 (m, 1 H), 6.00-6.10 (m, 1 H), 7.01 -7.05 (m, 2H), 7.29 (s, 1 H), 7.44-7.46 (m, 2H), 7.86-7.95 (m, 4H), 10.23 (s, 1 H).
HRMS (ESI): [M+H]+ calculated: 352.1543
found: 352.1550
[M+Na]+ calculated 374.1363
found: 374.1370
(E)-4-(3-(4-(allyloxy)phenyl)-2-methylacrylamido)benzoic acid
Figure imgf000431_0001
£)-Methyl 4-(3-(4-(allyloxy)phenyl)-2-methylacrylamido)benzoate (22) ( 1 eq, 0.34 mmol, 121 mg) was dissolved in THF (2 ml_). 0.5 M LiOH in water (2.5 eq, 0.86 mmol, 1 .7 ml_) was added. The mixture was stirred at room temperature for 20 h, then acidified to pH 2 and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgS04 and the solvent was evaporated to yield the product as a white solid (99 mg, 85 %).
Rf (CHCI3:CH3OH - 9:1 ) = 0.35
H-NMR (dmso-ds, 400 MHz): δ [ppm] 2.12 (d, = 0.98 Hz, 3H), 4.61 (d, J= 5.2 Hz, 2H), 5.28 (dd, Ji = 10.2 Hz, J2 = 1 .5 Hz, 1 H), 5.42 (dd, = 17.3 Hz, J2 = 1 .5 Hz, 1 H), 6.02-6.10 (m, 1 H), 7.03 (d, J = 8.7, 2H), 7.29 (s, 1 H), 7.45 (d, J = 8.7 Hz, 2H), 7.83-7.92 (m, 4H), 10.18 (s, 1 H).
HRMS (ESI): [M-H]" calculated: 336.1241
found: 336.1237 Short description of the figures
shows a comparison of 1H-NMR spectra of natural beta-Albicidin and synthesized beta-Albicidin measured with a Bruker Avancell 700 MHz spectrometer. A) natural beta-Albicidin in d8-THF (50 μΙ) B) synthesized beta-Albicidin d8-THF (500 μΙ); shows a HPLC-LR-ESI-(+)-MS2 experiment with A) beta-Albicidin (natural).
B) Asn-Albicidin (natural) and C) Carbamoyl-Albicidin (natural) determining the structure of the compounds. HPLC-DAD-LR-ESI-(+)-MS/MS data were recorded on a triple quad mass spectrometer (ESI-Triple-Quadrupol-MS, 6460 series, Agilent Technologies, Waldbronn, Germany; Collision energy 10 eV); shows a CD spectra of beta-Albicidin (natural);
shows a UV spectra of beta-Albicidin (natural);
shows a CD spectra of beta-Albicidin (synthesized);
shows a UV spectra of beta-Albicidin (synthesized);
shows a CD spectra of Enantio-beta-Albicidin (synthesized);
shows a UV spectra of Enantio-beta-Albicidin (synthesized);
shows a HPLC-DAD-Chromatogram (Agilent 1 100) of beta-(L)-Albicidin
(λ = 280 nm);
shows a UV spectrum of the beta-(L)-albicidin measured on the Exactive
Orbitrap HPLC-MS instrument (HPLC-DAD photodiode array detection,, Agilent 1 100 HPLC).
shows HPLC-LR-ESI-(+)-MS/MS data: A) beta-Albicidin m/z = 843.3 [M+H]+; B)
Asn-OMe-Albicidin m/z = 861 .28 [M+H]+; C) beta-OMe-Albicidin m/z = 873.31 [M+H]+; D) Asn-OMe-Albicidin m/z = 891 .32 [M+H]+. HPLC-DAD-LR-ESI-(+)- MS/MS data were recorded on a triple quad mass spectrometer (ESI-Triple- Quadrupol-MS, 6460 series, Agilent Technologies, Waldbronn, Germany; Collision energy 10 eV).
shows HPLC-LR-ESI-(+)-MS/MS data: A) beta-Albicidin m/z = 843.3 [M+H]+;.
E) Carbamoyl-Albicidin m/z = 886.31 [M+H]+; F) Carbamoyl-OMe-Albicidin m/z = 916.31 [M+H]+; G) Carbamoyl-OMe-Asn-Albicidin m/z = 934.33 [M+H]+. HPLC-DAD-LR-ESI-(+)-MS/MS data were recorded on a triple quad mass spectrometer (ESI-Triple-Quadrupol-MS, 6460 series, Agilent Technologies, Waldbronn, Germany; Collision energy 10 eV). shows HR-ESI-(+)-Orbitrap-MS data: beta-OMe-Albicidin m/z = 873.31 [M+H]+; Carbamoyl-Albicidin m/z = 886.31 [M+H]+; Asn-OMe-Albicidin m/z = 891 .32 [M+H]+; Carbamoyl-OMe-Albicidin m/z = 916.31 [M+H]+; Carbamoyl-OMe-Asn- Albicidin m/z = 934.33 [M+H]+.
shows the High-resolution-ESI-(+)-Orbitrap-MS analysis performed on a Orbitrap XL LC-MS (Thermo Fisher Scientific GmbH, Bremen). beta-Albicidin m/z = 843.30 [M+H]+ ; Asn-OMe-Albicidin m/z = 861 .28 [M+H]+; beta-OMe- Albicidin m/z = 873.31 [M+H]+; Carbamoyl-Albicidin m/z = 886.31 [M+H]+; Asn- OMe-Albicidin m/z = 891 .32 [M+H]+; Carbamoyl-OMe-Albicidin m/z = 916.31 [M+H]+; Carbamoyl-OMe-Asn-Albicidin m/z = 934.33 [M+H]+.
shows a HPLC-DAD-Chromatogram at 310 nm after the step 2 purification protocol, summarized in Table 1 . Rt15 min = Carbamoyl-OMe-Asn-Albicidin (labeled δ-albicidin); Rt18 min = Asn-OMe-Albicidin (labeled α-3-albicidin); Rt24 min = Carbamoyl-Albicidin (labelled γ-albicidin); Rt29 min = Carbamoyl-OMe- Albicidin (labelled ε-albicidin); Rt32 min = beta-Albicidin (labelled β-Albicidin); Rt38 min = beta-OMe-Albicidin (labelled ζ-albicidin).
shows a Table of biological test results of synthetic albicidin in comparison to natural albicidin syntesized by heterologous expression. The microbiological assay described by Zhang etal., (JAppl Microbiol., 1998, 85, 1023-8) was used to study cross-resistance between synthetic albicidin (10) and the natural product albicidin purified from albicidin heterologous host developed by Vivien et al. (Antimicrob Agents Chemother., 2007, 51, 1549-52). Several Escherichia coli strains expressing a wide range of albicidin resistance determinants were used for this microbiological bioassay: strain DH5aAlbr (a spontaneous albicidin-resistant DH5a derivative ;Rott et al., {J. Bacteriol., 1996, 178, 4590- 4596.) and strains harboring albD (an albicidin-detoxifying gene, Zhang and Birch (Proc. Natl. Acad. Sci. USA, 1997, 94, 9984-9989.),alb14 (an albicidin efflux pump gene conferring albicidin resistance in E. coli, Bostock et a\., (J. Appl. Microbiol., 2006, 101, 151-160.), alb19 (a McbG gene conferring albicidin resistance in E. coli, Hashimi et al. (Antimicrob. Agents Chemother., 2007, 51, 181-187.), or sbmC (a microcin B17 resistance gene, Baquero et al. (Mol. Microbiol., 1995, 18, 301-31 1 .) . The resistance pattern was exactly the same for both toxins (synthetic albicidin (10) and the natural product albicidin purified from albicidin heterologous host), confirming that both toxins exhibit the same mode of action. PREPARATIONS OF ALBICIDIN DERIVATIVES
According to another aspect, the invention relates to preparations of an antibiotically active compound having a molecular structure as defined by formula 1 , characterized in that the purity of the preparation is greater than 95%, 97%, 99%, 99,5% or 99,9%.
In some embodiments, the purity of the preparation is about 99%.
In some embodiments, the purity of the preparation is greater than 99%.
In some embodiments, the purity of the preparation is greater than 99,5%.
In some embodiments, the purity of the preparation is greater than 99,9%.
Similarly, a dosage form for the prevention or treatment of bacterial infection is provided, comprising a compound or preparation according to any of the above described aspects or embodiments of the invention. Dosage forms may be for enteral administration, such as nasal, buccal, rectal, transdermal or oral administration, or as an inhalation form or suppository. Alternatively, parenteral administration may be used, such as subcutaneous, intravenous, intrahepatic or intramuscular injection forms. Optionally, a pharmaceutically acceptable carrier and/or excipient may be present.
According to another aspect, the invention relates to a pharmaceutical preparation of an antibiotically active compound having a molecular structure as defined by formula 1 as active ingredient, characterized in that said pharmaceutical preparation is essentially free of (has a content of less than 5%, 3%, 1 %, 0,5%, 0,1 % (w/w) ) contaminants.
In some embodiments, the pharmaceutical preparation has a content of less than 1 % (w/w) contaminants.
In some embodiments, the pharmaceutical preparation has a content of less than 0,5 % (w/w) contaminants.
In some embodiments, the pharmaceutical preparation has a content of less than 0,1 % (w/w) contaminants.
In some embodiments, the pharmaceutical preparation is essentially free of contaminants.
According to a further aspect, the invention relates to an isolated antibiotically active compound having a molecular structure as defined by formula 1 , or to a pharmaceutical preparation of at least one antibiotically active compound having a molecular structure as defined by formula 1 as active ingredient for use in a method of treatment of disease, particularly in a method for the treatment of bacterial infections. In some embodiments, the pharmaceutical preparation of at least one antibiotically active compound comprises one essentially pure enantiomer according to the general formula 1 L or 1 D.
In some embodiments, the pharmaceutical preparation of an antibiotically active compound comprises a mixture of L- or D-enantiomers selected independently from each other from the compounds of the general formula 1 .
In some embodiments, the pharmaceutical preparation of an antibiotically active compound comprises mixture of the L-enantiomer and the respective D-enantiomer according to the general formula 1 L and 1 D, wherein Z and Y of the general formula 1 L are the same as Z and Y of the general formula 1 D, thus, pharmaceutical preparation comprises a mixture of the L- and D-enantiomer with the same molecular formula.
In some embodiments, the pharmaceutical preparation of at least one antibiotically active albicidin compound comprises one essentially pure enantiomer selected from the group of beta-Albicidin or Asn-Albicidin.
In some embodiments, the pharmaceutical preparation of at least one antibiotically active albicidin compound comprises one essentially pure enantiomer selected from the group of Enantio-beta-Albicidin or Enantio-Asn-Albicidin.
In some embodiments, the pharmaceutical preparation comprises beta-Albicidin as N essentially pure enantiomer.
In some embodiments, the pharmaceutical preparation comprises Enantio-beta-Albicidin as N essentially pure enantiomer.
In some embodiments, the pharmaceutical preparation of an antibiotically active albicidin compound comprises a mixture of L- or D-enantiomers selected from the group of beta- Albicidin, Asn-Albicidin, Carbamoyl-Albicidin, Carbamoyl-Asn-Albicidin, beta-OMe-Albicidin, Asn-OMe-Albicidin, Carbamoyl-OMe-Albicidin, Carbamoyl-OMe-Asn-Albicidin, Enantio-beta- Albicidin, Enantio-Asn-Albicidin, Enantio-Carbamoyl-Albicidin, Enantio-Carbamoyl-Asn- Albicidin, Enantio-beta-OMe-Albicidin, Enantio-Asn-OMe-Albicidin, Enantio-Carbamoyl-OMe- Albicidin or Enantio-OMe-Carbamoyl-Asn-Albicidin. This includes also the previously discussed diastereoisomers (1 L1 , 1 L2, 1 D1 , 1 D2), which are not specifically mentioned due to simplicity reasons.
In some embodiments, the pharmaceutical preparation of an antibiotically active albicidin compound comprises a mixture of L- Enantiomers selected from the group of beta-Albicidin, Asn-Albicidin Carbamoyl-Albicidin, Carbamoyl-Asn-Albicidin, beta-OMe-Albicidin, Asn-OMe- Albicidin, Carbamoyl-OMe-Albicidin, Carbamoyl-OMe-Asn-Albicidin. In some embodiments, the pharmaceutical preparation of an antibiotically active albicidin compound comprises a mixture of D- Enantiomers selected from the group of Enantio-beta- Albicidin, Enantio-Asn-Albicidin, Enantio-Carbamoyl-Albicidin, Enantio-Carbamoyl-Asn- Albicidin Enantio-beta-OMe-Albicidin, Enantio-Asn-OMe-Albicidin, Enantio-Carbamoyl-OMe- Albicidin or Enantio-OMe-Carbamoyl-Asn-Albicidin.
In some embodiments, the pharmaceutical preparation of an antibiotically active albicidin compound comprises mixture of the L-enantiomer and the respective D-enantiomer according to the general formula (1 L) and (1 D), wherein Rr, R2 and R3' of the general formula (1 L) are the same as Rr, R2 and R3' of the general formula (1 D), thus, pharmaceutical preparation comprises a mixture of the L- and D-enantiomer with the same molecular formula.
In some embodiments, the pharmaceutical preparation of an antibiotically active albicidin compound comprises mixture of
- beta-Albicidin and Enantio-beta-Albicidin, or
Asn-Albicidin and Enantio-Asn-Albicidin.
In some embodiments, the pharmaceutical preparation of an antibiotically active albicidin compound comprises mixture of
- beta-Albicidin and Enantio-beta-Albicidin.
In some embodiments, the bacterial infection is an infection by a gram-negative bacterium.
In some embodiments, the bacterial infection is an infection by a gram-negative bacterium.
In some embodiments, the bacterial infection is an infection by a gram-negative bacterium of the genus Acinetobacter, Bordatella, Borellia, Brucella, Camphylobacter, Chlamydia, Chlamydophila, Enterobacter, Escherichia, Francisella, Haemophilus, Helicobacter,
Klebisella, Legionella, Leptospira, Morganella, Moraxella, Neisseria, Proteus, Pseudomonas, Rickettsia, Shigella, Salmonella, Stenotrophomonas, Treponema or Yersinia.
In some embodiments, the bacterial infection is an infection by a gram-negative bacterium of the genus Bacteroides, Escherichia, Enterobacter, Salmonella, Klebisella, Pseudomonas, Haemophilus, Serratia, Shigella, Proteus or Morganella.
In some embodiments, the bacterial infection is an infection by a gram-negative bacterium selected from the group of Acinetobacter baumannii, Bacteriodis fragilis, Bordatella pertussis, Borrelia burgdorferi, Brucella abortus, Brucella abortus, Brucella canis, Brucella melitensis, Brucella suis, Campylobacter jejuni, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydophila psittaci, Enterobacter aerogenes, Enterobacter cloacae, Enterobacter sakazakii, Cronobacter sakazakii, Escherichia coli, Francisella tularensis, Haemophilus influenzae, Helicobacter pylori, Klebisella pneumonia, Legionella pneumophila, Leptospira interrogans, Moraxella catarrhalis, Morganella morganii, Moraxella lacunata, Moraxella bovis, Neisseria gonorrhoeae, Neisseria meningitidis, Proteus vulgaris, Proteus mirabilis,
Pseudomonas aeruginosa, Rickettsia rickettsii, Salmonella typhi, Salmonella enteritidis, Serratia marcescens, Shigella sonnei, Stenotrophomonas maltophilia, Treponema pallidum, Vibrio cholerae or Yersinia pestis.
In some embodiments, the bacterial infection is an infection by a gram-negative bacterium selected from the group of Escherichia coli, Enterobacter aerogenes, Enterobacter cloacae, Enterobacter sakazakii, Cronobacter sakazakii, Salmonella typhi, Klebisella pneumonia, Pseudomonas aeruginosa, Haemophilus influenza, Shigella sonnei, Proteus vulgaris, Proteus mirabilis or Morganella morganii.
In some embodiments, the bacterial infection is an infection by a gram-positive bacterium.
In some embodiments, the bacterial infection is an infection by a gram-positive bacterium of the genus Bacillus, Clostridium, Corynebacterium, Enterococcus, Listeria, Micrococcus, Staphylococcus or Streptococcus.
In some embodiments, the bacterial infection is an infection by a gram-positive bacterium of the genus of Staphylococcus, Streptococcus, Bacillus or Micrococcus.
In some embodiments, the bacterial infection is an infection by a gram-positive bacterium selected from the group of Bacillus anthracis, Clostridium botulinum, Clostridium difficile, Clostridium perfringens, Clostridium tetani, Corynebacterium diphtheriae, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Staphylococcus aureus,
Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus pneumoniae or Streptococcus pyogenes.
In some embodiments, the bacterial infection is an infection by a gram-positive bacterium selected from the group of Staphylococcus aureus, Staphylococcus epidermidis,
Streptococcus pyogenes, Bacillus subtilis, Bacillus megaterium or Micrococcus luteus.
In some embodiments, the bacterial infection is an infection by a bacterium of the family of Mycobacteriaceae, in particular a Mycobacterium, further in particular an infection by one of Mycobacterium tuberculosis, Mycobacterium leprae, Mycobacterium ulcerans or
Mycobacterium avium.
In some embodiments, the bacterial infection is an infection by a bacterium of the family of Mycoplasmataceae, in particular of the genus Mycoplasma, further in particular an infection by Mycoplasma pneumonia. In some embodiments, the bacterial infection is an infection by a bacterium resistant to a fluoroquinolone antibiotic. In some embodiments, the bacterium is resistant to the fluroquinolone antibiotic ciprofloxacin, levofloxacin or trovafloxacin.

Claims

Patent claims
1 . A compound characterized by a general formula (1 ),
X-BB— D— BC— D— BD— D— BE— X2
(1 ),
a. with X1 being
i. selected from a substituent group S1 or S2, or
ii. R4-D1-, with R4 being selected from a substituent group S3, S4 or S5, or iii. BA-D - with BA-D -being selected from
Figure imgf000439_0001
with E being selected from a substituent group S3, S4 or S5, and
b. with BB being selected from a substituent group S3 or S4, and
c. with BC
i. being selected from
Figure imgf000439_0002
with p being 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and with r being 2, 3, 4 or 5, in particular r being 2, or
ii. with -D2-BC- being
Figure imgf000440_0001
p being 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and
d. with BD being selected from a substituent group S3 or S4, and
e. with BE being selected from a substituent group S3, and
f. with X2 being
i. selected from a substituent group S1 or S2, and wherein a linker D5 may be optionally situated between BE and the substituent group S1 or S2, or ii. being -D5-BF, wherein BF is selected from a substituent group S2 with S1 being
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -N02, -OCH3, -OCF3, -NH2, -NHCH3, - N(CH3)2, -CH3, -CH2CH3 or -CF3,
with S2 being
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m- C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, - (CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, - (CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m- NRcC(=0)ORa, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m- NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m- P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, - (CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
- with Raa being selected independently from each other from -Ra or -ORa,
- with Rba being selected independently from each other from -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl, - with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 ,
- with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen, -CN, a substituent group S3, a substituent group S4 or a substituent group S5,
with S3 being
- a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or
unsubstituted C3-Cio halo cycloalkyl, or
- a substituted or unsubstituted C6-Cio aryl,
with S4 being
- a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or
unsubstituted C3-Cio halo heterocycle, in particular a substituted or unsubstituted C4-Ci0 heterocycle or a substituted or unsubstituted C4-Cio halo heterocycle, or
- a substituted or unsubstituted C5-Cio heteroaryl,
with S5 being
- a substituted or unsubstituted C Ci6 alkyl, a substituted or unsubstituted Cr Ci 6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C1 -C16 haloalkyl,
with R2 and R3 of BA being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH2, -N02, -NHCH3, -NH(CH3)2, a substituted or unsubstituted Ci-C3 alkyl, a substituted or unsubstituted Ci-C3 alkoxy or a Ci-C3 haloalkyl , in particular from -H, -F, -CN, -OH, -NH2, -N02, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCF3, -CH2CF3, - CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3,more particularly with R2 and R3 being selected independently from each other from -H, -F or -CH3,
with L , L2, L3, L4 or L5 being selected independently from each other from -H, -CH3, - CH2CH2CH2NHC(NRc)N(Rb)(Ra), -CH2CON(Rb)(Ra), -CH2C(=0)ORa, -CH2SRa, - CH2CH2C(=0)N(Rb)(Ra), -CH2CH2C(=0)ORa, -CH2(C3H3N2), -CH2CH2CH2CH2, - CH2CH2SCH3, -CH2(C6H5), -CH2CH2CH2-, -CH2ORa, -CH(ORa)CH3, -CH2(C8H6N)ORa, -CH2(C6H4)ORa, -CH(CH3)2, -CCH, -CN, -OCH3 -CF3, -Ra, -CH(Rb)(Ra), -CH2C(=0)Ra, -C(=0)ORa, -OC(=0)NRbRa, -C(=0)NRbRa, -CH2C(=0)NRb (ORa), -CH2S(02)Ra, - S(02)ORa, -CH2S(02)ORa, -CH2NRbC(=0)Ra, -CH2NRbS(02)Ra, - CH2P(=0)(ORb)(ORa), -CH2P(=0)(ORb)(Ra), -CH2P(=0)(Rb)(Ra) or -CH2S(02)NRbRa,
- with Ra and Rb being selected, where applicable, independently from each other from hydrogen, -CN, a substituent group S3, a substituent group S4 or a substituent group S5,
- with R8 of -D2-BC- being selected from -H, -CH3, -CH2CH3, -OCH3, -OCF3, - CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with R8 being selected from H or CH3, more particularly R8 is H.
with Y being selected from -CN, -C(=0)OH, -C(=0)OCH3, -C(=0)OCH2CH3, - C(=0)NHCH3, -C(=0)NHCH2CH3, -C(=0)N(CH3)2, -C(=0)N(CH2CH3)2, - C(=0)N(CH3)(CH2CH3), -CF3 or -C(=0)NH2, and
with Z being selected from -H, -OH, -CH3, -CH2CH3, -OCH3 ,-NH2, -NHCH3, -N(CH3)2 - N(CH3)3 +, in particular Z is H and Y is CN or -C(=0)NH2,
with D ,D2, D3, D4 or D5 being each, independently from each other, a linker which comprises carbon, sulphur, nitrogen, phosphor and/or oxygen atoms and which is covalently connecting the moiety, BA and BB (D ), BB and BC (D2), BC and BD (D3), BD and BE (D4) and BE and BF (D5).
2. The compound according to claim 1 , wherein the compound is characterized by a general formula (5),
Figure imgf000442_0001
(formula 5), with X1 , D2, BC, D3, D4, BE, D5 and BF having the same meaning as defined previously.
3. The compound according to claim 1 , wherein the compound is characterized by a general formula (7),
Figure imgf000442_0002
(formula 7), with X1 , D2, BC, D3, D4, R n, D5 and BF having the same meaning as defined previously.
4. The compound according to claim 1 , wherein the compound is characterized by a general formula (9),
Figure imgf000443_0001
(formula with X1 , D2, BC, D3, D4, R , D5 and BF having the same meaning as defined previously.
The compound according to claim 1 , wherein the compound is characterized by a general formula (12),
Figure imgf000443_0002
(formula 12), with X1 , D2, BC, D3, D4, R11 , R 0 n, T and D5 having the same meaning as defined previously.
6. The compound according to claim 1 , wherein the compound is characterized by a general formula (13),
Figure imgf000443_0003
(formula 13), with E, R2, R3, D1 , D2, BC, D3, D4, R11 , R 0 n, T and D5 having the same meaning as defined previously.
7. The compound according to claim 1 , wherein the compound is characterized by a general formula (14),
Figure imgf000444_0001
with R2, R3, D1 , D2, BC, D3, D4, R n, R11 , R 0 n, T and D5 having the same meaning as defined previously.
8. The compound according to claim 1 , wherein the compound is characterized by a general formula (15),
(formula 15), with Y, Z, R2,R3, D1 , D2, D3, D4, R11 , R 0 n, R n, T and D5 having the same meaning as defined previously.
9. The compound according to any one of the claims 1 to 5, wherein
X1 is
- -OH, -F, -CI, -Br, I, -CCH, -CN, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3 or -CF3,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m- C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, - (CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, - (CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m- NRcC(=0)ORa,-(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m- NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m- P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, - (CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa-(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
- with Raa being selected independently from each other from -Ra or -ORa,
- with Rba being selected independently from each other from -Rb or -ORb,
- with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl,
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 ,
- with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen, -CN,
- a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl, or
- a substituted or unsubstituted C6-Cio aryl,
- a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Cio halo heterocycle, in particular a substituted or unsubstituted C4-Ci0 heterocycle or a substituted or unsubstituted C4- Cio halo heterocycle, or
- a substituted or unsubstituted C5-Cio heteroaryl,
- a substituted or unsubstituted C Ci6 alkyl, a substituted or
unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C Ci6 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl.
10. The compound according to any one of the claims 1 to 5 or 9, wherein
X1 is
- -NRa 2, -NH Ra, -C(=0)ORa or -ORa,
with Ra being a substituted or unsubstituted C Ci 6 alkyl, a substituted or unsubstituted C Ci 6 alkoxy, a substituted or unsubstituted C Ci 6 carboxy, a substituted or unsubstituted C2-Ci 6 alkenyl, a substituted or unsubstituted C2-Ci 6 alkynyl, or a C Ci 6 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted C2- C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted Ci -C8 haloalkyl, or
- a substituted or unsubstituted C3-Ci 0 heterocycle or a substituted or
unsubstituted C3-Ci o halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
- a substituted or unsubstituted C5-C10 heteroaryl, in particular a substituted or unsubstituted 1 ,2,3-triazole, a substituted or unsubstituted 1 ,2,4-triazole, a substituted or unsubstituted indole, a substituted or unsubstituted isoindole, a substituted or unsubstituted quinoline or a substituted or unsubstituted
isoquinoline, or
- -[(CH2)m1-0-C(=0)-(CH2)m2]p1 -C(=0)ORd or -[(CH2)m1-0-(CH2)m2]p1 -ORd with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8.
1 1 . The compound according to any one of the claims 1 to 5 or 9 to 10, wherein
X1 is
- -NRa 2, -NH Ra or -C(=0)ORa, in particular X is -NRa 2 or -NH Ra,
with Ra being a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, or a substituted or unsubstituted CrC8 haloalkyl.
12. The compound according to any one of the claims 1 to 5, wherein X1 is R4-D1 -, with
D having the same meaning as defined previously, and wherein a substituted or unsubstituted C Ci 6 alkyl, a substituted or unsubstituted C1 -C16 alkoxy, a substituted or unsubstituted C1 -C16 carboxy, a substituted or unsubstituted C2-Ci 6 alkenyl, a substituted or unsubstituted C2-Ci 6 alkynyl, or a C1 -C16 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or
unsubstituted Ci -C8 haloalkyl, a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C3-C10 halo cycloalkyl.
a substituted or unsubstituted C3-C10 heterocycle or a substituted or
unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Ci o aryl.
13. The compound according to any one of the claims 1 to 5 or 12, wherein X1 is R4-D1-, with D having the same meaning as defined previously, and wherein
R4 is
a substituted or unsubstituted C5-C6 halo heterocycle, in particular a C5-C6 halo heterocycle comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F,
a substituted or unsubstituted C5-C6 heteroaryl,
a substituted C6 aryl, in particular a bicyclic C6 aryl such as tetraline or indane, a substituted or unsubstituted C5-C6 halo heteroaryl comprising one or two halogen atoms selected from CI of F, particularly comprising one CI or one F; or
R4 is selected from the group of substituted or unsubstituted pyrrole, furan, thiophene, benzothiophene, chromene, thiazole, pyrazine, pyridazine, pyridine, 1 ,2,3-triazole, 1 ,2,4-triazole, imidazole, oxazol, thiazol, indole, isoindole, quinoline, isoquinoline, naphatalene, coumarin, aminocoumarin, umbelliferon, benzotriazole, psoralen, benzofurane, benzothiophene, benzimidazol, benzthiazole, benzoxazole or benzpyridazin or hydroxylated, methylated or halogenated derivatives thereof.
14. The compound according to any one of the claims 1 to 5 or 12 to 13, wherein X1 is R4-D1-, with D having the same meaning as defined previously, and wherein R4 is
a substituted or unsubstituted C1-C5 alkyl or a substituted or unsubstituted C6-Cio cycloalkyl, a substituted or unsubstituted C5-C10 heteroaryl or a substituted or unsubstituted C6-Cio aryl, in particular R4 is selected from
Figure imgf000448_0001
15. The compound according to any one of the claims 1 to 5 or 12 to 14, wherein X1 is R4-D1-, with D having the same meaning as defined previously, and wherein
R4 is
an unsubstituted C1-C5 alkyl or an unsubstituted C6-Cio cycloalkyl.
16. The compound according to any one of the claims 1 to 6, wherein X1 is BA-D - with BA being selected from
Figure imgf000448_0002
in particular with BA being selected from BA1 , BA2 or BA4, more particularly BA is BA1 ,
with D having the same meaning as defined previously, and
with R2 and R3 being selected, where applicable, independently from each other from -H, -F, -CN, -OH, -NH2, -NO2, -NHCH3, -NH(CH3)2, a substituted or unsubstituted Ci- C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl, in particular with R2 and R3 being selected, where applicable, independently from each other from
-H, -F, -CN, -OH, -NH2, -N02, -NHCH3, -NH(CH3)2, -CH3, -CH2CH3, -OCH3, - OCH2CH3, -OCH2CH2CH3 ! -OCH(CH3)2, -OCF3, -CH2CF3, -CH FCF3, -CF2CF3, -CH F2, -CH2F or -CF3, more particularly with R2 and R3 being selected independently from each other from -H , -F or -CH3
with E being
- a substituted or unsubstituted C Ci 6 alkyl, a substituted or unsubstituted C1 -C16 alkoxy, a substituted or unsubstituted C1 -C16 carboxy, a substituted or
unsubstituted C2-Ci 6 alkenyl, a substituted or unsubstituted C2-Ci 6 alkynyl, or a Cr C16 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted Ci -C8 haloalkyl, a substituted or unsubstituted C3-Ci o cycloalkyl, or a substituted or unsubstituted C3-Ci o halo cycloalkyl,
- a substituted or unsubstituted C3-Ci o cycloalkyl or a substituted or unsubstituted C3-Ci o halo cycloalkyl,
- a substituted or unsubstituted C3-Ci 0 heterocycle or a substituted or unsubstituted C3-Ci o halo heterocycle; in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle,
- a substituted or unsubstituted C5-C10 heteroaryl,
- a substituted or unsubstituted C6-Ci o aryl.
17. The compound according to any one of the claims 1 to 8, wherein X1 is BA-D1- , with BA being selected from BA1 to BA6, in particular from BA1 , BA 2 or BA4, more particularly BA is BA1 ,with D and with R2 and R3 of BA1 to BA6 having the same meaning as defined previously, and
with E being
Figure imgf000449_0001
with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, particularly n of R n being 1 , and
with each R independently from any other R being selected from -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2-CH3, -CF3, -OCONH2 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m- C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, - (CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, - (CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m- NRcC(=0)ORa, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m- NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m- P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, - (CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl
with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen, -CN
- a substituted or unsubstituted C Ci6 alkyl, a substituted or unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C Ci6 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted CrC8 haloalkyl, a substituted or unsubstituted C3- Cio cycloalkyl, or a substituted or unsubstituted C3-Cio halo cycloalkyl, - a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl,
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle,
- a substituted or unsubstituted C5-C10 heteroaryl,
- a substituted or unsubstituted C6-Ci o aryl.
18. The compound according to any one of the claims 1 to 8 or 17, wherein X1 is BA-D1-, with BA being selected from BA1 to BA6, in particular from BA1 , BA 2 or BA4, more particularly BA is BA1 ,with D and with R2 and R3 of BA1 to BA6 having the same meaning as defined previously, and
with E being
Figure imgf000451_0001
- with n of R n being 0, 1 , 2, 3, 4 or 5, in particular n of R n being 0, 1 , 2 or 3, more particularly n of R n 1 , and
- with each R independently from any other R being selected from
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NH CH3, -N(CH3)2, -CH3, -CH2-CH3, -CF3, -OCONH2 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)ORa, -
(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -
(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-
C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-
OC(=S)Ra, -(CH2)m-OC(=S)ORa, -(CH2)m-OC(=S)NRaRb, -(CH2)m-
C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, -(CH2)m-S(02)Ra, -
(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, -(CH2)m-
NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa, -(CH2)m-
NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -
(CH2)m-NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-
P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, -(CH2)m-0-C(=0)-(M)-C(=0)ORa, - (CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), - (CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q- S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa, ,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, - CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -C6H5— CH2CeH5.
19. The compound according to claim 1 , wherein BB is
Figure imgf000452_0001
with n of R 3 n being 0, 1 , 2, 3 or 4, in particular n of R 3 n being 0, 1 or 2,
with each R 3 independently from any other R 3 being
-OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, - N(CH3)2, -CH3, -CH2CH3, -CF3 or -N02, in particular -OH, -F, -CI, -Br, -I, - CCH, -CN, -N3, -OCH3, -OCF3, -, -CH3, -CH2CH3 or -CF3, or with each R 3 independently from any other R 3 being
-OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, - N(CH3)2, -CH3, -CH2CH3, -CH3, -CF3 or -N02, in particular -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -, -CH3, -CH2CH3 or -CF3, wherein, each carbon atom of the cyclic system which comprises no substituent R 3 comprises F instead of H.
20. The compound according to any one of the claims 1 or 19, wherein
BB is
Figure imgf000453_0001
with n of R 3 n being 0, or
with n of R 3 n being 1 , 2, 3 or 4 with each R 3 being F, in particular n is 4 and each R
21 . The compound according to any one of the claims 1 to 7, wherein
BC is selected from
Figure imgf000453_0002
with p being 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and
with r being 2, 3, 4 or 5, in particular r being 2,
with L , L2, L4 or L5 being selected independently from each other from -H, -CH3, - CH2CH2CH2NHC(NRc)N(Rb)(Ra), -CH2CON(Rb)(Ra), -CH2C(=0)ORa, -CH2SRa, - CH2CH2C(=0)N(Rb)(Ra), -CH2CH2C(=0)ORa, -CH2(C3H3N2), -CH2CH2CH2CH2, - CH2CH2SCH3, -CH2(C6H5), -CH2CH2CH2-, -CH2ORa, -CH(ORa)CH3, -CH2(C8H6N)ORa, -CH2(C6H4)ORa, -CH(CH3)2, -CCH, -CN, -OCH3, -CF3, -Ra, -CH(Rb)(Ra), - CH2C(=0)Ra, -C(=0)ORa, -OC(=0)NRbRa, -C(=0)NRbRa, -CH2C(=0)NRb (ORa), - CH2S(02)Ra, -S(02)ORa, -CH2S(02)ORa, -CH2NRbC(=0)Ra, -CH2NRbS(02)Ra, - CH2P(=0)(ORb)(ORa), -CH2P(=0)(ORb)(Ra), -CH2P(=0)(Rb)(Ra) or -CH2S(02)NRbRa, and - with Ra and Rb being selected, where applicable, independently from each other from
- a substituted or unsubstituted CrC4 alkyl, a substituted or unsubstituted Ci-C4 alkoxy, a substituted or unsubstituted Ci-C4 carboxy, a substituted or unsubstituted C2-C4 alkenyl, a substituted or unsubstituted C2-C4 alkynyl, or a Ci-C4 haloalkyl, or
- a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl, or
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-Cio heterocycle or a substituted or unsubstituted C4-Cio halo heterocycle, or
- a substituted or unsubstituted C5-C10 heteroaryl, or
- a substituted or unsubstituted C6-Cio aryl,
with L3 being selected from -CH3, -CH2CH3, -OCH3, -OCH2CH3, a Ci-C2-fluoro alkyl, with Y being -CN, -C(=0)OH, -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)NHCH3, - C(=0)NHCH2CH3, -C(=0)N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3) or - C(=0)NH2, in particular Z is H and Y is CN and -C(=0)NH2,
with Z being -H, -OH, -CH3, -CH2CH3, -OCH3, -NH2 ,-NHCH3, -N(CH3)2 ,-N(CH3)3 + or with -D2-BC- being
Figure imgf000454_0001
p being 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and
with, where applicable, each R8 being selected independently from each other from - H, -CH3, -CH2CH3, -OCH3, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or - CF3, in particular with each R8 being selected independently from each other from H or CH3, more particularly each R8 being H.
22. The compound according to any one of the claims 1 to 7 or 21 , wherein BC is selected from
Figure imgf000455_0001
with p being 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and
with r being 2, 3, 4 or 5, in particular r being 2,
with L , L2, L4 or L5 being selected independently from each other from H, -CH3, - CH2CH2CH2NHC(NRc)N(Rb)(Ra), -CH2CON(Rb)(Ra), -CH2C(=0)ORa, -CH2SRa, - CH2CH2C(=0)N(Rb)(Ra), -CH2CH2C(=0)ORa, -CH2(C3H3N2), -CH2CH2CH2CH2, - CH2CH2SCH3, -CH2(C6H5), -CH2CH2CH2-, -CH2ORa, -CH(ORa)CH3, - CH2(C8H6N)ORa, -CH2(C6H4)ORa, -CH(CH3)2, -CCH, -CN, -OCH3, -CF3, -Ra, - CH(Rb)(Ra), -CH2C(=0)Ra, -C(=0)ORa, -OC(=0)NRbRa, -C(=0)NRbRa, - CH2C(=0)NRb (ORa), -CH2S(02)Ra, -S(02)ORa, -CH2S(02)ORa, - CH2NRbC(=0)Ra, -CH2NRbS(02)Ra, -CH2P(=0)(ORb)(ORa), -CH2P(=0)(ORb)(Ra), -CH2P(=0)(Rb)(Ra) or -CH2S(02)NRbRa, and with
L3 being selected from -CH3, -CH2CH3, -OCH3, -OCH2CH3, a Ci-C2-fluoro alkyl, with Y being -CN, -C(=0)OH, -C(=0)OCH3, -C(=0)OCH2CH3, -C(=0)NHCH3, - C(=0)NHCH2CH3, -C(=0)N(CH3)2, -C(=0)N(CH2CH3)2, -C(=0)N(CH3)(CH2CH3) or -C(=0)NH2, in particular Z is H and Y is CN and -C(=0)NH2, and wherein with Z being , -OH, -CH3, -CH2CH3, -OCH3 -NH2 ,-NHCH3, ,-N(CH3)2 ,-N(CH3)3 +.
- with Ra and Rb being selected, where applicable, independently from each other from CH3, -CH2CH3, -CH2CH2CH3, - CH2CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -C6H5 ,- CH2C6H5, mono methoxybenzyl, in particular para methoxybenzyl, or dimethoxybenzyl or trimethoxybenzy,
or
- with -D2-BC- being
Figure imgf000456_0001
p being 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and
with, where applicable, each R8 being selected independently from each other from -H, -CH3, -CH2CH3, -OCH3, -OCF3, -CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with each R8 being selected independently from each other from H or CH3, more particularly each R8 being H.
23. The compound according to any one of the claims 1 to 7 or 21 to 22, wherein
BC is selected from
Figure imgf000456_0002
with p, r, L , L2, L3, L4, L5, Y, Z, Ra or Rb having the same meaning as defined previously, or
- with -D2-BC- being
Figure imgf000456_0003
p being 1 , 2, 3, 4 or 5, in particular p being 2 or 3, and
with R8 being H or CH3.
24. The compound according to any one of the claims 1 to 7 or 21 to 23, wherein BC is
Figure imgf000457_0001
or , in particular
Figure imgf000457_0002
with p, r L , L2, L3, L4, L5, Y, Z, Ra or Rb having the same meaning as defined previously.
25. The compound according to any one of the claims 1 to 7 or 21 to 24, wherein BC is
Figure imgf000457_0003
or
Z^Y with p, r L , L2, L3, L4, L5, Y, Z, Ra Rb having the same meaning as defined previously.
26. The compound according to any one of the claims 1 to 8, wherein
BD is
Figure imgf000457_0004
with n of R 2 n being 0, 1 , 2, 3 or 4, in particular n of R 2 n being 0, 1 or 2,
with each R 2 independently from any other R 2 being
- -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2CH3, -CF3 or -N02, in particular -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, - OCH3, -OCF3, -CH3, -CH2CH3 or -CF3, or
with each R 2 independently from any other R 2 being
-OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, - N(CH3)2, -CH3, -CH2CH3, -CH3, -CF3 or -N02, in particular -OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -, -CH3, -CH2CH3 or -CF3, wherein each carbon atom of the cyclic system which comprises no substituent R 2 comprises F instead of H.
27. The compound according to any one of the claims 1 to 8, or 26 wherein
BD is
Figure imgf000458_0001
with n of R 2 n being 0, or
with n of R 2 n being 1 , 2, 3 or 4 with each R 2 being F, in particular n is 4 and each R 2 is F.
28. The compound according to any one of the claims 1 to 8, wherein BE is
Figure imgf000458_0002
with n of R n being 0, 1 , 2, 3 or 4, in particular n of R n being 0, 1 , 2 or 3, with each R being selected independently from any other R from -OH, -F, -CI, - Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, - CH2OCH3, -CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or - N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, or with each R being selected independently from any other R from -OH, -F, -CI, - Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, -CH2CH3, - CH2OCH3, -CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or - N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, wherein, each carbon atom of the cyclic system which comprises no substituent R comprises F instead of H.
29. The compound according to any one of the claims 1 to 8 or 28, wherein BE is
Figure imgf000459_0001
with n of R n being 2, and with each R independently from any other R being -OH, -OCH3 or -OCF3, in particular -OCH3 or -OCF3, more particularly with one R being - OH and the other R being -OCH3 or -OCF3, in particular -OCH3, wherein more particularly OH is in ortho and OCH3 or -OCF3 in meta position with respect to the attachment position of the phenyl moiety of BE to D5, or
with n of R n being 1 , and with R being -OH, wherein in particular OH is in ortho position with respect to the attachment position of the phenyl of BE to D5 or with n of R n being 1 , and with R being -OCH3 or -OCF3, in particular or -OCH3, wherein more particularly -OCH3 or -OCF3 is in meta position with respect to the attachment position of the phenyl of BE to D5, or
with n of R n being 0, or
with n of R n being 4 and each R is F.
30. The compound according to any one of the claims 1 to 8 or 28 to 29, wherein BE is
Figure imgf000459_0002
with n of R n being 1 , 2 or 3, in particular n of R n being 1 , 2 or 3,
with one R being a substituent Q, with Q being selected from
- -(CH2)m-C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORV
(CH2)m-0-S(02)OH, -(CH2)m-0-S(02)ORa, in particular -(CH2)m-0-S(02)OH, - (CH2)m-0-S(02)ORa, with m being selected from 0, 1 or 2, in particular from 0 or 1 , with Ra being -CH3, -CH2CH3, -C6H5 , -CH2CH2CH3! -CH(CH3)2, -CH2C6H or para-methoxybenzyl
-C(=0)-0-Ra, -0-C(=0)-Ra, in particular -0-C(=0)-Ra, with Ra being a substituted or unsubstituted C Ci6 alkyl, in particular an unsubstituted C Ci4 alkyl,
-(CH2)m-[(CH2)mrO-C(=0)-(CH2)m2]prC(=0)ORd, in particular -(CH2)-[-0- C(=0)-(CH2)2]p1-C(=0)ORd with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8, -(CH2)m-[(CH2)m1-0-(CH2)m2]p1-ORd, in particular -[-0-(CH2)2]p1-ORd, with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
-(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa), in particular from -(CH2)m-0-(CH2)q-P(=0)(Rba)(Raa),
with Raa and Rba being selected, where applicable, independently from each other from -Ra or -ORa and
- with Ra being hydrogen, -OCH3, -OCH2CH3, -CH3, -CH2CH3, -C6H5 , -CH2CH2CH3, -CH(CH3)2, -CH2C6H5 or para-methoxybenzyl
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 , and
with the other R being selected independently from any other R from -OH, F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, CH2CH3, -CH2OCH3, -CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, or with the other R being selected independently from any other R from -OH, F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, -CH3, CH2CH3, -CH2OCH3, -CHCH2, -CH2OH, -S02NH2, -S02N(CH3)2, -S02NHCH3, -CH3, -CF3 or -N02, in particular from -OH, -F, -OCH3, -OCF3 or -CF3, wherein, each carbon atom of the cyclic system which comprises no substituent R comprises F instead of H.
31 . The compound according to any one of the claims 1 to 8 or 28 to 30, wherein BE is
Figure imgf000461_0001
with n of R n being 0 or 2, and with one R being Q and the other R being -OCH3 or -OCF3, more particularly Q is in ortho and OCH3 or -OCF3 is in meta position with respect to the attachment position of the phenyl moiety of BB to D5, with Q having the same meaning as defined above.
32. The compound according to claim 1 , wherein
-OH, -F, -CI, -Br, -I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2CH3, -CH3, -CF3 or -N02,
-B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m- C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, - (CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, - (CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa, -(CH2)m- NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m- NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m- P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, - (CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
- with Raa being selected independently from each other from -Ra or -ORa,
- with Rba being selected independently from each other from -Rb or -ORb, - with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl,
- with m being selected from 0, 1 or 2, in particular 0 or 1 ,
- with q being selected from 0, 1 or 2, in particular 0 or 1 ,
- with each Ra, Rb or Rc being selected independently from each other from
- hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, - CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -C6H5— CH2CeH5.
33. The compound according compound according to any one of the claims 1 to 4,
wherein X2 is -D5-BF, and wherein D5 has the same meaning as defined previously, and
BF is
a substituted or unsubstituted C3-Ci o cycloalkyl or a substituted or unsubstituted C3-Ci o halo cycloalkyl, or
a substituted or unsubstituted C3-Ci 0 heterocycle or a substituted or
unsubstituted C3-Ci o halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or a substituted or unsubstituted C5-C10 heteroaryl, or
a substituted or unsubstituted C6-Ci o aryl.
34. The compound according to any one of the claims 1 to 8, wherein X2 is -D5-BF and BF is
Figure imgf000462_0001
wherein D5 has the same meaning as defined previously, and
with T being selected from
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, - N(CH3)2, -CH3, -CH2-CH3, -CF3 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m- C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m- OC(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m- C(=0)NRb(ORa), -(CH2)m-C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, -(CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, - (CH2)m-SRa, -(CH2)m-S(=0)Ra, -(CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, - (CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, -(CH2)m-NRaRb, -(CH2)m- NRcC(=0)Ra, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m-NRcC(=0)ORa, -(CH2)m- NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m-NRcC(=S)ORa, -(CH2)m- NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or - (CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, -(CH2)m-0-C(=0)- (M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q-
Figure imgf000463_0001
(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl
with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen,
- -CN
- a substituted or unsubstituted C Ci6 alkyl, a substituted or
unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C Ci6 haloalkyl, or
- a substituted or unsubstituted C3-Cio cycloalkyl or a substituted or unsubstituted C3-Cio halo cycloalkyl, or
- a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Cio halo heterocycle, in particular a substituted or unsubstituted C4-Ci0 heterocycle or a substituted or
unsubstituted C4-Cio halo heterocycle, or
- a substituted or unsubstituted C5-Cio heteroaryl, or
- a substituted or unsubstituted C6-Cio aryl,
R 0n being 0, 1 , 2, 3 or 4, in particular n of R 0 n being 0, 1 , 2 or 3, 4, and R 0 independently from any other R 0 being selected from
-OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2, - CH3, -CH2-CH3, -CF3 or -N02,
-B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, -(CH2)m- C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m- C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, - (CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, - (CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa, -(CH2)m- NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m- NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m- P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, - (CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl
with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen, -CN
- a substituted or unsubstituted C Ci6 alkyl, a substituted or
unsubstituted C Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C Ci6 haloalkyl, in particular a substituted or unsubstituted CrC8 alkyl, a substituted or unsubstituted CrC8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted CrC8 haloalkyl, a substituted or unsubstituted C3- Ci o cycloalkyl, or a substituted or unsubstituted C3-C10 halo
cycloalkyl,
- a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl,
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle,
- a substituted or unsubstituted C5-C10 heteroaryl,
- a substituted or unsubstituted C6-Ci o aryl.
35. The compound according to any one of the claims 1 to 8 or 34, wherein X2 is -D5-BF and BF is
Figure imgf000465_0001
wherein D5 and T have the same meaning as defined previously,
with n of R 0n being 0, 1 , 2, 3 or 5, in particular n of R 0 n being 0, 1 , 2 or 3, and with each R 0 independently from any other R 0 being selected from
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NH CH3, -N(CH3)2, -CH3, -CH2-CH3, -CF3 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, - (CH2)m-C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, - (CH2)m-OC(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m- NRcC(=0)ORa, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), - (CH2)m-C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m- OC(=S)ORa, -(CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m- SRa, -(CH2)m-S(=0)Ra, -(CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, - (CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, -(CH2)m-NRaRb, -(CH2)m- NRcC(=0)Ra, -(CH2)m-NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, - (CH2)m-NRcC(=S)NRaRb, -(CH2)m-NRcC(=S)ORa, -(CH2)m- NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m-P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, -(CH2)m-0- C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q- Pi^iR^iR^. -iCHgJm-Ci^O-iCHgJq-Pi^iR^iR^. -iCHgJm- C(=0)0-(CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa, with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl, in particular Ci to C2 alkyl,
with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, - CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -C6H5— CH2CeH5.
36. The compound according to any one of the claims 5 to 8, wherein
T is
- -OH, -F, -CI, -Br, I, -CCH, -CN, -N3, -OCH3, -OCF3, -NH2, -NHCH3, - N(CH3)2, -CH3, -CH2-CH3, -CF3 or -N02,
- -B(ORa)(ORb), -(CH2)m-Ra, -(CH2)m-ORa, -(CH2)m-C(=0)Ra, -(CH2)m-
C(=0)ORa, -(CH2)m-OC(=0)Ra, -(CH2)m-OC(=0)ORa, -(CH2)m-OC(=0)NRaRb, - (CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRaRb, -(CH2)m-C(=0)NRb(ORa), -(CH2)m- C(=S)Ra, -(CH2)m-C(=S)ORa, -(CH2)m-OC(=S)Ra, -(CH2)m-OC(=S)ORa, - (CH2)m-OC(=S)NRaRb, -(CH2)m-C(=S)NRaRb, -(CH2)m-SRa, -(CH2)m-S(=0)Ra, - (CH2)m-S(02)Ra, -(CH2)m-S(02)ORa, -(CH2)m-OS(02)Ra, -(CH2)m-OS(02)ORa, - (CH2)m-NRaRb, -(CH2)m-NRcC(=0)Ra, -(CH2)m-NRcC(=0)ORa, -(CH2)m- NRcC(=0)NRaRb, -(CH2)m-NRcC(=S)Ra, -(CH2)m-NRcC(=S)NRaRb, -(CH2)m- NRcC(=S)ORa, -(CH2)m-NRcS(02)Ra, -(CH2)m-P(=0)(ORb)(ORa), -(CH2)m- P(=0)(ORb)(Ra) or -(CH2)m-S(02)NRbRa, -(CH2)m-0-C(=0)-(M)-C(=0)OH, - (CH2)m-0-C(=0)-(M)-C(=0)ORa, -(CH2)m-0-C(=0)-(M)-Ra, -(CH2)m-0-(CH2)q- P(=0)(Rba)(Raa), -(CH2)m-C(=0)0-(CH2)q-P(=0)(Rba)(Raa), -(CH2)m-C(=0)0- (CH2)q-S(02)OH or -(CH2)m-C(=0)0-(CH2)q-S(02)ORa,
with Raa being selected independently from each other being -Ra or -ORa, with Rba being selected independently from each other being -Rb or -ORb, with M being a substituted or unsubstituted CrC8 alkyl, in particular an unsubstituted CrC8 alkyl with m being selected from 0, 1 or 2, in particular 0 or 1 ,
with q being selected from 0, 1 or 2, in particular 0 or 1 ,
with each Ra, Rb or Rc being selected, where applicable, independently from each other from
- hydrogen,
- -CN
- a substituted or unsubstituted C Ci6 alkyl, a substituted or unsubstituted Cr Ci6 alkoxy, a substituted or unsubstituted C Ci6 carboxy, a substituted or unsubstituted C2-Ci6 alkenyl, a substituted or unsubstituted C2-Ci6 alkynyl, or a C1-C16 haloalkyl, or
- a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or
unsubstituted C3-C10 halo cycloalkyl, or
- a substituted or unsubstituted C3-C10 heterocycle or a substituted or
unsubstituted C3-C10 halo heterocycle, in particular a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle, or
- a substituted or unsubstituted C5-C10 heteroaryl, or
- a substituted or unsubstituted C6-Cio aryl.
37. The compound according to any one of the claims 5 to 8 or 36, wherein
T is
d. -B(OH)2, -CN, -NH2, -OH, -OCH3, -C(=0)NH2, -C(=0)NH(CN), -C(=0)NH(OH), -CH2OH, -CH2C(=0)OH, -CH2C(=0)NH(OH), -CH2C(=0)NH2, - CH2NHS(02)OH, -CH2NHC(=0)OH, -P(=0)(OH)(OH), -CH2P(=0)(OH)(OH), - CH2S(02)OH, -S(02)OH or -S(02)NH2 or
e. -Ra, -CH2Ra, -SRa, -CH2SRa, -S(=0)Ra, -C(=0)NHRa, -CH2C(=0)NHRa, - CH2NHS(02)Ra, -C(=0)ORa, -ORa or -NHRa,-C(=0)ORa -CH2C(=0)NH(ORa), -C(=0)NHORa, -C(=0)NHRa, -CH2NHS(02)Ra, -CH2ORa, -CH2NHC(=0)Ra, - P(=0)(OH)(ORa), -CH2P(=0)(OH)(ORa), -P(=0)(OH)(Ra), - CH2P(=0)(OH)(Ra), -CH2S(02)ORa, -S(02)ORa, -S(02)Ra or -CH2S(02)Ra, or - S(02)NHRa,
with Ra being selected from
a substituted or unsubstituted C1-C16 alkyl, a substituted or
unsubstituted C1-C16 alkoxy, a substituted or unsubstituted C2-Ci4 alkenyl, a substituted or unsubstituted C2-C14 alkynyl, or a Ci-Ci4 haloalkyi, in particular a substituted or unsubstituted C1-C5 alkyl, more particularly Ra is -CH3 -CF3, -CH2CH3, -CH2CF3, -CN, ,-CH2CH2CH3, - CH(CH3)2, -CH2C6H5 or para-methoxybenzy
-[(CH2)m1-0-(CH2)m2]p1-ORd, -[(CH2)m1-C(=0)0-(CH2)m2]p1-ORd in particular - [-0-(CH2)2]p1-ORd, -[-C(=0)0-(CH2)2]p1-ORd, with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8, f. -Ra, -CH2Ra, -SRa, -CH2SRa, -S(=0)Ra, -C(=0)NHRa, -CH2C(=0)NHRa, - CH2NHS(02)Ra, -C(=0)ORa, -ORa or -NHRa,
with Ra being
a substituted or unsubstituted C3-Ci0 heterocycle or a substituted or unsubstituted C3-Cio halo heterocycle, in particular a substituted or unsubstituted C4-Cio heterocycle or a substituted or unsubstituted C4- C10 halo heterocycle, or
a substituted or unsubstituted C5-C10 heteroaryl, or a substituted or unsubstituted C6-Cio aryl.
38. The compound according to any one of the claims 5 to 8 or 36 to 37, wherein
T is -C(=0)ORa
with Ra being
a substituted or unsubstituted C1-C16 alkyl, in particular an unsubstituted C1-C16 alkyl,
-[(CH2)m1-0-(CH2)m2]p1-ORd, -[(CH2)m1-C(=0)0-(CH2)m2]p1-ORd, in particular -[-0-(CH2)2]p1-ORd, -[-C(=0)0-(CH2)2]p1 , , with
- Rd being -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C6H5 ml and m2 being selected independently from each other form 1 , 2 or 3, in particular ml and m2 are 2, and
- p1 being selected from 1 to 20, in particular from 1 to 8,
Figure imgf000469_0001
468 with each R8 being -H, or, where applicable, with each R8 being selected independently from each other from -H, -CH3, -CH2CH3, -OCH3, -OCF3, - CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with each R8 being selected independently from each other from H or CH3, more particularly R8 being H, and
with V being, where applicable, S, NH or O, in particular V being O.
40. The compound according to any one of the previous claims, wherein each D to D5 is selected independently from each other from
Figure imgf000470_0001
with each R8 being -H, or, where applicable, with each R8 being selected independently from each other from -H, -CH3, -CH2CH3, -OCH3, -OCF3, - CH2CF3, -CHFCF3, -CF2CF3, -CHF2, -CH2F or -CF3, in particular with each R8 being selected independently from each other from H or CH3, more particularly R8 being H, and
with V being, where applicable, S, NH or O, in particular V being O.
41 . The compound according to any one of the previous claims, the compound
characterized by the general formula 1 comprises at least one deuterium instead of a hydrogen.
42. The compound according to any one of the previous claims, wherein the compound is one of the compounds 1 to 50, 70 to 76 and 78 to 1 17 as depicted in the experimental section or the description.
43. A compound according to any one of claims 1 to 42 for use in a method of treatment of diseases, in particular for use in a method of treatment of bacterial infections.
44. The compound for use in a method according to claim 43, wherein the bacterial
infection is an infection by a gram-negative bacterium, particularly an infection by one of the genus Acinetobacter, Bordatella, Borellia, Brucella, Camphylobacter,
Chlamydia, Chlamydophila, Enterobacter, Escherichia, Francisella, Haemophilus, Helicobacter, Klebisella, Legionella, Leptospira, Morganella Moraxella, Neisseria, Proteus ,Pseudomonas, Rickettsia, Shigella, Salmonella, Stenotrophomonas, Treponema or Yersinia, further in particular by one of the genus Escherichia,
Enterobacter, Salmonella, Klebisella, Pseudomonas, Haemophilus, Shigella, Proteus or Morganella.
45. The compound for use in a method according to claim 44, wherein the bacterial
infection is an infection
- by a gram-positive bacterium, particularly an infection by one of the genus Bacillus, Chlostridium, Corynebacterium, Enterococcus, Listeria, Micrococcus, Staphylococcus or Streptococcus, further in particular by one of the genus of Staphylococcus, Streptococcus, Bacillus or Micrococcus or
- by a bacterium of the family of Mycobacteriaceae, in particular of the genus Mycobacterium, further in particular an infection by one of Mycobacterium tuberculosis, Mycobacterium leprae, Mycobacterium ulcerans or
Mycobacterium avium, or
- by a bacterium of the family of Mycoplasmataceae, in particular of the genus Mycoplasma, further in particular an infection by Mycoplasma pneumonia.
46. The compound for use in a method according to claim 44 or 45, wherein the bacterial infection is an infection by one of Staphylococcus aureus, Staphylococcus
epidermidis, Staphylococcus aureus Streptococcus pyogenes, Bacillus subtilis, Bacillus megaterium, Micrococcus luteus, Escherichia coli, Enterobacter aerogenes, Enterobacter cloacae, Enterobacter sakazakii, Cronobacter sakazakii, Salmonella typhi, Salmonella enteritidis, Klebisella pneumonia, Pseudomonas aeruginosa, Haemophilus influenza, Shigella sonnei, Proteus vulgaris, Proteus mirabilis or Morganella morganii.
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