Cystobactamid derivatives

Abstract

The present invention relates to novel cystobactamid derivatives of formula (I) and the use thereof for the treatment prophylaxis of bacterial infections.

Description

[0001] CYSTOBACTAMID DERIVATIVES

[0002] The present invention relates to novel cystobactamid derivatives and the use thereof for the treatment or prophylaxis of bacterial infections.

[0003] These novel cystobactamid derivatives show enhanced physicochemical and antibacterial activity when compared to previously described derivatives of cystobactamids. The present invention describes new synthetic methods and novel cystobactamid analogs with high biological activity against Gram-negative bacteria, especially against A. baumannii. Compared to previously described cystobactamids, superior activity and solubility was obtained.

[0004] Cystobactamids are natural products that have been isolated from myxobacterium Cystobacter velatus (MCy8071; internal name: Cystobacter ferrugineus). Cystobactamids exhibit a good antibiotic activity, especially against selected Gram-negative bacteria, such as E. coli, P. aeruginosa and A. baumannii, as well as a broad-spectrum activity against Gram-positive bacteria. Cystobactamids and derivatives thereof have e.g., been described in WO 2015 / 003816, WO2016 / 082934, WO 2019 / 038405, Angew. Chem. Int. Ed. 2014, 53, 14605- 14609 (doi:10.1002 / anie. 201409964), and in Angew. Chem. Int. Ed. 2017, 56, 12760-12764 (doi:10.1002 / anie.201705913), Synlett 2015, 26(09), 1175-1178 (doi: 10.1055 / s-0034- 1380509), Chem. Sci., 2020, 11, 1316 (doi: 10.1039 / C9SC04769G), Org. Lett. 2019, 21, 8369- 8372, and Chem. Eur. J. 2020, 26, 4289-4296.

[0005] Albicidin is a natural product produced by Xanthomonas albilineans possessing antibacterial activity. Albicidin and derivatives thereof are e.g., described in WO 2014 / 125075 and WO 2019 / 185806.

[0006] Although albicidin and cystobactamids share the same mechanism of action and a similar scaffold, studies suggested that cystobactamids are less prone to the resistance mechanisms against albicidin. Cystobactamids are less influenced by altered expressions of Tsx and Alb A. Additionally, the resistance protein AlbD did not modify the natural occurring Cys 919-2.

[0007] The novel synthetic derivatives of cystobactamid of the present invention exhibit higher activity, a broader spectrum, and better physicochemical properties than Albicidin and its analogues as well as former cystobactamid derivatives. The novel cystobactamid derivatives of the present invention are highly active with MICs in the low pg / ml range against Gram-positive and Gram-negative bacteria. In comparison to former cystobactamids, the activity against A. baumannii is significantly increased leading to highly potent compounds against multi-resistant A. baumannii strains.

[0008] Further, in some of the novel cystobactamid derivatives of the present invention the aqueous solubility is increased from < 1 pg / ml (compound 22 disclosed in Chem. Sci., 2020, 11, 1316) to up to 900 pg / ml at pH 7.4. Since solubility is an important pharmaceutical property of a drug, its increase constitutes a significant and unexpected advancement.

[0009] The present invention provides compounds of formula (I): wherein

[0010] Ar is selected from the following groups: R2is a Ci-6 alkyl group or a Ci-6 haloalkyl group;

[0011] L1is is a group of formula -CO-NH-; -CS-NH-; -C(=NH)-NH-; or -NH-CO-;

[0012] A is is selected from the following groups:

[0013] R3is hydrogen, -CN, fluorine or chlorine;

[0014] L2is selected from the following groups:

[0015] R4is selected from the following groups:

[0016] R is a group of formula -CH=CH2 or -C=CH;

[0017] W is CH, N, CF or COCF3; X is CH, N, CF or COCF3;

[0018] Y is CH, N, CF or COCF3;

[0019] Z is CH, N, CF or COCF3;

[0020] L3is a group of formula -CO-NH-; -CS-NH-; -C(=NH)-NH-; or -NH-CO-;

[0021] L4is a group of formula -CO-NH-; -CS-NH-; -C(=NH)-NH-; or -NH-CO-; and

[0022] R1is a group of formula -COOH or -SO2NH2; or a salt thereof.

[0023] The following compound (CN-DM-861) is excluded from the scope of the present invention:

[0024] Moreover, the following compound is excluded from the scope of the present invention:

[0025]

[0026] Further preferably, all compounds disclosed in WO 2019 / 185806 Al are excluded from the scope of the present invention.

[0027] Preferably, Ar is a group of the following formula: wherein L1is is a group of formula -CO-NH-; -CS-NH-; -C(=NH)-NH-; or -NH-CO-.

[0028] Further preferably, L1is is a group of formula -CO-NH-.

[0029] Moreover preferably, Ar is selected from the following groups:

[0030] These groups Ar are modifications having a strong influence on in vitro and in vivo activity (as has e.g. been shown for example SSA295).

[0031] Further preferably, R2is a C alkyl group or a C haloalkyl group. Especially preferably, R2is a group of formula -CH3 or -CH2CH3.

[0032] Further preferably, A is a group of the following formula:

[0033] Moreover preferably, R3is hydrogen.

[0034] Further preferably, R3is fluorine, chlorine or -CN.

[0035] Further preferably, A is selected from the following groups:

[0036] Moreover preferably, L2is a group of the following formula:

[0037] Further preferably, L2is a group of the following formula: Moreover preferably, R4is selected from the following groups:

[0038] Further preferably, R4is a group of the following formula:

[0039] Moreover preferably, L2is a group of the following formula:

[0040] Further preferably, L2is a group of the following formula:

[0041] Further preferably, L2is a group of the following formula: Preferably, R5is a group of formula -CH=CH2.

[0042] Moreover preferably, X is CH, CF or N.

[0043] Further preferably, Y is CH.

[0044] Moreover preferably, Z is CH.

[0045] Further preferably, W is CH.

[0046] Moreover preferably, L3is a group of formula -CO-NH- or -NH-CO-.

[0047] Especially preferably, L3is a group of formula -NH-CO-, and X is CH or CF. This combination significantly increases in vitro activity, as has e.g. been shown for example DK971. This modification also leads to stability against the resistance enzyme AlbD.

[0048] Further preferably, L4is a group of formula -CO-NH-.

[0049] Moreover preferably, R1is a group of formula -COOH.

[0050] Further preferably, R1is a group of formula -SO2NH2. This group leads to better plasma protein binding, which is reflected in higher in vivo activity (as has e.g. been shown for example DK1066).

[0051] Further preferably, L2is a group of the following formula: Moreover preferably, A is the following group:

[0052] Especially preferably, L2is a group of the following formula: and A is the following group:

[0053] This combination is characterized by good in vitro and in vivo activity, with significantly improved solubility. This has e.g. been shown for example Hdol80.

[0054] It is further preferred to combine the preferred embodiments of the present invention in any desired manner (e.g., any embodiment for Ar may be combined with any embodiment of L2).

[0055] The most preferred compounds of the present invention are the compounds disclosed in the examples or a salt thereof.

[0056] Further preferred are the following compounds or a salt thereof:

[0057] 4-(4-{4-[(2S)-2-{[4-(4-Cyanobenzamido)phenyl]formamido}pent-4-ynamido]benzamido}-2- hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid; 4-(4- { 4- [(25) -2 - { [4-(4-Cyanobenzamido)-3 -fluorophenyl] formamido } pent-4- ynamido]benzamido } -2 -hydroxy-3 -(propan-2-yloxy)benzamido)benzoic acid;

[0058] 4-(4-{4-[(25)-2-{[3-Chloro-4-(4-cyanobenzamido)phenyl]formamido}pent-4- ynamido]benzamido}-2-hydroxy-3 -(propan-2 -yloxy)benzamido)benzoic acid;

[0059] 4-(4-{4-[(25)-2-{[3-(4-Cyanobenzamido)bicyclo[l .1. l]pentan-l-yl]formamido}pent-4- ynamido]benzamido } -2-hydroxy-3 -(propan-2 -yloxy)benzamido)benzoic acid;

[0060] 4-(4-{4-[(25)-2-{[4-(4-Cyanobenzenethioamido)phenyl]formamido}pent-4-ynamido] benzamido } -2 -hydroxy-3 -(propan-2-yloxy)benzamido)benzoic acid;

[0061] 4-(4- {4-[(25)-2- { [4-(4-Cyanobenzeneimidamido)phenyl]formamido }pent-4-ynamido] benzamido } -2-hydroxy-3 -(propan-2-yloxy)benzamido)benzoic acid;

[0062] 4-(4- { 4- [(25)-2-( { 4- [(4-Cyanophenyl)carbamoyl]phenyl } formamido)pent-4-ynamido] benzamido } -2 -hydroxy-3 -(propan-2-yloxy)benzamido)benzoic acid;

[0063] 4-(4- { 4- [(25)-2-( { 3 -Chloro-4- [(4-cy anopheny l)carbamoy l]pheny 1 } formamido)pent-4- ynamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid;

[0064] 4-(4-{4-[(25)-2-({4-[(4-Cyanophenyl)carbamoyl]bicyclo[2.2.2]octan-l-yl}formamido) pent- 4-ynamido]benzamido } -2-hydroxy-3 -(propan-2-y loxy)benzamido)benzoic acid;

[0065] 4-(4-{4-[(25)-2-({8-[(4-Cyanophenyl)carbamoyl]cuban-l-yl}formamido)pent-4-ynamido] benzamido } -2-hydroxy-3 -(propan-2-yloxy)benzamido)benzoic acid;

[0066] 4-(4- {4- [2-( { 3 - [(4-Cy anopheny l)carbamoyl]bicyclo[ 1.1.1 ]pentan- 1 -yl } formamido)-3 -methyl-

[0067] 3-nitrobutanamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido) benzoic acid;

[0068] 4-(4- {4- [(25)-2- { [4-(5-Cyano- 1 -methyl- 1 H- 1 ,3 -benzodiazol-2-yl)phenyl] formamido }pent-4- ynamido]benzamido} -2 -hydroxy-3 -(propan-2 -yloxy)benzamido)benzoic acid;

[0069] 4-(4-{4-[(25)-2-{[4-(5-Cyano-l-ethyl-l / / -l,3-benzodiazol-2-yl)phenyl]formamido}pent-4- ynamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid;

[0070] 4 -(4 - { 4- [( 1 S, 2R) - 1 - [4-(5 -Cyano- 1 -methyl- 1 H- 1 ,3 -benzodiazol-2-yl)benzamido] -2-etheny 1- cyclopropaneamido]benzamido } -2-hydroxy-3 -(propan-2-yloxy)benzamido)benzoic acid;

[0071] 4- {4- [4-(2- { [4-(5-Cy ano- 1 -methyl- 1 H- 1 ,3 -benzodiazol-2-yl)pheny l]formamido } -3 -methyl-3- nitrobutanamido)benzamido]-2-hydroxy-3-(propan-2-yloxy)benzamido}benzoic acid;

[0072] 4-(4- {4- [(1 S2R)~ 1 - [3 -(5-Cyano- 1 -methyl- 1 H- 1 ,3 -benzodiazol-2-yl)bicyclo [1.1.1 ]pentane- 1 - amido]-2-ethenylcyclopropaneamido]benzamido}-2-hydroxy-3-(propan-2-yloxy) benzamido)benzoic acid; 4-(4- { 4- [(25)-2- { [4- (5 -Cyano- 1 -methyl- 1 H- 1 ,3 -benzodiazol-2-y l)bicyclo [2.2.2] octan- 1 -yl] formamido}pent-4-ynamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido) benzoic acid;

[0073] 4-(4-{4-[(l1S',2 ?)-l-[4-(5-Cyano-l-methyl-1 -l,3-benzodiazol-2-yl)bicyclo[2.2.2]octane-l- amido]-2-ethenylcyclopropaneamido]benzamido}-2-hydroxy-3-(propan-2-yloxy) benzamido)benzoic acid;

[0074] 4-(4- {4- [(25)-2- { [4-(6-Cyano- 1 -methyl- 1 H- 1 ,3 -benzodiazol-2-yl)phenyl]formamido }pent-4- ynamido]benzamido } -2 -hydroxy-3 -(propan-2 -yloxy)benzamido)benzoic acid;

[0075] 4-(4- {4-[(2<S)-2-{ [4-(6-Cyano- 1 -ethyl- 1 H- 1 ,3-benzodiazol-2-yl)phenyl]formamido}pent-4- ynamido]benzamido } -2 -hydroxy-3 -(propan-2-yloxy)benzamido)benzoic acid ;

[0076] 4-(4- {4- [( 1 S,2R)- 1 -[3-(6-Cyano- 1 -methyl- 1 H- 1 ,3 -benzodiazol-2-yl)bicyclo [1.1.1 ]pentane- 1 - amido]-2-ethenylcyclopropaneamido]benzamido}-2-hydroxy-3-(propan-2-yloxy) benzamido)benzoic acid;

[0077] 4-(4- {4- [( 1 S,2R~)~ 1 -[3-(6-Cyano- 1 -ethyl- 177-1 ,3-benzodiazol-2-yl)bicyclo [1.1.1 ]pentane- 1 - amido]-2-ethenylcyclopropaneamido]benzamido}-2-hydroxy-3-(propan-2-yloxy) benzamido)benzoic acid;

[0078] 4-{4-[4-(2-{[4-(4-Cyanobenzamido)phenyl]formamido}-3-methyl-3-nitrobutanamido) benzamido]-2-hydroxy-3-(propan-2-yloxy)benzamido}benzoic acid;

[0079] 4-(4-{4-[(lS',27?)-l-[4-(4-Cyanobenzamido)benzamido]-2-ethenylcyclopropaneamido] benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid;

[0080] 4-(4- {4-[(17?,2S)- 1 -[4-(4-Cyanobenzamido)benzamido]-2-ethenylcyclopropaneamido] benzamido } -2-hydroxy-3 -(propan-2-yloxy)benzamido)benzoic acid;

[0081] 4-(4-{4-[(15',27?)-l-[3-(4-Cyanobenzamido)bicyclo[l .1. l]pentane-l -amido] -2-ethenyl- cyclopropaneamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid; 4-(4- {4- [( 1 S.2R)- 1 - { 3 -[(4-Cyanophenyl)carbamoyl]bicyclo [1.1.1 ]pentane- 1 -amido } -2- ethenyl-cyclopropaneamido]benzamido } -2 -hydroxy-3 -(propan-2-yloxy)benzamido)benzoic acid;

[0082] 4-(4- { 4- [( 1 S.2R)- 1 - [3 -(4-Cy anobenzamido)bicy clo [1.1.1 ]pentane- 1 -amido] -2-ethyny 1- cyclopropaneamido]benzamido } -2-hydroxy-3 -(propan-2-yloxy)benzamido)benzoic acid; 4-[4-({4-[(2 )-2-{[4-(4-Cyanobenzamido)phenyl]foimamido]pent-4-ynamido]phenyl] carbamoyl)-2-hydroxy-3-(propan-2-yloxy)benzamido]benzoic acid; 4-[4-({4-[(2S)-2-{[4-(4-Cyanobenzamido)phenyl]formamido}pent-4-ynamido]-2- fluorophenyl}carbamoyl)-2-hydroxy-3-(propan-2-yloxy)benzamido]benzoic acid;

[0083] 4-[4-({5-[(2S)-2-{[4-(4-Cyanobenzamido)phenyl]formamido}pent-4-ynamido]pyridin-2- yl}carbamoyl)-2-hydroxy-3-(propan-2-yloxy)benzamido]benzoic acid;

[0084] 4-(4- { 5 - [(2S)-2-( { 3 - [(4-Cy anophenyl)carbanioyl] bicyclo [1.1.1 ]pentan- 1 -y 1 } formamido)-3 - cyclopropylpropanamido]pyridine-2-amido}-2-hydroxy-3-(propan-2-yloxy)benzamido) benzoic acid;

[0085] 4-(4- { 5 - [(2S)-2- { [4-(5 -Cyano- 1 -methyl- 1 H- 1 ,3 -benzodiazol-2-y l)pheny 1] formamido } pent-4- ynamido]pyridine-2-amido } -2-hydroxy-3 -(propan-2 -yloxy)benzamido)benzoic acid;

[0086] 4-(4- { 5- [( IS, 27?)- 1 - [4-(5-Cyano- 1 -methyl- 1 H- 1 ,3 -benzodiazol-2-yl)benzamido]-2- ethenylcyclopropaneamido]pyridine-2-amido}-2-hydroxy-3-(propan-2-yloxy) benzamido)benzoic acid;

[0087] 4-(4- { 5 - [( 1 S,27?)- 1 - [3 -(5-Cyano- 1 -methyl- 1 7- 1 ,3 -benzodiazol-2-yl)bicy clo [1.1.1 ]pentane- 1 - amido]-2-ethenylcyclopropaneamido]pyridine-2-amido}-2-hydroxy-3-(propan-2-yloxy) benzamido)benzoic acid;

[0088] 4-(4-{5-[(2S)-2-{[3-Chloro-4-(5-cyano-l-methyl-177-l,3-benzodiazol-2-yl)phenyl] formamido}pent-4-ynamido]pyridine-2-amido}-2-hydroxy-3-(propan-2-yloxy) benzamido)benzoic acid;

[0089] 4-(4-{4-[(2S,37?)-2-{[4-(4-Cyanobenzamido)phenyl]formamido}-3-hydroxybutanamido] benzamide } -2-hydroxy-3 -(propan-2 -yloxy)benzamido)benzoic acid;

[0090] 4-(4- {4- [(2S,37?)-2- { [3 -Cyano-4-(4-cyanobenzamido)phenyl]formamido } -3 - hydroxybutanamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid;

[0091] 4-(4- { 4- [(2S,37?)-2- { [4-(6-Cyano- 1 -methyl- 177-1,3 -benzodiazol-2-yl)phenyl] formamido } -3 - hydroxybutanamido]benzamido } -2-hydroxy-3 -(propan-2-yloxy)benzamido)benzoic acid;

[0092] 4-(4-{4-[(2S,35)-2-{[4-(4-Cyanobenzamido)phenyl]formamido}-3-hydroxybutanamido] benzamido } -2-hydroxy-3 -(propan-2-yloxy)benzamido)benzoic acid;

[0093] 4-[4-({4-[(2 ,3^)-2-{[4-(6-Cyano-l-methyl-17 -l,3-benzodiazol-2-yl)phenyl]formamido}-3- hydroxybutanamido]-2-fluorophenyl}carbamoyl)-2-hydroxy-3-(propan-2-yloxy) benzamido]benzoic acid;

[0094] 4-[4-({4-[(2S)-3-Carbamoyl-2-{[4-(6-cyano-l-methyl-1 7-l,3-benzodiazol-2-yl)phenyl] formamido } propanamido] -2-fluoropheny 1 } carbamoy l)-2-hy droxy-3 -(propan-2-y loxy) benzamido]benzoic acid; 4- [4-( {4- [( 1 S,2R)~ 1 -[3 -(5 -Cyano- 1 -methyl- 1H- 1 ,3 -benzodiazol-2-yl)bicyclo [1.1.1 ]pentane- 1 - amido]-2-ethenylcyclopropaneamido]phenyl}carbamoyl)-2-hydroxy-3-(propan-2- yloxy)benzamido]benzoic acid;

[0095] 4- [4-( { 4-[( 1 S,2R)- 1 -[3 -(6-Cyano- 1 -methyl- 1 H- 1 ,3 -benzodiazol-2-yl)bicyclo [1.1.1 ]pentane- 1 - amido]-2-ethenylcyclopropaneamido]phenyl}carbamoyl)-2-hydroxy-3-(propan-2- yloxy)benzamido]benzoic acid; and

[0096] 4- { 4- [(251, 37?)-2- { [4-(6-Cyano- 1 -methyl- 1 H- 1 ,3 -benzodiazol-2-y l)pheny 1] formamido } -3 - hydroxybutanamido]benzamido } -2-hydroxy-3 -(propan-2-y Ioxy)-7V-(4-sulfamoylphenyl) benzamide.

[0097] The expression Ci-6 alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 6 carbon atoms, for example a methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, n-hexyl, or 2,2-dimethylbutyl group. The expression CM alkyl refers to a saturated, straight-chain or branched hydrocarbon group that contains from 1 to 4 carbon atoms. Examples are a methyl (Me), ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl group.

[0098] The expression Ci-6 haloalky 1 refers to a Ci-6 alkyl group in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl) such as, for example, a 2,2,2- trichloroethyl or a trifluoromethyl group. The expression C haloalkyl refers to a CM alkyl group in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl).

[0099] Owing to their substitution, the compounds of the present invention may contain one or more centers of chirality. The present invention therefore includes both all pure enantiomers and all pure diastereoisomers and also mixtures thereof in any mixing ratio. The present invention moreover also includes all cis / trans-isomers of the compounds of the present invention and also mixtures thereof. The present invention moreover includes all tautomeric forms of the compounds of the present invention. The present invention further provides pharmaceutical compositions comprising one or more compounds described herein or a salt thereof, optionally in combination with one or more carrier substances and / or one or more adjuvants.

[0100] The present invention furthermore provides compounds or pharmaceutical compositions as described herein for use in the treatment and / or prophylaxis of bacterial infections, especially caused by E. coli, P. aeruginosa, A. baumannii, K. pneumoniae, other Gram-negative bacteria, and Gram-positive bacteria.

[0101] The present invention furthermore provides compounds or pharmaceutical compositions as described herein for use as a medicament, in particular for the treatment and / or prophylaxis of bacterial infections, especially caused by E. coli, P. aeruginosa, A. baumannii, K. pneumoniae, other Gram-negative bacteria, and Gram-positive bacteria.

[0102] Especially preferably, the present invention provides compounds or pharmaceutical compositions as described herein for use in the treatment and / or prophylaxis of bacterial infections caused by A. baumannii.

[0103] The present invention moreover provides compounds as described herein or pharmaceutical compositions as described herein for the preparation of a medicament for the treatment and / or prophylaxis of bacterial infections, especially caused by E. coli, P. aeruginosa, A. baumannii, K. pneumoniae, other Gram-negative bacteria, and Gram-positive bacteria.

[0104] Especially preferably, the present invention provides compounds as described herein or pharmaceutical compositions as described herein for the preparation of a medicament for the treatment and / or prophylaxis of bacterial infections caused by A. baumannii.

[0105] The present invention further provides a method for the treatment and / or prophylaxis of a bacterial infection in a subject (especially caused by E. coli, P. aeruginosa, A. baumannii, K. pneumoniae, other Gram-negative bacteria, and Gram-positive bacteria), which comprises administering to the subject an effective amount of a compound as described herein, or a salt thereof. The present invention moreover provides a method for the treatment and / or prophylaxis of a bacterial infection in a subject (especially caused by E. coli, P. aeruginosa, A. baumannii, K. pneumoniae, other Gram-negative bacteria, and Gram-positive bacteria), which comprises administering to the subject an effective amount of a pharmaceutical composition as described herein.

[0106] Especially preferably, the present invention provides a method for the treatment and / or prophylaxis of a bacterial infection caused by A. baumannii, which comprises administering to the subject an effective amount of a compound as described herein, or a salt thereof.

[0107] Moreover, especially preferably, the present invention provides a method for the treatment and / or prophylaxis of a bacterial infection caused by A. baumannii, which comprises administering to the subject an effective amount of a pharmaceutical composition as described herein.

[0108] Examples of salts (especially of pharmacologically acceptable salts) of sufficiently basic compounds are salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p- toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic, fumaric, maleic and salicylic acid. Further, a sufficiently acidic compound may form alkali or earth alkali metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2- hydroxyethyl)amine, lysine or arginine salts; all of which are also further examples of salts of the compounds described herein. Preferred pharmacologically acceptable salts are ammonium salts.

[0109] The compounds described herein may be solvated, especially hydrated. The hydratization / hydration may occur during the process of production or as a consequence of the hygroscopic nature of the initially water free compounds. The solvates and / or hydrates may e.g., be present in solid or liquid form. The therapeutic use of the compounds described herein, their salts (especially their pharmacologically acceptable salts), solvates and hydrates, respectively, as well as formulations and pharmaceutical compositions also lie within the scope of the present invention.

[0110] As mentioned above, therapeutically useful agents that contain compounds described herein, their solvates, salts or formulations are also comprised in the scope of the present invention. In general, the compounds described herein will be administered by using the known and acceptable modes known in the art, either alone or in combination with any other therapeutic agent.

[0111] For oral administration such therapeutically useful agents can be administered by one of the following routes: oral, e.g. as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatine capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g. as an injectable solution or suspension, rectal as suppositories, by inhalation or insufflation, e.g. as a powder formulation, as microcrystals or as a spray (e.g. liquid aerosol), transdermal, for example via an transdermal delivery system (TDS) such as a plaster containing the active ingredient or intranasal. For the production of such tablets, pills, semisolids, coated tablets, dragees and hard, e.g. gelatine, capsules the therapeutically useful product may be mixed with pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel, starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like. For the production of soft capsules one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat, and polyols. For the production of liquid solutions, emulsions or suspensions or syrups one may use as excipients e.g. water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal or synthetic oils. Especially preferred are lipids and more preferred are phospholipids (preferred of natural origin; especially preferred with a particle size between 300 to 350 nm) preferred in phosphate buffered saline (pH = 7 to 8, preferred 7.4). For suppositories one may use excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat and polyols. For aerosol formulations one may use compressed gases suitable for this purpose, as are e.g. oxygen, nitrogen and carbon dioxide. The pharmaceutically useful agents may also contain additives for conservation, stabilization, e.g. UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants.

[0112] In general, in the case of oral or parenteral administration to adult humans weighing approximately 80 kg, a daily dosage of about 1 mg to about 10,000 mg, preferably from about 5 mg to about 1 ,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion or subcutaneous injection.

[0113] EXAMPLES

[0114] General Methods

[0115] Bruker Advance-Ill HD 500 MHz and Broker Advance-Ill HD 700 MHz spectrometer were used to measure NMR spectra. The chemical shifts forJH,13C and19F spectra are reported in ppm at a temperature of 300 K.19F spectra lack an internal reference. One dimensional13C were measured with ’H decoupling. Multiplicities are specified with following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, hept. / sept. = septet, m = multiplet, br = broad signal and combinations thereof.

[0116] LCMS reaction controls were carried out by Agilent 1260 Infinity II LC connected to an Agilent 6130 (quadrupole MS) in ESI mode by a Phenomenex Gemini NX-C18 (50 mm x 2 mm, 3 pm) column. The gradient went from 0 % - 100 % acetonitrile to water with 0.1 % formic acid in both solvents over three minutes at a flow rate of 1.5 ml / min.

[0117] High-resolution mass spectra were measured at a Bruker maXis HD spectrometer in positive or negative ESI mode.

[0118] Thin-layer chromatography analytics were carried out on pre-coated silica gel 60 F254 plates (Merck). The sample was detected by UV light at 254 nm or 366 nm. Non-UV-absorbent samples were stained by a cerium-ammonium-molybdate, potassium permanganate or ninhydrin.

[0119] Chromatographic seperations by flash chromatography were carried out by Grace Reveleris X2 (Buchi) with FlashPure EcoFlex cartridges (Buchi). A Pure C-850 FlashPrep (Biichi) with FlashPure EcoFlex cartriges (Biichi) was utilized for reversed phase flash chromatography. For manual columns silica gel 60 0.04-0.063 mm; 230-400 mesh (Machery-Nagel) was used. Purifications by high performance liquid chromatography (HPLC) were performed by a Thermo Scientific Dionex UltiMate 3000 system with a Phenomenex Luna Cl 8 column (250 mm x 21.2 mm, 5 pm) column under basic (10 mM NH4HCO3) or acidic (0.1 % formic acid or acetic acid) conditions.

[0120] A Christ Alpha 1-4 LCSbasic was used for the lyophilization of the products after purification by HPLC.

[0121] General Procedure 1 - Amide coupling with acid chloride

[0122] 0.68 mmol of the desired benzoic acid (1.00 eq.), 2 ml dry CH2Q2 and one drop of dry DMF were added to a diy flask under nitrogen atmosphere. The mixture was cooled to 0 °C and 0.08 ml oxalyl chloride (0.93 mmol, 1.40 eq.) was slowly added to the stirring mixture. The reaction was controlled by TLC with a part of crude product in methanol and petroleum ether / EtOAc as solvent mixture. The solvent was evaporated under reduced pressure. The crude product was dried under high vacuum and used without further purifications.

[0123] 0.6 mmol of the desired amine (1.00 eq.) and 0.63 mmol of the desired benzoyl chloride (1.04 eq.) were added to a dry flask and further dried under high vacuum. 4.0 ml dry CH2CI2 was added under nitrogen atmosphere and the mixture was cooled down to 0 °C. 0.15 ml dry pyridine (1.86 mmol, 3.1 eq) were slowly added to the stirring mixture while maintaining 0 °C. After 15 minutes, the reaction was allowed to reach rt. The reaction was stirred overnight and controlled by TLC. After the reaction was completed, 5 ml 1 M HC1 and 5 ml water were added to the mixture. The organic phase was separated and stored. The aqueous phase was extracted with 3 x 8 ml of EtOAc and all organic phases were combined. The organic phase was washed with 3 x 10 ml of a sat. NaHCO solution. The organic phase was concentrated under reduced pressure and dried under high vacuum. General Procedure 2 - Ester hydrolysis with LiOH

[0124] 0.19 nunol of the desired ester (1.00 eq.) was dissolved in 0.9 ml water and 0.6 ml THF. 0.76 mmol lithium hydroxide hydrate (4.00 eq.) was added to the mixture. The reaction was controlled by TLC. After completion, the mixture was acidified with 1 M HC1. The solid was filtered off and washed with 1 M HC1. The solid residue was added to a flask and the remaining solvent was evaporated under reduced pressure.

[0125] General Procedure 3 - Allyl deprotection with palladium and phenylsilane

[0126] 0.16 mmol of the desired allyl ester (1.00 eq), 0.05 mmol phenylsilane (3.00 eq) and 4 ml dry THF were added to a dry flask under nitrogen atmosphere. 0.02 mmol tetrakis(triphenylphosphine)palladium(0) (0.10 eq.) was added and the mixture was stirred overnight at rt. The reaction was controlled by TLC. After the starting material vanished completely, the solvent was removed under reduced pressure. The residue was dissolved in 4 ml 0.1 M NaOH and washed with 2 x 4 ml CH2CI2. The aqueous phase was acidified to pH 1 with 6 M HC1 and the precipitate was filtered off. The precipitate was washed with 1 M HC1 and dried under high vacuum.

[0127] General Procedure 4 - Deprotection of methyl esters via trimethyl tin hydroxide in DCE 1.11 mmol ofthe desired ester (1.00 eq.) was dissolved in 2.5 ml 1,2-dichloroethane. 3.33 mmol trimethyltin hydroxide (3.00 eq) was added and the mixture was heated up to 80 °C in a sealed pressure stable vial. After completion, the solvent was removed under reduced pressure. The crude solid was washed with 2 M HC1 and dried under reduced pressure.

[0128] General Procedure 5 - Amide coupling with T3P

[0129] 0.18 mmol of amine (1.00 eq.) and 0.27 mmol of the desired acid (1.50 eq.) were added to a dry flask and further dried under high vacuum. 0.61 mmol dry pyridine (3.40 eq.) and 0.4 ml dry EtOAc were added under nitrogen atmosphere. The reaction mixture was cooled down to 0 °C. 0.25 ml T3P solution (50 wt % in EtOAc, 0.42 mmol, 2.30 eq.) was added very slowly while keeping the temperature below 0 °C. The reaction was stirred at 0 °C overnight and controlled by LCMS. After completion, the reaction was quenched with 4 ml 1 M HC1 and 12 ml brine and extracted with 3 x 6 ml EtOAc. The combined organic phases were washed with a sat. NaHCOs solution and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography with petroleum ether and EtOAc or used without further purification.

[0130] General Procedure 6 - Fmoc deprotection

[0131] 0.09 mmol (1.00 eq.) of the crude carbamate was dissolved in 0.8 ml ACN and 0.3 ml diethylamine (2.9 mmol, 31.5 eq.) at 0 °C and stirred for 1 hour. The reaction was controlled by LCMS. The solvent was evaporated under reduced pressure and coevaporated with ACN 3 times. Optionally, the crude product was purified by RP flash or RP HPLC with ACN and water mixed with 0.1 % HCOOH.

[0132] General Procedure 7 - Amide coupling with HATU

[0133] 82.6 pmol of the desired carboxylic acid (1.20 eq.) and 78.9 pmol HATU (1.20 eq.) were added to a separate flask and dried under high vacuum. 0.5 ml dry DMF and 38 pl DIPEA (3.00 eq.) were added under nitrogen atmosphere and the reaction was stirred for 30 minutes. The solution was added to the amine or amine hydrochloride and stirred at 0 °C. The reaction was controlled by LCMS. After completion, the reaction was quenched with 8 ml of 0.1 M HC1 and 4 ml brine. The inorganic layer was extracted with 3 x 6 ml of EtOAc. The organic phases were combined and washed with 2 x 5 ml brine. The solvent was removed under reduced pressure. The crude product was used without further purification.

[0134] General Procedure 8 - Amide coupling with HATU

[0135] 65.5 pmol of the desired amine (hydrochloride) (1.00 eq.), 79.0 pmol HATU (1.20 eq.) and 79.0 pmol of the desired carboxylic acid (1.20 eq.) were added to a dry flask and further dried under high vacuum. 0.4 ml dry DMF and 35 pl DIPEA (3.1 eq) were added under nitrogen atmosphere at 0 °C. The solution was stirred at 0 °C and controlled by LCMS. After completion, the reaction was quenched with 6 ml of 0.1 M HO and 10 ml brine. The inorganic layer was extracted with 3 x 4 ml of EtOAc. The organic phases were combined and washed with 2 x 4 ml brine. The crude product was used without further purification.

[0136] General Procedure 9 - Allyl deprotection with palladium and phenylsilane

[0137] 65.5 pmol of the desired allyl protected alcohol and 198 pmol phenylsilane (3.00 eq) were added to a dry flask under nitrogen atmosphere. 1.2 ml dry THF and 6.5 pmol tetrakis(triphenylphosphine)pa!ladium(0) (0.10 eq.) were added and the mixture was stirred for 3 hours at rt. The reaction was controlled by LCMS. After completion, the solvent was removed under reduced pressure. 3 ml 0.1 M HC1 and 10 ml brine were added to the residue and extracted with 3 x 4 ml EtOAc. The combined organic phases purified by flash chromatography with petroleum ether and EtOAc mixed with 2 % acetic acid.

[0138] General Procedure 10 - Allyl deprotection with palladium and aniline

[0139] 65.5 pmol of the desired allyl protected alcohol and 198 pmol aniline (3.00 eq) were added to a dry flask under nitrogen atmosphere. 1.2 ml dry THF and 6.5 pmol tetrakis(triphenylphosphine)palladium(0) (0.10 eq.) were added and the mixture was stirred for 3 hours at rt. The reaction was controlled by LCMS. After completion, the solvent was removed under reduced pressure. 3 ml 0.1 M HC1 and 10 ml brine were added to the residue and extracted with 3 x 4 ml EtOAc. The combined organic phases were purified by flash chromatography with petroleum ether and EtOAc mixed with 2 % acetic acid or with CH2CI2 and methanol.

[0140] General Procedure 11 - ter / -Butyl ester deprotection with TFA

[0141] 65.5 pmol of the desired / ert-butyl protected acid (1.00 eq.) was added to a dry flask and further dried under high vacuum. 0.5 ml dry CH2CI2 and, if necessary, 14 pl anisol (2 eq.) were added under nitrogen atmosphere and the solution was cooled down to 0 °C. 0.24 ml of trifluoracetic acid (3.1 mmol, 54 eq.) was added under nitrogen atmosphere. The solution was stirred for 3 hours at 0 °C and controlled by LCMS. After completion, the solvent was removed under reduced pressure. The residue was coevaporated with CH2CI2 twice. The crude product was purified by RP-HPLC.

[0142] General Procedure 12 - tert-Butyl ester deprotection with TFA

[0143] 65.5 pmol of the desired fert-butyl protected acid (1.00 eq.) was added to a dry flask and further dried under high vacuum. 0.5 ml dry CH2CI2 was added under nitrogen atmosphere and the solution was cooled down to 0 °C. 0.24 ml of trifluoracetic acid (3.1 mmol, 54 eq.) and 40 pl triisopropylsilane (195 pmol, 3.00 eq.) were added under nitrogen atmosphere. The solution was stirred for 3 hours at 0 °C and controlled by LCMS. After completion, the solvent was removed under reduced pressure. The residue was coevaporated with CH2CI2 twice. The crude product was purified by RP-HPLC. General Procedure 13 - Amide coupling with T3P and deprotection

[0144] 111.0 pmol of the desired carboxylic acid (1.3 eq) and 85.1 pmol of the desired aniline (1 eq) were added to a dry flask and further dried under high vacuum. 0.5 ml dry EtOAc and 21 pl dry pyridine (260.7 pmol, 3.1 eq) were added under argon atmosphere. 0.10 ml propanephosphonic acid anhydride solution (50 % in EtOAc, 168.0 pmol, 2.0 eq) was added under argon atmosphere. The reaction was stirred at rt and controlled by LCMS. After the amine vanished, 23 pl aniline (252.3 pmol, 3.0 eq) and 0.8 ml dry THF were added and the reaction was stirred for 15 minutes. 5.0 mg tetrakis(triphenylphosphine)palladium(0) (4.3 pmol, 0.05 eq) was added under argon atmosphere and the reaction was controlled by LCMS. After full deally lation, the crude product was concentrated under reduced pressure. The crude product was directly purified by flash chromatography.

[0145] General Procedure 14 - Amide coupling of the terephthal with T3P

[0146] 176 pmol 3 -(allyloxy)-4-((4-(tert-butoxycarbonyl)phenyl)carbamoyl)-2 -isopropoxybenzoic acid (1 eq) and 320 pmol of the desired amine (1.8 eq) were added to a dry flask and further dried under high vacuum. 43 pl dry pyridine (0.53 mmol, 3.0 eq) and 0.9 ml dry EtOAc were added under argon atmosphere. 0.15 ml T3P solution (50 wt % in EtOAc, 0.25 mmol, 1.4 eq) was added to the stirring mixture dropwise. The reaction was warmed up to 50 °C and stirred for 3 - 7 days. The reaction was controlled by LCMS. After completion, the reaction was quenched with 9 ml brine and 1 ml 1 M HC1. The aqueous layer was extracted with 3 x 5 ml EtOAc. The combined organic layers were concentrated under reduced pressure. The product was purified by flash chromatography.

[0147] General Procedure 15 - Reduction with terephthal

[0148] 176 pmol of the desired nitro derivative (1 eq) and 172 mg zinc dust (2.63 mmol, 15.0 eq) were suspended in 0.7 ml THF and 0.6 ml ethanol. 0.16 ml acetic acid (2.80 mmol, 15.9 eq) was added dropwise to the stirring mixture over 1 hours. The mixture was controlled by TLC and LCMS. After completion, the zinc dust was filtered off and washed with EtOAc, ethanol and THF. The solvent was concentrated under reduced pressure and the acetic acid was coevaporated with EtOAc. 10 ml sat. NaHCOa and 10 ml brine were added and the product was extracted with 3 x 8 ml EtOAc. The combined organic layers were concentrated under reduced pressure and the product was purified by flash chromatography.

[0149] General Procedure 16 - Amide coupling CDE to central AA with EEDQ

[0150] 0.09 mmol of the desired aniline (1 eq) and 0.14 mmol of the desired amino acid (1.5 eq) were added to a dry flask and were further dried under high vacuum. 0.15 ml dry CH2CI2 was added under nitrogen atmosphere and the mixture was cooled down to 0 °C. 33.0 mg EEDQ (0.13 mmol, 1.5 eq) dissolved in 0.15 ml dry CH2CI2 was added to the stirring solution. The reaction was stirred at 0 °C for 30 minutes and slowly warmed up to rt, afterwards. The reaction was controlled by LCMS. After completion, the reaction was quenched with 2 ml 1 M HC1 and 6 ml brine and extracted with 3 x 3 ml CH2CI2. The combined organic phases were washed with brine and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography

[0151] AB-Fragments

[0152] Fragment Al-1

[0153] Step a: Methyl 3-bromo-4-(4-cyanobenzamido)benzoate

[0154] The aniline (0.22 mmol) was coupled with the benzoic acid using General Procedure 1. The crude product was of sufficient purity for further reactions. Colorless solid, 76 mg (97%).lH- NMR (500 MHz, Aceton-d6, 300 K): 5 (ppm) = 9.35 (br s, 1H), 8.35 (d, 1H, J = 8.5 Hz), 8.26 (d, 1 H, J = 1.9 Hz), 8.23 (d, 2H, J = 8.7 Hz), 8.07 (dd, 1H, J = 1 .9 Hz, 8.5 Hz), 8.01 (d, 2H, J = 8.7 Hz), 3.91 (s, 3H).13C-NMR (126 MHz, Aceton-d6, 300 K): 5 (ppm) = 165.7, 165.0, 141.1, 139.2, 134.5, 133.7, 130.3, 129.4, 129.0, 124.9, 118.7, 116.6, 116.5, 52.8. HRMS (ESI) calculated 356.9875 / 358.9854 [M-H+], 356.9881 / 358.9861 found.

[0155] Step b: 3-Bromo-4-(4-cyanobenzamido ben2oic acid The methyl ester (0.19 mmol) was hydrolyzed using General Procedure 2. The crude product was of sufficient purity for further reactions. White to rose-red solid, 55 mg (82%). *H-NMR (700 MHz, DMSO-de, 300 K): δ (ppm) = 13.34 (br s, 1H), 10.44 (s, 1H), 8.19 (d, 1H, J = 1.9 Hz), 8.14 (d, 2H, J = 8.6 Hz), 8.06 (d, 2H, J = 8.6 Hz), 7.98 (dd, 1H, J = 1.9 Hz, 8.3 Hz), 7.76 (d, 1H, J = 8.3 Hz).13C-NMR (176 MHz, DMSO-d6, 300 K): δ (ppm) = 165.7, 164.1, 140.0, 137.7, 133.5, 132.7, 129.1, 128.6, 128.1, 124.5, 119.6, 118.2, 114.3. HRMS (ESI) calculated 344.9875 / 346.9854 [M+H+], 344.9866 / 346.9847 found.

[0156] Fragment Al-2

[0157] Step a: Allyl 3-chloro-4-(4-cyanobenzamido)benzoate

[0158] The aniline (0.19 mmol) was coupled with the benzoic acid using General Procedure 1. The crude product was of sufficient purity for further reactions. Off-white solid, 58 mg (91%). *H- NMR (500 MHz, CDC13, 300 K): δ (ppm) = 8.69 (d, 1H, J = 8.7 Hz), 8.61 (s, 1H), 8.16 (d, 1H, J = 1.9 Hz), 8.07 (dd, 1H, J = 1.9 Hz, 8.7 Hz), 8.04 (d, 2H, J = 8.5 Hz), 7.86 (d, 2H, J = 8.5 Hz), 6.06 (ddt, 1H, J = 5.8 Hz, 10.6 Hz, 16.2 Hz), 5.43 (dd, 1H, J = 1.4 Hz, 17.2 Hz), 5.32 (dd, 1H, J = 1.2 Hz, 10.4 Hz), 4.85 (d, 2H, J = 5.7 Hz).13C-NMR (126 MHz, CDCI3, 300 K): δ (ppm) =

[0159] 164.5, 163.5, 138.0, 137.9, 132.9, 131.9, 130.5, 129.7, 127.8, 126.9, 122.7, 120.5, 118.7, 117.7, 116.2, 66.9. HRMS (ESI) calculated 341.0693 [M+H+], 341.0686 found.

[0160] Step b: 3-Chloro-4-(4-cyanobenzamido)benzoic acid

[0161] The ester (0.16 mmol) was deprotected using General Procedure 3. The crude product was of sufficient purity for further reactions. Colorless solid, 30 mg (62%). *H-NMR (500 MHz, DMSO-de, 300 K): δ (ppm) = 13.29 (br s, 1H), 10.47 (s, 1H), 8.14 (d, 2H, J = 8.6 Hz), 8.05 (d, 2H, J = 8.6 Hz), 8.03 (d, 1H, J = 1.9 Hz), 7.95 (dd, 1H, J = 1.9 Hz, 8.3 Hz), 7.82 (d, 1H, J = 8.4 Hz).13C-NMR (126 MHz, DMSO-d6, 300 K): δ (ppm) = 165.7, 164.2, 138.6, 137.7, 132.6, 130.3, 129.7, 128.6, 128.4, 127.5, 118.2, 114.3. HRMS (ESI) calculated 299.0223 [M-H+J, 299.0229 found. Fragment A1 -4

[0162] Step a: Methyl 3 -(4-cyanobenzamido)bicyclo[ 1.1.llpentane-1 -carboxy late

[0163] Under N2 atmosphere, to a suspension of the amine hydrochloride (800 mg, 4.50 mmol, 1.00 eq.) in CH2CI2 (8.6 mL) was added NEta (1.70 mL, 12.2 mmol, 2.70 eq.) at 0° C. The acid chloride (895 mg, 5.40 mmol, 1.20 eq.) dissolved in CH2CI2 (8.6 mL) was added dropwise over 5 min and stirring was continued for 18 h at rt. Upon completion, sat. NaHCCh solution (30 mL) was added and extracted with CH2CI2 (3 x 30 mL). The combined organic layers were washed with HC1 solution (0.5 M, 30 mL) and brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography (CHaCh / MeOH). Colorless solid, 1.12 g (92%). ‘H-NMR (500 MHz, CDCh, 300 K): δ (ppm) = 9.35 (s, 1H), 7.98 (d, 2H, J = 8.7 Hz), 7.95 (d, 2H, J = 8.7 Hz), 3.63 (s, 3H), 2.34 (s, 6H).13C-NMR (126 MHz, CDCh, 300 K): δ (ppm) = 169.3, 165.2, 137.9, 132.4, 128.0, 118.3, 113.8, 53.9, 51.6, 45.8, 35.8. HRMS (ESI) calculated 271.1083 [M+H+], 271.1078 found.

[0164] Step b: 3-(4-Cyanobenzamido bicyck>ri.l.l]pentane-l -carboxylic acid

[0165] The methyl ester (1.11 mmol) was deprotected using General Procedure 4. The crude product was of sufficient purity for further reactions. Colorless solid, 190 mg (66%). 'H-NMR (500 MHz, DMSO-de, 300 K): δ (ppm) = 12.45 (s, 1H), 9.32 (s, 1H), 7.98 (d, 2H, J = 8.7 Hz), 7.95 (d, 2H, J = 8.7 Hz), 2.29 (s, 6H).13C-NMR (126 MHz, DMSO-d6, 300 K): δ (ppm) = 170.6, 165.2, 138.0, 132.4, 128.0, 118.3, 113.7, 53.7, 45.6, 36.1. HRMS (ESI) calculated 257.0926 [M+H+], 257.0918 found.

[0166] Fragment A 1-5

[0167] Step a: 4-(4-Cyanobenzamido)benzoic acid The compound was prepared according to the established literature procedure; see Dong, Y. et al.’, Bioorg. Med. Chem. Lett. 2014, 24, 3, 944-948.

[0168] Fragment Al-6

[0169] Step a: Methyl 3-cyano-4-(4-cyanobenzamido)benzoate

[0170] 100 mg methyl 4-amino-3 -cyanobenzoate (0.57 mmol, 1 eq) and 104 mg 4-cyanobenzoyl chloride (0.63 mmol, 1.11 eq) were added to a dry flask and were further dried under high vacuum. 4 ml dry CH2Q2 was added and the mixture was cooled down to 0 °C. 0.14 ml dry pyridine (1.74 mmol, 3.1 eq) was slowly added to the mixture under argon atmosphere. The reaction was stirred overnight and controlled by TLC and LCMS. After completion, the reaction was quenched with 3 ml 1 M HC1 and 15 ml brine. The aqueous layer was extracted with 3 x 5 ml EtOAc. The combined organic layer suspensions were washed with sat. NaHCCh solution and concentrated under reduced pressure. The crude product was purified by flash chromatography but still contained impurities.

[0171] Step b: 3-Cvano-4-(4-cyanobenzamido)benzoic acid

[0172] The crude ester (0.53 mmol, 1 eq) was added to 3 ml THF and 3 ml water. 110 mg lithium hydroxide hydrate (2.6 mmol, 5 eq) was added and the reaction was stirred at rt. The reaction was controlled by LCMS. After completion, the reaction was neutralized by 1 M HC1. The solvent was concentrated under reduced pressure. The residue was washed with 0.1 M HC1 and a small amount of MeOH. The solid was dried under high vacuum. The crude product was of sufficient purity for further reactions. Colorless solid, 134 mg (81% over 2 steps). 'H-NMR (500 MHz, DMSO-de, 300 K): δ (ppm) = 13.50 (br s, 1H), 11.10 (s, 1H), 8.34 (d, 1H, J = 2.0 Hz), 8.26 (dd, 1H, J = 2.0 Hz, 8.5 Hz), 8.15 (d, 2H, J = 8.5 Hz), 8.09 (d, 2H, J = 8.5 Hz), 7.77 (d, 1H, J = 8.5 Hz).13C-NMR (126 MHz, DMSO-d6, 300 K): δ (ppm) = 165.4, 164.5, 143.5, 137.3, 134.5, 134.2, 132.8, 128.8, 128.7, 126.3, 118.2, 116.1, 114.7, 108.8.

[0173] Fragment A2-1

[0174]

[0175] Step a: tert-Butyl 4-(4-cyanobenzamido)benzoate tert-Butyl-4-aminobenzoate (5.84 g, 30.2 mmol, 1.00 equiv.) was dissolved at 0 °C in a sat. NaHCCh solution (23.3 mL) und THF (23.3 mL). 4-Cyanobenzoyl chloride (5.00 g, 30.19 mmol, 1.00 equiv.) was added in portions. The mixture was stirred at rt for 3 h. Afterwards, a 1 M HC1 solution (50 mL) was added. The aq. phase was extracted with EtOAc (3x 150 mL). The combined organic phases were dried over NazSC , filtered and concentrated under reduced pressure to furnish tert-butyl 4-(4-cyanobenzamido)benzoate (9.49 g, 29.4 mmol, 97%) as colorless solid. ’H-NMR (400 MHz, CDCh) 8 = 8.02 (d, 2H, J= 8.7 Hz), 7.99 (d, 2H, J= 8.7 Hz), 7.90 (s, 1H), 7.82 (d, 2H, J= 8.7 Hz), 7.70 (d, 2H, J= 8.7 Hz), 1.60 (s, 9H) ppm.13C-NMR (100 MHz, CDCh) 8 = 165.4, 164.3, 141.3, 138.7, 132.7, 130.8, 128.4, 128.0, 119.5, 118.0, 115.7, 81.4 , 28.3 ppm. HRMS (ESI): m / z calculated for C19H17N2O3 [M+H]+: 321.1239, found: 321.1230.

[0176] Step b: tert-Butyl 4-(4-cyanobenzenethioamido)benzoate tert-Butyl 4-(4-cyanobenzamido)benzoate (197 mg, 0.61 mmol, 1.00 equiv.) was dissolved in pyridine (509 pL) and P2S5 (203 mg, 0.91 mmol, 1.50 equiv.) was added. The mixture was stirred at 110 °C for 6 h. Afterwards, H2O (5 mL) was added. The aq. phase was extracted with CH2CI2 (3x 10 mL). The combined organic phases were washed with a 1 M HC1 solution (5 mL) and H2O (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EtOAc = 4:1) to furnish tert-Butyl 4- (4-cyanophenylthioamido)benzoate (153 mg, 0.45 mmol, 74%) as yellow solid. ’H-NMR (400 MHz, CDCh) 8 = 9.30 (s, 1H), 8.03 (d, J= 8.1 Hz, 2H), 7.88 (m, 4H), 7.68 (d, J= 8.2 Hz, 2H), 1.59 (s, 9H) ppm.13C-NMR (100 MHz, CDCh) 8 = 164.9, 142.1, 132.6, 130.6, 130.5, 127.6, 122.6, 118.1, 114.5, 81.6, 28.3 ppm. HRMS (ESI): m / z calculated for C19H17N2O2S [M+H]+: 337.1011, found: 337.1004. Step c: 4-(4-cyanobenzenethioamido)benzoic acid terf-Butyl 4-(4-cyanophenylthioamido)benzoate (122 mg, 0.37 mmol, l.OO equiv.) was dissolved in CH2CI2 (3.90 mL). TFA (1.58 mL) was added dropwise at 0 °C. The mixture was stirred at rt for 4 h. Afterwards, Et20 (10 mL) was added at 0 °C. The solvent was removed under reduced pressure to furnish the product (110 mg, 0.39 mmol, quant.) as orange solid, which was used without further purification. *H-NMR (400 MHz, DMSO) 8 = 12.21 (s, 1H), 8.08-7.99 (m, 4H), 7.99-7.90 (m, 4H) ppm.13C-NMR (100 MHz, DMSO) 8 = 196.2, 166.7, 146.4, 143.4, 132.2, 129.9, 128.3, 128.2, 123.2, 118.4, 112.9 ppm. HRMS (ESI): m / z calculated for C15H9N2O2S [M+H]+: 281.0385, found: 281.0381.

[0177] Fragment A2-2

[0178] Step a: 4-Cyanobenzene-l -carbothioamide

[0179] The compound was prepared according to the established literature procedure; see Mayhoub,

[0180] A. S. et al.,' Bioorg. Med. Chem. 2012, 20, 1, 510-520.

[0181] Step b: r(Benzylsulfanyl)(4-cyanophenyl)methylidenelazanium bromide

[0182] To a solution of the thioamide (194 mg, 1.20 mmol, 1.00 eq.) in dry chloroform (2.40 mL) was added benzyl bromide (142 pL, 1.20 mmol, 1.00 eq.) and the resulting mixture was stirred at reflux for 7 h. After the reaction mixture was cooled to 0 °C, a filtration was performed. The remaining residue was washed with cold CH2CI2 and dried under reduced pressure. The crude product was used without further purification. Colorless solid, 377 mg (95%).

[0183] Step c: tert- Butyl 4-(4-cyanobenzeneimidamido)benzoate

[0184] To a solution of the imidothioic acid ester hydrobromide (130 mg, 0.390 mmol, 1.00 eq.) in dry DMF (1.50 mL) was added tert-butyl 4-aminobenzoate (75 mg, 0.390 mmol, 1.00 eq.) and the resulting mixture was stirred for 24 h. Upon completion, NaOH solution (I M, 10 mL) was added and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with NaOH solution (0.2 M, 10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (CH2C12 / MeOH). Colourless solid, 100 mg (80%). ‘H NMR (500 MHz, DMSO-D6): δ (ppm) = 1.54 (s, 9H), 6.74 (s, 1H), 6.88 - 6.96 (m, 2H), 7.85 (d, 2H, J= 7.0 Hz), 7.92 (d, 2H, J= 8.5 Hz), 8.13 (s, 2H).I3C NMR (126 MHz, DMSO-D6): δ (ppm) = 27.9, 80.0, 112.7, 118.6, 121.6, 124.9, 128.1, 130.5, 132.2, 139.8, 152.8, 155.1, 165.1.

[0185] Step d: {r(4-Carboxynhenyl)amino](4-cyanophenyl)methvIidene}azanium trifluoroacetate

[0186] To a solution of the tert-butyl ester (97 mg, 0.302 mmol, 1.00 eq.) in dry CH2CI2 (2.39 mL) was added TFA (930 pL, 12.1 mmol, 40.0 eq.) at 0 °C and the resulting solution was stirred for 3.75 h at 0 °C. All volatiles were removed in vacuo and the crude product was used without further purification. Colorless solid, quantitative yield.

[0187] Fragment A3-1

[0188] Step a: Methyl 4-r(4-cvanophenyl)carbamoyl]benzoate

[0189] The aniline (0.52 mmol) was coupled with the benzoic acid using General Procedure 1. The crude product was of sufficient purity for further reactions. Brown solid, 121 mg (84%).1H- NMR (500 MHz, DMSO-d6, 300 K): δ (ppm) = 10.82 (br s, 1H), 8.13 - 8.06 (m, 4H), 7.99 (d, 2H, J = 8.8 Hz), 7.84 (d, 2H, J = 8.8 Hz), 3.90 (s, 3H).13C-NMR (126 MHz, DMSO-d6, 300 K) = 165.6, 165.3, 143.2, 138.4, 133.2, 132.4, 129.2, 128.3, 120.3, 119.0, 105.7, 52.5. HRMS (ESI) calculated 281.0926 [M+H+], 281.0921 found.

[0190] Step b: 4-r(4-Cvanophenyl)carbamoyl]benzoic acid

[0191] The methyl ester (0.39 mmol) was deprotected using General Procedure 4. The crude product was of sufficient purity for further reactions. Off-white solid, 47 mg (45%). 'H-NMR (500 MHz, DMSO-d6, 300 K): δ (ppm) = 13.30 (br s, 1H), 10.79 (s, 1H), 8.09 (d, 2H, J = 8.6 Hz), 8.05 (d, 2H, J = 8.6 Hz), 8.00 (d, 2H, J = 8.9 Hz), 7.84 (d, 2H, J = 8.8 Hz).l3C-NMR (126 MHz, DMSO-d6, 300 K) = 166.7, 165.5, 143.2, 138.1, 133.7, 133.2, 129.4, 128.1, 120.3, 119.0, 105.6.

[0192] HRMS (ESI) calculated 267.0770 [M+H+], 267.0764 found.

[0193] Fragment A3-2

[0194] Step a: Methyl 3-chloro-4-I(4-cvanophenyl)carbamoyl]benzoate

[0195] 60 mg 4-aminobenzonitrile (0.51 mmol, 1.0 eq) and 120 mg 2-chloro-4-

[0196] (methoxycarbonyl)benzoic acid (0.56 mmol, 1.1 eq) were added to a dry flask and further dried under high vacuum. 1.8 ml dry CH2CI2 and 0.12 ml dry pyridine (118 mg, 1.5 mmol, 2.9 eq) were added under nitrogen atmosphere. The reaction mixture was cooled down to 0 °C and 51 pl phosphoryl trichloride (0.55 mmol, 1.1 eq) was slowly added. The reaction was stirred overnight and controlled by TLC. After completion, the reaction was quenched with 16 ml brine and 2 ml 1 M HC1. The aqueous layer was extracted with 3 x 6 ml EtOAc. The crude product was purified by flash chromatography but still contained impurities.

[0197] Step b: 3-Chloro-4-r(4-cyanophenyl)carbamoyl]benzoic acid

[0198] The crude ester (0.43 mmol, 1 eq) was added to 2.4 ml THF and 2.4 ml water. 143 mg lithium hydroxide hydrate (3.4 mmol, 8 eq) was added and the reaction was stirred at rt. After completion, the reaction was neutralized by 1 M HC1. The solvent was removed under reduced pressure. 1 ml 1 M HC1 and 9 ml water were added and the aqueous layer was extracted with 4 x 5 ml EtOAc. The combined organic layers were dried with anhydrous sodium sulfate and the solid was filtered off. The solvent was removed under reduced pressure and dried under high vacuum. The crude product was of sufficient purity for further reactions. Colourless solid, 114 mg (75% over 2 steps). 'H-NMR (700 MHz, DMSO-d6, 300 K): δ (ppm) = 13.57 (br s, 1H), 11.07 (s, 1H), 8.03 (d, 1H, J = 1.5 Hz), 8.00 (dd, 1H, J = 1.6 Hz, 7.9 Hz), 7.90 (d, 2H, J = 8.8 Hz), 7.84 (d, 2H, J = 8.8 Hz), 7.77 (d, 1H, J = 7.9 Hz).13C-NMR (176 MHz, DMSO-d6, 300 K): δ (ppm) = 165.6, 164.9, 142.8, 139.8, 133.6, 133.4, 130.2, 130.1, 129.3, 128.1, 119.7, 118.9, 105.9. Fragment A3-3

[0199] Step a: Methyl 3-r(4-cyanophenyl)carbamoyl1bicyclori.L11pentane-l-carboxylate

[0200] To a solution of 3 -(Methoxycarbonyl)bicyclo[l.l.l]pentane-1 -carboxylic acid (60 mg, 0.353 mmol, 1.00 eq.) in dry CH2CI2 (609 pL) were added oxalyl chloride (30 pL, 0.353 mmol, 1.00 eq.) and DMF (1 drop). After stirring at rt for 1.5 h, all volatiles were removed under reduced pressure.

[0201] The acid chloride was dissolved in CH2CI2 (1.35 mL) and the solution was cooled to 0°C. After 4-aminobenzonitrile (46 mg, 0.388 mmol, 1.00 eq.) and NEts (147 pL, 1.06 mmol, 3.00 eq.) were added, stirring was continued at rt for 19 h. Sat. NaHCCh (10 mL) was added to the reaction mixture and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with sat. NaHCCL (10 mL), brine (10 mL), dried (Na2SC>4) and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / EtOAc). Colourless solid, 53 mg (56%). 'H NMR (500 MHz, DMSO-D6): δ (ppm) = 2.31 (s, 6H), 3.63 (s, 3H), 7.75 - 7.79 (m, 2H), 7.82 - 7.86 (m, 2H), 10.04 (s, 1H).13C NMR (126 MHz, DMSO-D6): δ (ppm) = 36.4, 39.6, 51.6, 52.1, 105.4 , 119.0, 119.7, 133.2, 142.8, 168.0, 169.3. LC-MS: m / z = 271.0 (calcd. 271.11 for CI5HI5N2O3+[M+H+]).

[0202] Step b: 3-r(4-Cvanophenyl)carbamoyl]bicvclori.l.l]pentane-l-carboxylic acid

[0203] To a solution of the ester (47 mg, 0.174 mmol, 1.00 eq.) in 1,2-dichloroethane (392 pL) was added (CH3 SnOH (94 mg, 0.522 mmol, 3.00 eq.) and the reaction was stirred at 80 °C for 5 h. After completion, HC1 (I M, 10 mL) was added to the reaction mixture and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with HC1 solution (1 M, 10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was used without further purification. White solid, quantitative yield.

[0204] Fragment A3-4

[0205] Step a: Methyl 4-r(4-cyanophenyl)carbamoyl]bicyclor2.2.21octane-l-carboxylate

[0206] To a solution of 4-(Methoxycarbonyl)bicyclo[2.2.2]octane-l-carboxylic acid (425 mg, 2.00 mmol, 1.00 eq.) in dry CH2CI2 (5.0 mL) were added oxalyl chloride (290 pL, 3.38 mmol, 1.69 eq.) and DMF (1 drop). After stirring at 0 °C for 2 h, all volatiles were removed under reduced pressure.

[0207] Under argon atmosphere, the acid chloride was dissolved in CH2CI2 (6.0 mL). After 4- aminobenzonitrile (224 mg, 1.90 mmol, 0.95 eq.) and pyridine (806 pL, 10.0 mmol, 5.00 eq.) were added, stirring was continued at rt for 15 h. HC1 solution (1 M, 20 mL) was added to the reaction mixture and the aqueous layer was extracted with CH2Q2 (1 x 48 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried (Na2SC>4) and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / EtOAc). Off white solid, 526 mg (84%). ’H-NMR (500 MHz, DMSO-d6, 298 K): 8 = 1.72-1.78 (m, 6H), 1.78-1.84 (m, 6H) 3.58 (s, 3H), 7.73 (d, 2H, J= 8.9 Hz), 7.84 (d, 2H, J= 9.0 Hz), 9.59 (s, 1H) ppm.13C-NMR (126 MHz, DMSO-d6): 8 = 27.1, 27.6, 38.2, 39.6,

[0208] 51.7, 104.9, 119.2, 119.9, 133.1, 143.7, 176.3, 177.2 ppm.

[0209] Step b: 4-r(4-cvanophenyl)carbamoyl]bicvclor2.2.2]octane-l -carboxylic acid

[0210] To a solution of the methyl ester (312 mg, 1.00 mmol, 1.0 eq.) in THF / water (1 :1, 12.0 mL) was added LiOH (120 mg, 5.0 mmol, 5.0 eq.). After the emulsion was stirred for 3 h at rt, LiOH (60 mg, 2.5 mmol, 2.5 eq.) was added and stirring was continued for 0.5 h. Upon completion, HC1 solution (1 M) was added and the THF was removed under reduced pressure. The remaining aqueous layer was extracted twice with EtOAc before the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was used without further purification. Off white solid, quant, yield. ’H-NMR (500 MHz, DMSO-d6, 298 K): 8 = 1.69- 1.77 (m, 6H), 1.77-1.85 (m, 6H), 7.73 (d, 2H, J= 8.9 Hz), 7.86 (d, 2H, J= 9.0 Hz), 9.57 (s, 1H) ppm.13C-NMR (126 MHZ, DMSO-d6, 298 K): 8 = 27.2, 27.6, 37.7, 39.6, 104.8, 119.1, 119.8, 133.0, 143.6, 176.4, 178.5 ppm. Fragment A3-5

[0211] Step a: Methyl 8-r(4-cyanophenyl)carbamoyl1cubane-l-carboxylate

[0212] 61 mg 4-aminobenzonitrile (0.52 mmol, 1.0 eq) and 122 mg 4- methoxycarbonylcubanecarboxylic acid (0.59 mmol, 1.15 eq) were added to a dry flask and further dried under high vacuum. 2.0 ml dry CH2CI2 and 0.13 ml dry pyridine (128 mg, 1.6 mmol, 3.1 eq) were added under nitrogen atmosphere. The reaction mixture was cooled down to 0 °C and 55.0 pl phosphoryl trichloride (91 mg, 0.59 mmol, 1.14 eq) was slowly added. The reaction was stirred overnight and controlled by TLC. After completion, 3 ml 1 M HC1 and 9 ml brine were added. The aqueous layer was extracted with 3 x 4 ml EtOAc. The combined organic phases were washed with saturated NaHCCh solution. The solvent was evaporated under reduced pressure.

[0213] Step b: 8-r(4-Cvanophenyl)carbamoyl]cubane-l -carboxylic acid

[0214] 100 mg crude ester (0.33 mmol, 1 eq) was dissolved in 0.6 ml 1,2-dichloroethane. 177.0 mg trimethyltin hydroxide (0.98 mmol, 3.0 eq) was added and the mixture was heated up to 80 °C and stirred for 48 h. After completion, the solvent was removed under reduced pressure. The crude solid was washed with 2 M HC1 and dried under reduced pressure. Colourless solid, 45 mg (30% over 2 steps). ‘H-NMR (500 MHz, DMSO-d6, 300 K): 5 (ppm) = 12.37 (br s, 1H), 10.08 (s, 1H), 7.86 (d, 2H, J = 8.9 Hz), 7.76 (d, 2H, J = 8.9 Hz), 4.27 - 4.24 (m, 3H), 4.15 - 4.12 (m, 3H).13C-NMR (126 MHZ, DMSO-d6, 300 K): δ (ppm) = 172.5, 170.2, 143.3, 133.1, 119.5, 119.1 , 104.9, 57.8, 55.3, 46.5, 45.9.

[0215] Fragment A4-1

[0216] Step a: fert-Butyl 4-(5-cyano-l-methyl-l / / -l,3-benzodiazol-2-yl)benzoate

[0217] 380 mg 3-amino-4-(methylamino)benzonitrile (2.58 mmol, 1 eq) and 535 mg tert-butyl 4- formylbenzoate (2.59 mmol, 1 eq) were dissolved in 4.5 ml methanol and 2.7 ml THF and stirred under open atmosphere. After the starting materials had vanished, 25 mg Cu(AcO)2-H2O (0.13 mmol, 0.05 eq) was added and air was bubbled through the reaction mixture. After complete oxidation, the solvents were removed under reduced pressure. The crude product was purified by flash chromatography with ethyl acetate and petroleum ether as solvent mixture. Bright yellow needles, 729.1 mg (85 %). ‘H-NMR (500 MHz, DMSO-d6, 300 K): 5 (ppm) = 8.29 (d, 1H, J = 1.4 Hz), 8.09 (d, 2H, J = 8.4 Hz), 8.03 (d, 2H, J = 8.4 Hz), 7.89 (d, 1H, J = 8.5 Hz), 7.74 (dd, 1H, J = 1.5 Hz, 8.4 Hz), 3.95 (s, 3H), 1.58 (s, 9H).13C-NMR (126 MHz, DMSO- d6, 300 K): 5 (ppm) = 164.4, 154.7, 141.9, 139.6, 133.3, 132.6, 129.8, 129.4, 126.1, 124.3, 120.0, 112.6, 104.4, 81.4, 32.3, 27.8.

[0218] Step b: 2-(4-Carboxyphenyl)-5-cvano-l-methyl-177-l,3-benzodiazol-3-ium trifluoroacetate 725 mg ttr / -butyl ester (2.2 mmol, 1 eq) was dissolved in 10 ml dry CH2CI2 under argon atmosphere. 4.2 ml TFA (54.9 mmol, 25 eq) was added to the mixture. After completion, the solvent was removed under reduced pressure. The excess of TFA was removed by coevapoation with CH2CI2 and n-heptane. The product was dried under high vacuum and used without further purification.

[0219] Fragment A4-2

[0220] Step a: Methyl 3-(5-cyano-l-methyl- 3-benzodiazol-2-yl) l- carboxylate Under N2 atmosphere, the carboxylic acid (1.42 g, 8.36 mmol, 1.00 eq.) and the diamine (1.29 g, 8.78 mmol, 1.05 eq.) were dissolved in dry toluene (20.7 mL) and P(OPh)3 (2.86 mL, 10.9 mmol, 1.30 eq.) was added. After the reaction was stirred overnight at reflux, sat. NaHCCh solution (50 mL) was added and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (CH2C12 / MeOH). colourless solid,

[0221] 1.70 g (72%). *H NMR (500 MHz, DMSO-D6): δ (ppm) = 2.58 (s, 6H), 3.66 (s, 3H), 3.88 (s, 3H), 7.63 (d, 1H, J= 7.1 Hz), 7.74 (d, 1H, J= 8.4 Hz), 8.12 (q, 1H, J= 1.1 Hz).13C NMR (176 MHz, DMSO-D6): δ (ppm) = 30.8, 35.6, 39.0, 51.6 , 53.4 , 103.8, 111.6, 120.0, 123.7, 125.6, 138.9, 141.3, 153.7, 169.0.

[0222] Step b: Potassium 4-(5-cyano-l-methyl-177-l,3-benzodiazol-2-yl)benzoate

[0223] To a solution of the ester (1.70 mg, 6.06 mmol, 1.00 eq.) in THF (6.67 mL) was added KOH solution (1 M, 6.67 mL, 6.67 mmol, 1.10 eq.) and the resulting emulsion was stirred for 2 h at rt. Upon completion, the THF was removed in vacuo and the product was freeze dried, colourless solid, quant, yield. *H NMR (700 MHz, DMSO): 8 = 8.06 (dd, 1H, J= 1.6, 0.6 Hz),

[0224] 7.70 (dd, 1H, J= 8.4, 0.7 Hz), 7.59 (dd, 1H, J= 8.3, 1.6 Hz), 3.85 (s, 3H), 2.21 (d, 6H, J= 0.9 Hz).13C NMR (176 MHz, DMSO): 8 = 172.1, 155.9, 141.5, 139.0, 125.2, 123.4, 120.1, 111.4, 103.4, 53.1, 43.1, 34.4, 30.8.

[0225] Fragment A4-3

[0226] Step a: Methyl 4-(5-cvano-l-methyl-l / / -l,3-benzodiazol-2-yl)bicyclol2.2.21octane-l- carboxylate

[0227] The aldehyde (388 mg, 1.98 mmol, 1.00 eq.) and 4-(methylamino)-3-nitrobenzonitrile (350 mg, 1.98 mmol, 1.00 eq.) were dissolved in DMSO (13.2 mL) and Na2S2O4 (1.03 g, 5.93 mmol, 3.00 eq.) was added. After the resulting reaction mixture was stirred for 2 h at 90°C, sat. NaHCOs solution (20 mL) was added and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by flash chromatorgraphy (CH2Cl2 / MeOH). colourless solid, 460 mg (72%). 'H NMR (500 MHz, DMSO-D6): 5 (ppm) = 1.82 - 1.89 (m, 6H), 2.05 - 2.12 (m, 6H), 3.61 (s, 3H), 3.96 (s, 3H), 7.60 (dd, J= 8.4 / 1.5 Hz, 1H), 7.70 (dd, J= 8.4 / 0.7 Hz, 1H), 8.09 (dd, J= 1.6 / 0.6 Hz, 1H).13C NMR (126 MHz, DMSO-D6): δ (ppm) = 27.5, 28.2, 32.9, 34.2, 38.1, 51.6, 103.4, 111.4, 120.1, 123.5, 125.3, 140.2, 140.7, 162.1, 177.1.

[0228] Step b: 4-(5-Cyano-l-methyl-lH-l,3-benzodiazol-2-yl)bicyclor2.2.21octane-l-carboxylic acid To a solution of the methyl ester (72 mg, 0.223 mmol, 1.00 eq.) in THF / water (1 :1, 3.0 mL) was added LiOH (11 mg, 0.445 mmol, 2.00 eq.). After the emulsion was stirred for 2.25 h at rt, HC1 solution (1 M, 0.88 mL) was added and the THF was removed under reduced pressure. The precipitate was filtered off, washed with water (2 x 2 mL) and dried in vacuo. The crude product was used without further purification. Off white solid, 46 mg (67%).

[0229] Fragment A4-4

[0230] Step a: terf-Butyl 4-(6-cyano-l-methyl-177-L3-benzodiazol-2-yl)benzoate

[0231] After a solution of the aldehyde (110 mg, 0.533 mmol, 1.00 eq.) and diamine (78 mg, 0.533 mmol, 1.00 eq.) in CH3OH (880 pL) and THF (550 pL) was stirred at rt for 18 h, CU(ACO)2-H2O (21 mg, 0.107 mmol, 0.20 eq.) and I2(27 mg, 0.107 mmol, 0.20 eq.) were added and stirring was continued under open atmosphere for 48 h. Upon completion, NaOH solution (0.5 M, 10 mL) was added and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SC>4 and concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2 / MeOH). Colourless to slightly greenish needles, 101 mg (57%). 'H-NMR (500 MHz, DMSO-de, 300 K): δ (ppm) = 8.35 (dd, 1H, J = 0.6 Hz, 1.5 Hz), 8.09 (d, 2H, J = 8.6 Hz), 8.03 (d, 2H, J = 8.6 Hz), 7.88 (dd, 1H, J = 0.6 Hz, 8.4 Hz), 7.66 (dd, 1H, J = 1.5 Hz, 8.4 Hz), 3.96 (s, 3H), 1.59 (s, 9H).13C-NMR (126 MHz, DMSO-d6, 300 K): 8 (ppm) == 164.4, 155.3, 145.2, 136.5, 133.2, 132.6, 129.8, 129.3, 125.6, 120.3, 119.9, 116.4, 104.4, 81.3, 32.3, 27.8.

[0232] Step b: 4-(6-Cvano-l-methyl-177’-l,3-benzodiazol-2-yl)benzoic acid

[0233] To the tert-butyl ester (101 mg, 0.303 mmol, 1.00 eq.) in dry CH2CI2 (2.32 mL) was added TFA (1.17 mL, 15.1 mmol, 50.0 eq.) at 0 °C. After the resulting solution was stirred for 3 h at 0 °C, all volatiles were removed in vacuo. The crude product was used without further purification. Off-white solid, quant, yield.

[0234] Fragment A4-5

[0235] Step a: Methyl 3 -(6-cyano-l -methyl- 177- 1,3 -benzodiazol-2-yl)bicvclor 1.1.1 lpentane-1- carboxylate

[0236] After 3 -(Methoxy carbonyl)bicyclo[l.l.l]pentane-l -carboxylic acid (220 mg, 1.29 mmol, 1.00 eq.), 4-Amino-3-(methylamino)benzonitrile (200 mg, 1.36 mmol, 1.05 eq.) and P(OPh)a (442 pL, 1.68 mmol, 1.30 eq.) were dissolved in dry toluene (3.20 mL), the reaction mixture was stirred at reflux for 16 h. Upon completion, sat. NaHCO? solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried (Na2SC>4) and concentrated in vacuo. The residue was purified by flash chromatography (CIUCh / MeOH). Colourless solid, 308 mg (85%). 'H NMR (700 MHz, DMSO-D6): 5 (ppm) - 2.58 (s, 6H), 3.66 (s, 3H), 3.88 (s, 3H), 7.56 (d, J= 8.3 Hz, 1H), 7.72 (d, J= 8.3 Hz, 1H), 8.19 (s, 1H).13C NMR (126 MHz, DMSO-D6): 3 (ppm) = 30.9, 35.6, 39.0, 51.7, 53.4, 103.9, 115.6, 119.9, 120.0, 125.1, 135.8, 144.8, 154.5, 169.1.

[0237] Step b: Potassium 3-(6-cvano-l-methyl-177-1.3-benzodiazol-2-yl)bicyclori.l.l]pentane-l- carboxylate To a solution of the ester (303 mg, 1.08 mmol, 1.00 eq.) in THF (1.19 mL) was added KOH solution (1 M, 1.19 mL, 1.19 mmol, 1.10 eq.) and the resulting emulsion was stirred for 2 h at rt. Upon completion, the THF was removed in vacuo and the product was freeze dried. Colorless solid, quantitative yield. LC-MS: m / z = 268.2 (calcd. 268.11 for CisHuNsOz - [M+H+]).

[0238] Fragment A4-6

[0239] Step a: Methyl 4-(5-cyano-l-ethyl-lLr-l,3-benzodiazol-2-yl)benzoate

[0240] The carboxylic acid (223 mg, 1.24 mmol, 1.00 eq.), the diamine (200 mg, 1.24 mmol, 1.00 eq.) and P(OPh)3 (424 pL, 1.61 mmol, 1.30 eq.) were dissolved in dry toluene (3.10 mL) and the reaction mixture was stirred at reflux for 16 h. After EtOAc and MTBE were added, the precipitate was filtered off, washed with MTBE and dried in vacuo to furnish the product. Rose solid, 137 mg (36%).!H NMR (500 MHz, DMSO-D6) 8(ppm) = 8.29 (d, 1H, J = 1.4 Hz), 8.19 - 8.15 (m, 2H), 8.00 - 7.96 (m, 2H), 7.94 (d, 1H, J = 8.4 Hz), 7.73 (dd, 1H, J = 8.4, 1.5 Hz), 4.41 (q, 2H, J = 7.2 Hz), 3.92 (s, 3H), 1.33 (t, 3H, J = 7.2 Hz,).13C NMR (126 MHz, DMSO- D6) 8(ppm) = 165.7, 154.2, 138.4, 133.8, 131.0, 129.7, 129.6, 126.1, 124.4, 119.8, 112.6, 108.4, 104.5, 52.5, 37.3, 15.0. HRMS (ESI) calculated 306.1237 [M+H+], 306.1239 found.

[0241] Step b: Potassium 4-(5-cyano-l-ethyl-l / / -l,3-benzodiazol-2-yl)benzoate

[0242] To a solution of the ester (0.132 mg, 0.432 mmol, 1.00 eq.) in THF (1.2 mL) was added KOH solution (1 M, 492 pL, 0.492 mmol, 1.14 eq.) and water (0.6 mL). The resulting emulsion was stirred for 3 h at 40 °C. Upon completion, HC1 solution (1 M, 65 pL) was added. After all volatiles were removed in vacuo, the remaining residue was coevaporated with ACN (2x), dissolved in ACN / water and freeze-dried. The crude product was used without further purification. Dark purple resin, quant, yield.

[0243] Fragment A4-7

[0244] Step a: Methyl 4-(6-cyano-l -ethyl- 177- 1,3 -benzodiazol-2-yl)benzoate

[0245] The carboxylic acid (218 mg, 1.21 mmol, 1.30 eq.), the diamine (150 mg, 0.93 mmol, 1.00 eq.) and P(OPh)3 (367 pL, 1.40 mmol, 1.50 eq.) were dissolved in dry toluene (2.33 mL) and the reaction mixture was stirred at 90° C for 2 h. After stirring was continued at 70 °C for 64 h, additional P(OPh)3 (294 pL, 1.12 mmol, 1.20 eq.) was added and the reaction mixture was stirred at 70 °C for another 24 h. Upon completion, KOH solution (1 M, 50 mL) and brine (30 mL) were added and extracted with EtOAc (50 mL). After the EtOAc layer was washed with KOH solution (I M, 50 mL), the aq. phase was extracted with EtOAc (50 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (C^Ch / MeOH). Rose solid, 140 mg (49%). *H NMR (500 MHz, DMSO-D6) 8(ppm) = 8.40 (d, J = 1.4 Hz, 1H), 8.19 - 8.15 (m, 2H), 8.01 - 7.97 (m, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 8.4, 1.5 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 3.92 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H).13C NMR (126 MHz, DMSO-D6) 5(ppm) = 165.7, 154.9, 145.4, 135.2, 133.8, 131.0, 129.7, 129.6, 125.7, 120.5, 119.9, 116.5, 104.5, 52.5, 15.0. HRMS (ESI) calculated 306.1237 [M+H+], 306.1232 found.

[0246] Step b: Potassium 4-(6-cyano-l -ethyl- lH-L3-benzodiazol-2-yl)benzoate

[0247] To a solution of the ester (0.135 mg, 0.442 mmol, 1.00 eq.) in THF (1.2 mL) was added KOH solution (1 M, 510 pL, 0.510 mmol, 1.15 eq.) and water (0.7 mL). The resulting emulsion was stirred for 3 h at 40 °C. After all volatiles were removed in vacuo, the remaining residue was coevaporated with ACN (2x), dissolved in ACN / water and freeze-dried. The crude product was used without further purification. Brown solid, quant, yield. ’H NMR (700 MHz, DMSO-d6) 8(ppm) = 8.33 (s, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 7.9 Hz, 2H), 7.63 (dd, J = 8.3, 1.4 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H).13C NMR (126 MHz, DMSO) 8(ppm) = 167.4, 156.6, 145.6, 143.9, 135.1, 129.2, 128.7, 128.0, 125.4, 120.1, 116.1, 103.9, 15.0. HRMS (ESI) calculated 292.1081 [M+H+], 292.1078 found. Fragment A4-8

[0248] Step a: Methyl 3-(6-cvano-l-ethyl-177-l,3-benzodiazol-2-yl')bicvclo[l.l.l]pentane-l- carboxylate

[0249] The carboxylic acid (205 mg, 1.21 mmol, 1.30 eq.), the diamine (150 mg, 0.93 mmol, 1.00 eq.) and P(0Ph)3 (367 pL, 1.40 mmol, 1.50 eq.) were dissolved in dry toluene (2.3 mL) and the reaction mixture was stirred at 70 °C for 16 h. After all volatiles were removed in vacuo, the residue was purified by flash chromatography (Cyclohexane / EtOAc). Off-white solid, 114 mg (41%). 'H NMR (500 MHz, DMSO-D6) 8(ppm) = 8.24 (dd, J = 1.6, 0.7 Hz, 1H), 7.74 (dd, J = 8.3, 0.6 Hz, 1H), 7.57 (dd, J = 8.4, 1.5 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 3.66 (s, 3H), 2.59 (s, 6H), 1.30 (t, J = 7.2 Hz, 3H).13C NMR (126 MHz, DMSO-D6) 8(ppm) = 169.0, 153.9, 144.9, 134.6, 125.2, 120.0, 115.6, 115.2, 104.0, 53.6, 51.7, 35.5, 15.5. HRMS (ESI) calculated 296.1394 [M+H+], 296.1393 found.

[0250] Step b: Potassium 3-(6-cyano-l-ethyl-177-l,3-benzodiazol-2-yl)bicyclo[l.l.l]pentane-l- carboxylate

[0251] To a solution of the ester (0.110 mg, 0.372 mmol, 1.00 eq.) in THF (1.0 mL) was added KOH solution (1 M, 430 pL, 0.430 mmol, 1.15 eq.) and water (0.6 mL). The resulting emulsion was stirred for 3 h at 40 °C. After all volatiles were removed in vacuo, the remaining residue was coevaporated with ACN (2x), dissolved in ACN / water and freeze-dried. The crude product was used without further purification. Colorless solid, quant, yield. ’H NMR (700 MHz, DMSO- d6) 8(ppm) = 8.18 (d, J = 1.5 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.54 (dd, J = 8.3 Hz, 1.5 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 2.20 (s, 5H), 1.30 (t, J = 7.2 Hz, 3H).13C NMR (126 MHz, DMSO) 8(ppm) = 156.2, 145.2, 134.6, 125.0, 120.1, 119.7, 115.2, 103.5, 53.4, 42.9, 34.3, 15.4. HRMS (ESI) calculated 282.1237 [M+H+], 282.1237 found.

[0252] Fragment A5-1

[0253] Step a: -2-H4-(4-Cvanobenzamido)phenyl1formamido}pent-4-ynoic acid 4-(4-Cyanobenzamido)benzoic acid (762 mg, 2.86 mmol, 1.0 Eq.) and HATU (1.09 mg, 2.86 mmol, 1.0 Eq.) were dissolved in dry DMF (20 mL) and DIPEA (1.0 mL, 2.0 Eq.) was added. The reaction was stirred for 2 h at RT while being monitored by LCMS. Then a solution of (S)-l -methoxy- 1 -oxopent-4-yn-2-aminium chloride (492 mg, 3.01 mmol, 1.05 Eq) in dry DMF (7 mL) and DIPEA (1.0 mL, 2.0 Eq.) were added and the reaction mixture was stirred for 1.5 h. The solution was neutralized with HC1 (2 M, 5.7 mL) and concentrated to a volume of -5 mL. CH2CI2 (~5mL) and water were added to the concentrate until precipitate formation was complete. The precipitate was removed with a pore size 4 fritted funnel and washed several times with water before it was dried under reduced pressure to give -0.94 g of the crude product. The filtrate was reextracted with CH2CI2 (3x) and EtOAc (3x), the combined org. phases were dried over Na2SC>4 and the solution was concentrated urp. Water was added to the remaining DMF-solution. The precipitate was then filtered off and washed with water. This precipitate and the precipitate from before were combined.

[0254] The combined precipitates were suspended in a THF / water mixture (1:1, 40 mL) and LiOH-FLO (0.96 g, 8.0 Eq.) was added. The reaction was stirred for 1.5 h before the reaction emulsion was partitioned between H2O (80 mL) and EtOAc (80 mL). The aqueous phase was acidified with HC1 (2 M, 15 mL) and extracted with EtOAc (1 x 80 mL, 2 x 50 mL). The organic phases were combined, dried over Na2SO4 and the solvent removed under reduced pressure and by coevaporation (3-4x) with chloroform and heptane. The crude product was used without further purification. Colorless solid, 849 mg (82%). *H NMR (500 MHz, DMSO): 5(ppm) = 12.88 (br s, 1H), 10.70 (s, 1H), 8.70 (d, J = 7.9 Hz, 1H), 8.13 (d, J= 8.7 Hz, 2H), 8.04 (d, J= 8.5 Hz, 2H), 7.93 - 7.87 (m, 4H), 4.54 (ddd, J= 8.9 Hz, 7.8 Hz, 5.4 Hz, 1H), 2.87 (t, J= 2.6 Hz, 1H), 2.80 - 2.67 (m, 2H).13C NMR (126 MHz, DMSO): 5(ppm) = 172.0, 165.7, 164.5, 141.6, 138.7, 132.5, 129.0, 128.6, 128.2, 119.6, 118.3, 114.0, 80.9, 72.8, 51.7, 20.8.

[0255] Fragment A5-2

[0256]

[0257] Step a: O-(tert-butyl)-N-(4-(4-cyanobenzamido)benzoyl)-L-threonine

[0258] 600 mg perfluorophenyl 4-(4-cyanobenzamido)benzoate (1.39 mmol, 1 eq) and 300 mg O- (tert-butyl)-L-threonine (1.71 mmol, 1.2 eq) were added to a dry flask and the solids were dried under high vacuum. 10 ml diy CH2CI2 was added under argon atmosphere and the mixture was cooled down to 0 °C. 0.58 ml dry triethylamine (4.2 mmol, 3 eq) was added under argon atmosphere. The reaction was slowly warmed up to rt and controlled by LCMS. After completion, the reaction was quenched with 0.23 ml acetic acid (4.0 mmol, 2.9 eq) and the crude mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography. Colorless solid, 419 mg (71%). *H-NMR (500 MHz, DMSO-dg, 300 K): δ (ppm) = 12.78 (br s, 1H), 10.72 (s, 1H), 8.13 (d, 2H, J = 8.7 Hz), 8.05 (d, 2H, J = 8.6 Hz), 7.89 (br s, 4H), 7.70 (d, 1H, J = 8.7 Hz), 4.45 (dd, 1H, J = 3.3 Hz, 8.7 Hz), 4.19 (qd, 1H, J = 3.4 Hz, 6.2 Hz), 1.16 (d, 3H, J = 6.3 Hz), 1.14 (s, 9H).13C-NMR (500 MHz, DMSO-d6, 300 K): 8 (ppm) = 172.1, 166.0, 164.5, 141.7, 138.7, 132.5, 129.1, 128.7, 128.2, 119.7, 118.3, 114.1, 73.4, 67.1, 58.2, 28.3, 20.7.

[0259] LinkerCDE-F ragments

[0260] Fragment Bl-1 and Fragment Bl-1-2

[0261]

[0262] Step a: Butyl 4-(2-(allyloxy)-4-(4-aminobenzamido)-3-isopropoxybenzamido)benzoate 465 mg terf-butyl 4-(2-(allyloxy)-4-amino-3-isopropyloxybenzamido)benzoate (1.1 mmol, 1 eq) and 304 mg 4-nitrobenzoyl chloride (1.6 mmol, 1.5 eq) were added to a dry flask under nitrogen atmosphere. 9 ml of dry CH2CI2 was added and the mixture was cooled down to 0° C. 0.35 ml of dry pyridine (344 mg, 4.3 mmol, 4 eq) was slowly added to the stirring mixture. The reaction was allowed to get to rt and stirred for 2 hours. The reaction was quenched with 9 ml 1 M NaHSO4 and 28 ml water. The organic phase was separated and stored while the water phase was extracted with 4 x 18 ml CH2Q2. The organic phases were combined and washed with 2 x 30 ml sat. NaHCCh solution. The solvent was evaporated under reduced pressure. The crude product was used without further purification. Yield: 693 mg (crude).

[0263] 693 mg of crude terf-butyl-4-(2-(allyloxy)-3-isopropoxy-4-nitrobenzamido)benzoate (1.2 mmol, 1 eq) was dissolved in 5.7 ml THF and 4.8 ml ethanol. 1.1 ml acetic acid (1154 mg, 19.2 mmol, 16.0 eq) was added to the stirring mixture and the mixture was cooled to 0 °C. 1.18 g zinc dust (18.1 mmol, 15.0 eq) was added in small portions. The mixture was allowed to reach rt and was stirred for 3 hours. The zinc dust was filtered off. 65 ml sat. NaHCCh solution was added and the aqueous phase was extracted with 3 x 50 ml EtOAc. The solvent of the combined organic phases was evaporated under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / EtOAc). The product was a yellow solid. Yield 425 mg (71 % over 2 steps). ‘H-NMR (500 MHz, DMSO-d6, 300 K): δ (ppm) = 10.49 (s, 1H), 9.05 (s, 1H), 7.95 (d, 1H, J = 8.7 Hz), 7.89 (d, 2H, J = 8.7 Hz), 7.83 (d, 2H, J = 8.6 Hz), 7.69 (d, 2H, J = 8.6 Hz), 7.40 (d, 1H, J = 8.6 Hz), 6.63 (d, 2H, J = 8.7 Hz), 6.07 - 5.98 (m, 1H), 5.88 (br s, 2H),

[0264] 5.38 (dq, 1H, J = 1.6 Hz, 17.2 Hz), 5.21 (ddd, 1H, J = 1.3 Hz, 3.0 Hz, 10.5 Hz), 4.60 (d, 2H, J = 5.5 Hz), 4.53 (hept, 1H, J = 6.1 Hz), 1.55 (s, 9H), 1.28 (d, 6H, J = 6.2 Hz).13C-NMR (126 MHz, CDCh, 300 K): δ (ppm) = 164.6, 164.5, 164.4, 152.6, 149.3, 143.0, 141.2, 136.3, 133.6, 130.1, 129.0, 126.0, 125.8, 123.9, 119.9, 118.8, 117.8, 117.4, 112.9, 80.3, 76.1, 74.3, 27.8, 22.4. HRMS (ESI) calculated 546.2604 [M+H+], 546.2604 found.

[0265] Step b: tert-Butyl 4-(4-{4-r(2S)-2-( fluoren-9-yI)methoxy]carbonyI}amino)pent-4- vnamido]benzamido}-2-(nrop-2-en-l-yloxy)-3-(propan-2-yloxy)benzamido)benzoate

[0266] After a suspension of the aniline (1.53 g, 2.81 mmol, 1.00 eq.) in dry EtOAc (20.5 mL) was cooled down to 0 °C, (2JS)-2-({[(9 / Z-fluoren-9-yl)methoxy]carbonyl}amino)pent-4-ynoic acid (1.32 g, 3.94 mmol, 1.40 eq.) and dry pyridine (770 pL, 9.56 mmol, 3.40 eq.) were added. T3P solution (50% in EtOAc, 3.35 mL, 5.62 mmol, 2.00 eq.) was added dropwise over 15 min and the resulting solution was stirred for 2.5 h at 0 °C. The reaction mixture was diluted with aq. HC1 (1 M, 30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with NaHCCh solution (30 mL) and brine (30 mL), dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by flash chromatography (petroleum ether / EtOAc). Colorless solid, 2.11 g (87%). ’H-NMR (500 MHz, CDCI3, 300 K): δ (ppm) = 10.16 (s, 1H), 8.74 (s, 1H), 8.49 (d, 1H, J = 8.9 Hz), 8.07 (d, 1H, J = 8.9 Hz), 7.98 (d, 2H, J = 8.8 Hz), 7.89 (d, 2H, J = 8.7 Hz), 7.77 (d, 2H, J = 7.5 Hz), 7.73 (d, 2H, J = 8.8 Hz), 7.69 (d, 2H, J = 8.8 Hz), 7.59 (d, 2H, J = 7.4 Hz), 7.40 (t, 2H, J = 7.5 Hz), 7.30 (t, 2H, J = 7.4 Hz), 6.14 (ddt, 1H, J = 5.9 Hz, 10.4 Hz, 17.1 Hz), 5.64 - 5.57 (m, 1H), 5.49 (dq, 1H, J = 1.4 Hz, 17.1 Hz), 5.41 (dq, 1H, J = 1.1 Hz, 10.4 Hz), 4.75 (hept., 1H, J = 6.2 Hz), 4.69 (dt, 2H, J = 1.2 Hz, 5.9 Hz), 4.57 - 4.46 (m, 3H), 4.25 (t, 1H, J = 6.7 Hz), 2.94 - 2.68 (m, 2H), 2.17 (t, 1H, J = 2.6 Hz), 1.60 (s, 9H),

[0267] 1.38 (d, 6H, J = 6.2 Hz).13C-NMR (126 MHz, CDCh, 300 K): δ (ppm) = 168.5, 165.6, 164.3, 162.8, 156.7, 149.4, 143.6, 142.3, 141.5, 141.0, 139.1, 137.6, 132.3, 130.8, 130.4, 128.3, 128.0, 127.6, 127.5, 127.3, 125.1, 121.7, 120.3, 120.2, 120.0, 119.2, 115.8, 81.0, 79.0, 76.9, 75.1, 72.5, 67.7, 54.2, 47.2, 29.8, 28.4, 23.0. Step c: (l1S')-l-r('4- Butoxy)carbonyl]phenyl}carbamoyl)-3-(prop-2-en-l- - 2-(propan-2-yloxy)phenyl]carbamoyl 1 phenyl)carbamoyl]but-3 -yn- 1 -aminium chloride

[0268] A solution of the Fmoc protected amine (1.93 g, 2.24 mmol, 1.00 eq.) in ACN (9.7 mL) was cooled down to 0 °C and diethylamine (3.64 mL, 35.2 mmol, 15.75 eq.) was added. After stirring at 0 °C was continued for 1 h, all volatiles were removed under reduced pressure. The residue was dissolved in diethylether (150 mL) and insoluble were filtered off (fritted funnel pore size 5). The amine was precipitated with HC1 (2.00 M in diethyl ether, 1.23 mL, 2.46 mmol, 1.10 eq.), the resulting hydrochloride was filtered off, washed with diethyl ether and dried in vacuo. Pale yellow solid, 1.35 g (89%). The product was obtained by removing all volatiles under reduced pressure after the reaction.

[0269] NMR data of free amine:

[0270] ‘H-NMR (700 MHz, CDC13, 300 K): 3 (ppm) = 10.17 (s, 1H), 9.96 (br s, 1H), 8.74 (s, 1H), 8.47 (d, 1H, J = 8.9 Hz), 8.04 (d, 1H, J = 8.9 Hz), 7.97 (d, 2H, J = 8.7 Hz), 7.88 (d, 2H, J = 8.6 Hz), 7.80 (d, 2H, J = 8.4 Hz), 7.72 (d, 2H, J = 8.7 Hz), 6.13 (ddt, 1H, J = 5.9 Hz, 10.4 Hz, 16.3 Hz), 5.49 (ddd, 1H, J = 1.3 Hz, 2.7 Hz, 17.1 Hz), 5.40 (dd, 1H, J = 1.1 Hz, 10.4 Hz), 4.74 (hept., 1H, J = 6.1 Hz), 4.69 (d, 2H, J = 5.9 Hz), 2.89 - 2.76 (m, 2H), 2.11 (br s, 1H), 1.59 (s, 9H), 1.37 (dd, 6H, J = 1.4 Hz, 6.1 Hz).

[0271] 13C-NMR(176 MHz, CDCI3, 300 K): δ (ppm) = 170.9, 165.5, 164.4, 162.8, 149.4, 142.3, 141.3, 139.1, 137.8, 132.3, 130.8, 129.9, 128.3, 127.6, 127.4, 121.7, 120.2, 119.5, 119.2, 115.8, 80.9, 79.5, 76.9, 75.1, 72.2, 53.8, 28.4, 24.5, 23.0.

[0272] Step d: fert-Butyl 4-(4-f4-r(2S)-2-aminopent-4-vnamido]benzamido}-2-hvdroxy-3-('propan-2- yloxy)benzamido)benzoate

[0273] The allyl ether was deprotected according to General Procedure 10. The product was purified by RP-HPLC.

[0274] Fragment B1-2

[0275]

[0276] Step a: fert-Butyl 4-(4-14-[(15',27?)-l--[r(tert-butoxy)carbonyl1amino}-2-ethenylcyclopropane amido]benzamido 1 -2-(prop-2-en- 1 -yloxy)-3-(propan-2-yloxy)benzamido)benzoate

[0277] After a suspension of the aniline (150 mg, 0.275 mmol, 1.00 eq.) in dry EtOAc (2.00 mL) was cooled down to 0 °C, (1S,2R2) -1-{[(tert-butoxy)carbonyl]amino}-2-ethenylcyclopropane-l- carboxylic acid (62 mg, 0.275 mmol, 1.00 eq.) and dry pyridine (75 pL, 0.935 mmol, 3.40 eq.) were added. T3P solution (50% in EtOAc, 327 pL, 0.550 mmol, 2.00 eq.) was added dropwise over 15 min and the resulting solution was stirred for 2.5 h at 0 °C. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with NaHCOa solution (10 mL) and brine (10 mL), dried (NaaSCU) and concentrated in vacuo. The resulting residue was purified by flash chromatography(petroleum ether / EtOAc). Colorless solid, 156 mg (75%). *H NMR (500 MHz, CDC13): δ (ppm) = 1.36 - 1.39 (m, 6H), 1.51 (s, 10H), 1.60 (s, 9H), 1.91 (s, 1H), 2.17 (q, J= 8.6 Hz, 1H), 4.69 (d, J= 5.8 Hz, 2H), 4.75 (h, .7= 6.1 Hz, 1H), 5.12 (dd, J= 10.3 Hz, 1.8 Hz, 1H), 5.30 (dd, J= 17.1 Hz, 2.0 Hz, 1H), 5.35 - 5.44 (m, 2H), 5.49 (dd, J= 17.1 Hz, 1.4 Hz, 1H), 5.64 (s, 1H), 6.09 - 6.18 (m, 1H), 7.67 (d, J= 8.7 Hz, 2H), 7.73 (d, J= 8.7 Hz, 2H), 7.86 (d, J = 8.7 Hz, 2H), 7.96 - 7.99 (m, 2H), 8.06 (d, J= 8.9 Hz, 1H), 8.48 (d, J= 9.0 Hz, 1H), 8.73 (s, 1H), 9.45 (s, 1H), 10.18 (s, 1H).I3C NMR (126 MHz, CDCI3): δ (ppm) = 20.0, 22.9 - 23.0 (m), 28.4, 28.4, 34.0, 43.1, 75.1, 80.9, 81.9, 115.8, 118.0, 119.2, 119.5, 120.2, 121.6, 127.4, 127.6, 128.3, 129.6, 130.8, 132.3, 133.5, 137.8, 139.1, 142.3, 149.4, 157.3, 162.8, 164.4, 165.6, 168.2.

[0278] Step b: Butoxy)carbonyl]phenyncarbamoyl)-3-(prop-2-en-l- yloxy)-2-(propan-2-yloxy)phenyllcarbamoyl}phenyl)carbamoyl]-2-ethenylcvclopropan-l- aminium chloride

[0279] To a solution of the Boc-protected amine (1.07 g, 1.41 mmol, 1.00 eq.) in EtOAc (2.35 mL) were added tert-Butyl acetate (573 pL, 4.24 mmol, 3.00 eq.) and HC1 in EtOAc (1.00 M, 11.3 mL, 11.3 mmol, 8.00 eq.) at 0 °C. After the reaction mixture was stirred for 40 h at 0 °C, NaOH solution (LOO M, 30 mL) was added and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with NaOH solution (0.25 M, 30 mL) and brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was used without further purification. Yellowish solid, 859 mg (93%). For the preparation of the hydrochloride, no extraction was performed and the volatiles were removed in vacuo.

[0280] Fragment Bl-3

[0281] Step a: ( 1 S.2R )- 1 - ( 14-((4- l(4-Carboxyphenyl)carbamoyl1-3 -(prop-2-en- 1 -yloxy)-2-(propan-2- yloxy)phenvBcarbamoyl)phenyl]carbamoyn-2-ethenylcyclopropan-l-aminium chloride

[0282] To the Boc-protected amine (140 mg, 0.185 mmol, 1.00 eq.) was added HC1 in Dioxane (4.00 M, 1.85 mL, 7.42 mmol, 40.0 eq.) at 0 °C and stirred for 8 hours. Afterwards, all volatiles were removed, the residue transferred on a fritted funnel, washed with Et?O (3 x 1.5 mL) and dried in vacuo. Colorless solid, 90 mg (76%).

[0283] Fragment Bl-4

[0284] Step a: tert-Butyl 4-(4-f4-r(17?,25)-l-fr(ferLbutoxy)carbonyl]amino}-2-ethenylcvclopropane amido]benzamido}-2-(prop-2-en-l-yloxy)-3-(propan-2-loxy)benzamido)benzoate After a suspension of the aniline (150 mg, 0.275 mmol, 1.00 eq.) in dry EtOAc (2.00 mL) was cooled down to 0 °C, (1R,,2S)-l-{[(terf-butoxy)carbonyl]amino}-2-ethenylcyclopropane-1- carboxylic acid (62 mg, 0.275 mmol, 1.00 eq.) and dry pyridine (75 pL, 0.935 mmol, 3.40 eq.) were added. T3P solution (50% in EtOAc, 327 pL, 0.550 mmol, 2.00 eq.) was added dropwise over 15 min and the resulting solution was stirred for 2.5 h at 0 °C. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with NaHCCb solution (10 mL) and brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by flash chromatography (petroleum ether / EtOAc). Colorless solid, 71 mg (34%).

[0285] Step b: (17?,25)-l-ir4-({4-r(4-Carboxyphenyl)carbamoyll-3-(prop-2-en-l-yloxy)-2-(propan-2- yloxy)phenyl 1 carbamoyl)phenyl]carbamoyl } -2-ethenylcyclopropan- 1 -aminium chloride

[0286] To the Boc-protected amine (68 mg, 0.090 mmol, 1.00 eq.) was added HC1 in Dioxane (4.00 M, 901 pL, 3.60 mmol, 40.0 eq.) at 0 °C and stirred for 8 hours. Afterwards, all volatiles were removed, the residue transferred on a fritted funnel, washed with EtiO (3 x 1.5 mL) and dried in vacuo. Colorless solid, 50 mg (88%).

[0287] Fragment Bl-5

[0288] Step a: Methyl (1.5,2R )- 1-{[( / er / -butoxy)carbonyl1amino}-2-ethenylcyclopropane-1- carboxylate

[0289] Under N2 atmosphere, K2CO3 (365 mg, 2.64 mmol, 2.00 eq.) and Mel (123 pL, 1.98 mmol,

[0290] 1.50 eq.) were added to a solution of (1.5,2R )-1-{[( / er / -Butoxy)carbonyl]amino}-2- ethenylcyclopropane- 1 -carboxylic acid (300 mg, 1.32 mmol, 1.00 eq.) in dry DMF (2.56 mL). After the reaction mixture was stirred for 22 h at rt, water was added to the reaction mixture and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / EtOAc). Colorless resin, 274 mg (86%). *H NMR (500 MHz, DMSO-D6): 5 (ppm) = 1.29 (dd, J= 9.4 Hz, 5.1 Hz, 1H), 1.37 (s, 9H), 1.57 (dd, J= 8.0 Hz, 5.1 Hz, 1H), 2.11 (q, J= 8.8 Hz, 1H), 3.59 (s, 3H), 5.06 (dd, J= 10.3 Hz, 2.0 Hz, 1H), 5.23 (dd, J= 17.2 Hz, 2.0 Hz, 1H), 5.61 (dt, J= 17.0 Hz, 9.6 Hz, 1H), 7.65 (s, 1H).

[0291] Step b: Methyl (kS'.27?)-l-{[ butoxy)carbonyl1amino)-2-ethvnylcvclopropane-l- carboxylate

[0292] DMAP (25 mg, 0.201 mmol, 0.20 eq.) was added to a solution of the Boc-protected amine (242 mg, 1.00 mmol, 1.00 eq.) in ACN (2.12 mL). A solution of BOC2O (657 mg, 3.01 mmol, 3.00 eq.) in ACN (955 pL) was dropwise added over 40 min. After the resulting reaction mixture was heated to 50 °C for 20 h all volatiles were removed in vacuo. The residue was dissolved in EtOAc (30 mL) and the organic layer was washed with water (10 mL) and brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was used without further purification.

[0293] The alkene (342 mg, 1.00 mmol, 1.00 eq.) was dissolved in CCI4 (5.03 mL) and the solution was cooled to 0°C. Bromine (62 pL, 1.20 mmol, 1.20 eq.) in CCI4 (1.20 mL) was dropwise added over 30 min at 0°C and stirring was continued at rt for 2.5 h. After CH2CI2 (20ml) and Na2S2O3-5H2O (174 mg, 0.701 mmol, 0.70 eq.) in water (10 mL) were added, stirring was continued for 20 min. The two phases were separated and the organic layer was washed with HC1 solution (0.1 M, 10 mL), water (10 mL) and brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was used without further purification. Brown residue, 486 mg (97%).

[0294] A solution of the crude dibromide (486 mg, 0.970 mmol, 1.00 eq.) in THF (4.05 mL) was cooled to 0°C and / BuOK in THF (1 M, 3.88 mL, 3.88 mmol, 4.00 eq.) was added. After stirring was continued for 1 h at 0°C, acetic acid (235 pL, 4.11 mmol, 4.24 eq.) was added to the reaction mixture and all volatiles were removed in vacuo at 35°C. The remaining residue was dissolved in EtOAc (30 mL) and the organic layer was washed with water (2 x 10 mL) and brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / EtOAc). Brown oil, 38 mg (11%). 'H NMR (500 MHz, DMSO-De): δ (ppm) = 1.30 - 1.32 (m, 1H), 1.36 (s, 9H), 1.70 (dd, J= 7.7 / 5.1 Hz, 1H), 2.02 (td, J= 7.7 / 4.0 Hz, 1H), 2.89 (d, J= 2.3 Hz, 1H), 3.63 (s, 3H), 7.75 (s, 1H).13C NMR (176 MHz, DMSO-D6): δ (ppm) = 17.0, 22.7, 28.1, 40.3, 51.9, 71.4, 78.5, 80.5, 155.4, 169.6.

[0295] Step c: (IS, 2R)-l-fr(ferf-Butoxy)carbonyl1 amino) -2-ethyny Icy clopropane-1 -carboxylic acid To a solution of the methyl ester (38 mg, 0.159 mmol, 1.00 eq.) in THF (476 pL) was added LiOH solution (1 M, 476 pL, 0.476 mmol, 3.00 eq.) and the resulting emulsion was stirred for 3 h at rt. Upon completion, HC1 solution (1 M, 10 mL) was added and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with HC1 solution (I M, 10 mL) and brine, dried over NaiSCU and concentrated in vacuo. The crude product was used without further purification. Colorless resin, 33 mg (93%).

[0296] Step d: tert-Butyl 4-(4-f4-r(lS,2R)-l-f [(tert-butoxyfcarbonyl] amino )-2-ethynylcyclopropane amidolbenzamido ) -2-(prop-2-en- 1 -yloxy)-3 -(propan-2-yloxy)benzamido)benzoate

[0297] A solution of crude the carboxylic acid (33 mg, 0.147 mmol, 1.00 eq.), the aniline derivative (80 mg, 0.147 mmol, 1.00 eq.) and dry pyridine (35 pL, 0.440 mmol, 3.00 eq.) in dry EtOAc (1.07 mL) was cooled to 0°C. T3P solution (50% in EtOAc, 175 pL, 0.293 mmol, 2.00 eq.) was added dropwise over 20 min and stirring was continued for 2.5 h at 0°C. Upon completion, HC1 solution (0.1 M, 10 mL) was added and extracted with EtOAc (3 x 10 mL). The organic layer was washed with HC1 solution (0.1 M, 10 mL) and brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (petroleum ether / EtOAc). Beige solid, 49 mg (44%). *H NMR (500 MHz, DMSO-De): δ (ppm) = 1.26 (d, J= 6.0 Hz, 6H), 1.39 (s, 9H), 1.54 (s, 9H), 1.92 (dd, J= 7.4 / 5.0 Hz, 1H), 2.16 (t, J= 7.5 Hz, 1H), 2.86 (d, J= 22 Hz, 1H), 4.49 (p, J= 6.1 Hz, 1H), 4.61 (d, J= 5.5 Hz, 2H), 5.20 (dq, J= 10.5 / 1.3 Hz, 1H), 5.37 6.02 (ddt, J= 17.1 / 10.7 / 5.5 Hz, 1H), 7.40 (d, J= 8.5 Hz, 1H), 7.59 (s, 1H), 7.82 (dd, J= \4,2IZ.6 Hz, 5H), 7.89 (d, J= 8.8 Hz, 2H), 7.98 (d, J = 8.8 Hz, 2H), 9.58 (s, 1H), 9.99 (s, 1H), 10.56 (s, 1H). The signal for the BoCNH proton is not seen in the spectrum.13C NMR (176 MHz, DMSO-De): δ (ppm) = 16.4, 21.2, 22.3, 27.9, 28.0, 71.4, 74.3, 76.2, 79.2, 80.3, 80.9, 117.8, 118.8, 118.9, 119.2, 123.6, 126.0, 127.1, 128.3, 128.5, 130.1, 133.7, 135.7, 142.2, 142.5, 143.0, 149.5, 155.6, 164.3, 164.5, 164.6,

[0298] 167.1.

[0299] Step e: (l£270-l-r(4-H4-(14-r(terLButoxy)carbonyl]phenyl}carbamoyl)-3-hydroxy-2-

[0300] ( propan-2 -yloxy)phenyl] carbamoyl } phenvDcarbamo yll -2-ethynylcyclopropan- 1 -aminium chloride

[0301] A solution of Boc-protected amine (79 mg, 0.105 mmol, 1.00 eq.) in dry EtOAc (205 pL) was cooled to 0°C and HC1 solution in EtOAc (1 M, 525 pL, 0.525 mmol, 5.00 eq.) was added. After the resulting mixture was stirred at 0°C for 17 h, all volatiles were removed in vacuo. The crude product was used without further purification. Off-white solid, quant, yield.

[0302] Fragment Bl-6

[0303] Step a: 2-Amino-3-methy 1-3 -nitrobutanoic acid

[0304] To a solution of KOH (14.1 g, 251 mmol, 2.20 equiv.) in H2O (280 mL), 2-nitropropane (20.0 mL, 223 mmol, 1.95 equiv.), NH3 (25% in H2O, 0.93 mol, 150 mL, 8.54 equiv.) and a solution of glyoxylic acid monohydrate (10.5 g, 114 mmol, 1.00 equiv.) in H2O (40.0 mL) were added. The mixture was stirred for 2 h at ambient temperature. Then, the reaction was terminated by adjusting the pH to 0 with cone. HC1 whereby a blue coloration of the solution appeared. The aqueous phase was washed with CH2CI2 (3x) and the solvent was removed under reduced pressure. The residue was diluted in EtOH, filtered and the filtrate was concentrated to about half under reduced pressure, mixed in equal parts with Et2O, filtered again and aniline (10-30 mL) was added to the filtrate until a turbidity of the solution appeared. The turbid solution was stored at 2-8 °C for 16 h. It was then filtered, the solid was washed with EtOH and dried under high vacuum for 16 h. 2-Amino-3-methyl-3-nitrobutanoic acid (10.0 g, 61.8 mmol, 54%) was obtained as a colorless solid. ’H-NMR (D20, 400 MHz): 84.35 (s, 1H), 1.81 (s, 3H), 1.77 (s, 3H) ppm.13C-NMR (D20, 100 MHz): 8 170.2, 88.3, 60.8, 24.6, 23.5 ppm.

[0305] Step b: 2-(f r(977-Fluoren-9-yl)methoxy]carbonynamino)-3-methyl-3-nitrobutanoic acid 2-Amino-3-methyl-3-nitrobutanoic acid (1.03 g, 6.43 mmol) was dissolved in 1,4-dioxane (30 mL) and a 10% Na2CO3 solution was added at 0 °C, followed by a solution of FmocCl (1.83 g, 7.07 mmol, 1.10 equiv) in 1 ,4-dioxane (30 mL) via a dropping funnel. The mixture was stirred for 18 h while warming to rt. Afterwards, the mixture was diluted with H2O and Et20. The aq. phase was washed with Et2O (2x), acidified with a 6 M HC1 solution and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was coevaporated with PhMe (4x), MeOH (3x) and CH2CI2 (4x) to furnish the product (1.40 g, 3.65 mmol, 57%) as colorless solid. 'H-NMR (400 MHz, DMSO-d6) = 8 13.40 (s, 1H), 8.12-8.09 (d, J= 9.9 Hz, 1H), 7.91-7.89 (d, J= 7.6 Hz, 2H), 7.73 (d, J= 6.5 Hz, 2H), 7.42 (t, J= 7.4 Hz, 2H), 7.32 (dt, J= 1.0 Hz, 7.4 Hz, 2H), 4.98 (d, J= 9.9 Hz, 1H), 4.40 (dd, J= 7.2, 10.4 Hz, 1H), 4.35-4.31 (m, 1H), 4.27-4.23 (m, 1H), 1.58 (s, 3H), 1.50 (s, 3H) ppm.13C-NMR (101 MHz, DMSO-d6) = 8 169.8, 156.6, 143.6,

[0306] 143.6, 140.7, 140.7, 127.8, 127.8, 127.1, 127.1, 125.3, 125.3, 120.2, 120.2, 88.4, 66.1, 59.2,

[0307] 46.6, 24.7, 21.1 ppm. HRMS (ESI) calculated for C20H19N2O6 [M-H]‘: 383.1243, found: 383.1244.

[0308] Step c: ferf-Butyl 4-(4-{4-r fluoren-9-yl)methoxy]carbonyI}amino)-3-methyl-3- nitrobutanamidolbenzamido 1 -2-hydroxy-3 -(propan-2-yloxy)benzamido)benzoate terf-Butyl 4-(2-(allyloxy)-4-(4-aminobenzamido)-3-isopropoxybenzamido)benzoate (100 mg, 0.18 mmol) and the acid (98.6 mg, 0.26 mmol, 1.40 equiv.) were dissolved in EtOAc (400 pL) and pyridine (45 pL, 0.55 mmol, 3.00 equiv.) was added. T3P (50% in EtOAc, 200 pL, 0.33 mmol, 1.80 equiv.) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 2 h. H2O was added and the aq. phase was extracted with EtOAc (3x). The combined organic phases were washed with a sat. NaHCOs solution, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (dry load, PE / EtOAc = 2: 1) to furnish the product (127 mg, 0.14 mmol, 76%) as yellowish solid. ’H-NMR (500 MHz, DMSO-d6) = 10.73 (s, 1H), 10.53 (s, 1H), 9.56 (s, 1H), 8.25 (d, J= 8.6 Hz, 1H), 7.99 (d, J= 8.7 Hz, 2H), 7.90-7.88 (m, 4H), 7.84-7.75 (m, 7H), 7.43-7.39 (m, 3H), 7.34-7.29 (m, 2H), 6.06-5.98 (m, 1H), 5.39-5.35 (dq, J= 1.6, 17.2 Hz, 1H), 5.21-5.17 (m, 2H), 4.60 (d, J= 5.5 Hz, 2H), 4.50 (sept, J= 6.1 Hz, 1H), 4.42-4.36 (m, 1H), 4.29-4.23 (m, 2H), 1.67 (s, 3H), 1.64 (s, 3H), 1.55 (s, 9H), 1.26 (d, J= 6.1 Hz, 6H) ppm.13C-NMR (126 MHz, DMSO- d6) = 166.8, 164.6, 164.5, 164.2, 156.2, 149.5, 143.7, 143.7, 143.0, 142.7, 141.4, 140.7, 135.6, 133.7, 130.1, 129.1, 128.5, 127.7, 127.7, 127.2, 127.1, 127.1, 126.0, 125.4, 125.4, 123.6, 120.1, 120.1, 119.4, 119.1, 118.8, 117.8, 89.0, 80.3, 76.3, 74.3, 66.2, 60.5, 46.6, 27.9, 23.2, 22.3 ppm. HRMS (ESI) calculated for CsiHssNsOnNa [M+Na]+: 934.3639; found: 934.3634.

[0309] Step d: tert-Butyl 4-(4-r4-(2-amino-3-methyl-3-nitrobutanamido)benzamido1-2-hydroxy-3- (propan-2-yloxy)benzamido } benzoate

[0310] The carbamate (400 mg, 0.44 mmol) was dissolved in piperidine (1.3 mL) and MeCN (5.3 mL) and the mixture was stirred at rt for 2 h, before it was concentrated under reduced pressure and coevaporated with MeCN (3x) to furnish the product (quant.) as yellow solid, which was used in the next step without further purification.

[0311] Fragment Bl-7

[0312] Step a: tert-Butyl 4-r4-(5-nitropyridine-2-amido)-2-(prop-2-en-l-yloxy)-3-(propan-2-yloxy) benzamido]benzoate

[0313] 100.0 mg 5 -nitropicolinic acid (0.59 mmol, 1 eq), 1.5 ml dry CH2CI2 and one drop of dry DMF were added to a dry flask under nitrogen atmosphere. The mixture was cooled to 0 °C and 0.08 ml oxalyl chloride (0.93 mmol, 1.6 eq) was slowly added to the stirring mixture. The reaction stirred for 3.5 hours. After completion, the solvent was removed under reduced pressure. The faint rose solid was dried under high vacuum. The crude product was used without further purification. Yield: 108 mg (crude).

[0314] 230 mg tert-butyl 4-(2-(allyloxy)-4-amino-3-isopropyloxybenzamido)benzoate (0.54 mmol, 1 eq) and 108 mg 5-nitropicolinoyl chloride (0.58 mmol, 1.1 eq) were added to a dry flask under nitrogen atmosphere. 4.0 ml of dry CH2Q2 was added and the mixture was cooled down to 0 °C. 0.13 ml of dry pyridine (1.61 mmol, 3.0 eq) was slowly added to the stirring mixture. The reaction was allowed to reach rt and controlled by LCMS. After completion, the reaction was quenched with 5 ml 1 M HC1 and 10 ml brine. The aqueous phase was extracted with 3 x 5 ml EtOAc. The organic solvent was removed under reduced pressure and the crude product was used for further reactions. Yield: 310 mg (crude).

[0315] Step b: tert-Butyl 4-(2-(allyloxy)-4-(5-aminopicolinamido)-3-isopropoxybenzamido)benzoate 310 mg crude tert-butyl 4-(2-(allyloxy)-3-isopropoxy-4-(5-nitropicolinamido)benzamido) benzoate (0.54 mmol, 1 eq) was dissolved in 2.4 ml THF and 2.0 ml ethanol and cooled down to 0 °C. 528.0 mg zinc dust (8.07 mmol, 15.0 eq) was added. 0.48 ml acetic acid (8.4 mmol, 15.6 eq) was added to the stirring mixture over the timespan of 30 minutes and the mixture was allowed to reach rt. The reaction was controlled by LCMS. After completion, the zinc dust was filtered off. 30 ml sat. NaHCCh solution was added to the solution and the aqueous phase was extracted with 3 x 18 ml EtOAc. The organic phases were combined and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (petroleum ether / EtOAc). Yield: 178 mg (60% over 2 steps). ’H-NMR (500 MHz, CDCI3, 300 K): δ (ppm) = 10.65 (s, 1H), 10.25 (s, 1H), 8.54 (d, 1H, J = 8.9 Hz), 8.09 - 8.04 (m, 3H), 7.98 (d, 2H, J = 8.8 Hz), 7.74 (d, 2H, J = 8.8 Hz), 7.08 (dd, 1H, J = 2.8 Hz, 8.4 Hz), 6.15 (ddt, 1H, J = 5.9 Hz, 10.4 Hz, 16.3 Hz), 5.49 (dd, 1H, J = 1.4 Hz, 17.1 Hz), 5.39 (dd, 1H, J = 1.2 Hz, 10.4 Hz), 4.73 (d, 2H, J = 5.9 Hz), 4.65 (hept., 1H, J = 6.1 Hz), 4.14 (br s, 2H), 1.60 (s, 9H), 1.42 (d, 6H, J = 6.2 Hz).l3C-NMR (126 MHz, CDCI3, 300 K): δ (ppm) = 165.6, 163.0, 162.8, 149.9, 145.6, 142.5, 140.2, 139.5, 138.2, 135.4, 132.6, 130.8, 127.6, 127.3, 123.9, 121.3, 121.0, 120.0, 119.1, 115.4, 80.9, 75.0, 28.4, 22.7. HRMS (ESI) calculated 547.2557 [M+H+], 547.2552 found.

[0316] Step c and d: tert-butyl 4-(4-{5-ft21S)-2-Aminopent-4-ynamido]pyridine-2-amido}-2-(prop-2- en-l-yloxy)-3-(propan-2-yloxy)benzamido)benzoate The aniline (0.18 mmol) was coupled with (25)-2-({[(9 / / -Fluoren-9-yl)methoxy]carbonyl} amino)pent-4-ynoic acid using General Procedure 5 and deprotected with General Procedure 6. Off-white solid, 100 mg (71% over 2 steps). ‘H-NMR (500 MHz, CDC13, 300 K): δ (ppm) = 10.72 (d, 1H, J = 2.6 Hz), 10.23 (s, 1H), 9.96 (br s, 1H), 8.91 (s, 1H), 8.50 - 8.46 (m, 1H), 8.23 - 8.19 (m, 1H), 8.18 - 8.14 (m, 1H), 8.03 - 7.99 (m, 1H), 7.97 - 7.93 (m, 2H), 7.73 - 7.69 (m, 2H), 6.19 - 6.10 (m, 1H), 5.52 - 5.46 (m, 1H), 5.41 - 5.37 (m, 1H), 4.73 (d, 2H, J = 5.9 Hz), 4.68 - 4.61 (m, 1H), 3.71 - 3.66 (m, 1H), 2.83 - 2.73 (m, 2H), 2.10 - 2.08 (m, 1H), 1.58 - 1.56 (m, 9H), 1.42 - 1.38 (m, 6H).13C-NMR (126 MHz, CDC13, 300 K): δ (ppm) = 171.8, 165.5, 162.9, 161.9, 149.8, 145.0, 142.3, 139.5, 139.4, 137.7, 137.2, 132.4, 130.7, 127.4, 127.3, 127.0, 123.2, 121.3, 120.0, 119.1, 115.3, 80.9, 79.6, 76.6, 74.9, 72.0, 53.8, 28.3, 24.6, 22.7. HRMS (ESI) calculated 642.2928 [M+H+], 642.2923 found.

[0317] Fragment B1-8

[0318] Step a: fert-Butyl 4-(4-{5-l cyclopropyl-2-(f r(9H-fIuoren-9-yl)methoxy1carbonyl} amino)propanamidolpyridine-2-amido I -2-hydroxy-3 -(propan-2-yloxy)benzamido)benzoate The aniline derivative (200 mg, 0.37 mmol) and (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl) amino)-3 -cyclopropylpropanoic acid (180 mg, 0.51 mmol, 1.40 equiv.) were dissolved in EtOAc (800 pL) and pyridine (90 pL, 1.10 mmol, 3.00 equiv.) was added. T3P (50% inEtOAc, 392 pL, 0.66 mmol, 1.80 equiv.) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 2 h. H2O was added and the aq. phase was extracted with EtOAc (3x). The combined organic phases were washed with a sat. NaHCOs solution, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (dry load, Petrolum ether / EtOAc = 1 : 1) to furnish the product (313 mg, 0.36 mmol, 97%) as yellow solid. ‘H-NMR (600 MHz, DMSO-d6) = 8 10.68 (s, 1H), 10.67 (s, 1H), 10.48 (s, 1H), 9.02-8.98 (m, 1H), 8.34 (d, J= 8.6 Hz, 1H), 8.29 (dd, J= 2.3 Hz, 8.6 Hz, 1H), 8.19 (d, J= 8.6 Hz, 1H), 7.90-7.88 (m, 4H), 7.84-7.82 (m, 3H), 7.75 (t, J= 7.7 Hz, 2H), 7.48 (d, J= 8.6 Hz, 1H), 7.42 (td, J= 3.3, 7.4 Hz, 2H), 7.33 (t, J= 7.4 Hz, 2H), 6.05-5.99 (m, 1H), 5.38 (dq, J= 1.6, 17.2 Hz, 1H), 5.21 (dq, J= 1.6, 10.5 Hz, 1H), 4.65 (sept, J = 6.1 Hz, 1H), 4.61 (d, J= 5.5 Hz, 2H), 4.34- 4.23 (m, 4H), 1.81-1.76 (m, 1H), 1.55 (s, 9H), 1.48-1.44 (m, 1H), 1.36 (dd, J= 6.2, 8.8 Hz, 6H), 0.86-9.81 (m, 1H), 0.47-0.37 (m, 2H), 0.19-0.09 (m, 2H) ppm.13C-NMR (151 MHz, DMSO- d6) = 172.3, 164.6, 164.3, 161.1, 156.1, 149.3, 143.8, 143.8, 143.3, 143.0, 140.7, 139.4, 139.3, 138.8, 135.5, 133.5, 130.1, 127.6, 127.6, 127.1, 126.0, 125.8, 125.3, 124.6, 122.9, 120.1, 120.1, 118.8, 118.0, 113.8, 80.3, 76.3, 74.3, 65.7, 56.2, 46.7, 36.4, 27.9, 22.3 (d, J= 9.2 Hz), 7.9, 4.6, 3.9 ppm. HRMS (ESI) calculated for CsiHssNsOgNa [M+Na]+: 902.3741; found: 902.3748.

[0319] Step b: fert-Butyl 4-(4-f5-r(2 )-2-amino-3-cvclopropylpropanamido1pyridine-2-amido}-2- hydroxy-3-(propan-2-yloxy)benzamido)benzoate

[0320] The carbamate (305 mg, 0.35 mmol) was dissolved in MeCN (4 mL) and piperidine (1 mL) was added. The mixture was stirred at rt for 90 min, before it was concentrated under reduced pressure. The residue was coevaporated with MeCN (3x) to furnish the product, which was used in the next step without further purification.

[0321] Fragment Bl-9

[0322]

[0323] Step a: Prop-2-en-l-yl 4-[4-(5-nitropyridine-2-amido)-2-(prop-2-en-l-yloxy -3-(propan-2- yloxy)benzamido]benzoate

[0324] 5 -Nitropicolinic acid (110 mg, 1.0 eq.) was filled in a Schlenk flask and a solution of DMF in CH2CI2 (10 mM, 3.3 mL) was added under Schlenk conditions. To the suspension oxalyl chloride (59 pL, 1.05 eq.) was added in counterflow. The mixture was stirred for 1.5 h at rt while being screened with LCMS (a MeOH quench of the sample was applied). After 1.5 h a solution of allyl 4-[2-(allyloxy)-4-amino-3-isopropoxybenzamido]benzoate (256 mg, 0.95 eq.) and dry pyridine (126 pL, 2.5 eq.) in dry CH2CI2 (3.1 mL) was added dropwise and the mixture was stirred further at rt while being monitored with LCMS. The mixture was quenched after 1 h by adding brine (30 mL). The aqueous phase was extracted with EtOAc(3 x 20 mL) before drying the combined organic phases over Na2SCU and removing solvent under reduced pressure and by coevaporation with acetone / heptane. The crude product was used without further purification. Yellow solid, 318 mg (91%).!H NMR (500 MHz, CDCI3): 8(ppm) = 10.78 (s, 1H), 10.27 (s, 1H), 9.51 (d, J= 2.6 Hz, 1H), 8.73 (dd, J= 8.5, 2.4 Hz, 1H), 8.54 (d, J= 8.9 Hz, 2H), 8.10 (d, J = 8.9 Hz, 1H), 8.07 (d, J= 8.7 Hz, 2H), 7.77 (d, J= 8.7 Hz, 2H), 6.16 (ddt, J= 16.3, 10.4, 5.8 Hz, 1H), 6.05 (ddt, J= 17.4, 10.7, 5.6 Hz, 1H), 5.52 (dq, J = 17.2, 1.6 Hz, 1H), 5.46 - 5.38 (m, 2H), 5.30 (dq, J= 10.4, 1.4 Hz, 1H), 4.82 (dt, J= 5.6, 1.4 Hz, 2H), 4.78 - 4.70 (m, 3H), 1.44 (d, J= 6.3 Hz, 6H).13C NMR (126 MHz, CDC13): 8(ppm) = 166.0, 162.7, 159.9, 154.0, 149.8, 145.9, 144.1, 142.8, 139.9, 136.8, 133.3, 132.5, 132.3, 131.1, 127.7, 125.5, 123.4,

[0325] 122.4, 120.3, 119.3, 118.3, 115.6, 75.1, 65.6, 22.8.

[0326] Step b: Prop-2-en-l-yl 4-r4-(5-aminopyridine-2-amido)-2-(prop-2-en-l-yloxy)-3-(propan-2- yloxy)benzamido1benzoate

[0327] The nitropyridine (223 mg, 1.0 eq.) was dissolved in THF / EtOH (2.0 mL / 1.0 mL) and AcOH (0.46 mL, 20 eq.) and Zn dust (260 mg, 10 eq.) were added. The mixture was stirred vigorously for 1 h while being screened with LCMS. Sat. NaHCO3 solution (100 mL) and EtOAc(50 mL) were added, the mixture was filtered through a pore size 4 fritted funnel and the aqueous phase was extracted with EtOAc (3 x 30mL). The combined organic phases were dried over NazSO4 and solvents were removed under reduced pressure. The crude product was purified by flash column chromatography (solid loading, Petroleum ether / EtOAc, 40% -> 50% EtOAc). Pale yellow amorphous solid, 121 mg (57%). *H NMR (700 MHz, CDCI3): δ(ppm)= 10.72 - 10.35 (m, 1H), 10.29 - 10.20 (m, 1H), 8.55 - 8.42 (m, 1H), 8.38 - 8.23 (m, 1H), 8.12 - 7.97 (m, 4H), 7.79 - 7.67 (m, 2H), 7.32 (s, 1H), 6.18 - 6.10 (m, 1H), 6.04 (ddt, J= 17A, 10.4, 5.6 Hz, 1H), 5.52 - 5.46 (m, 1H), 5.44 - 5.37 (m, 2H), 5.30 - 5.26 (m, 1H), 4.83 - 4.77 (m, 2H), 4.76 - 4.69 (m, 2H), 4.68 - 4.62 (m, 1H), 1.48 - 1.35 (m, 6H).13C NMR (176 MHz, CDCI3): δ(ppm) = 166.0, 163.0, 161.9 (br s), 149.9, 144.7, 142.9, 139.6, 137.8, 135.6 (br s), 132.5, 131.1, 127.5,

[0328] 125.4, 124.0, 123.2 (br s), 121.3, 120.0, 119.3, 118.3, 115.6, 75.0, 65.6, 22.8.

[0329] Step c: Prop-2-en-1-yl 4-(4-f5-f(l1S',27?)-l-f r(terf-butoxy)carbonyl1amino}-2- ethenylcyclopropaneamido]pyridine-2-amido}-2-(prop-2-en-l-yloxy)-3-(propan-2-yloxy) benzamido)benzoate

[0330] The amine (50 mg, 1.0 Eq.), (1S,2R )-1-((terbutoxycarbonyl)amino)-2-vinylcyclopropane-l- carboxylic acid (22.5 mg, 1.05 eq.) and DMAP (1.3 mg, 0.11 eq.) were suspended in EtOAc (1.0 mL). Pyridine (22.8 pL, 3.0 eq.), and T3P (50% in EtOAc, 84.1 pL, 1.5 eq.) were added and the solution was stirred at rt while being monitored with TLC. After 3 days, HC1 solution was added to adjust the pH to 2-3 and the mixture was extracted with EtOAc (3 x 15 mL). The combined organic phases wzere dried over Na2SO4 and solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (solid loading, Petroleum ether / EtOAc, 40% EtOAc). Off white solid, 26 mg (37%). *H NMR (700 MHz, CDCh): 8 = 10.70 (s, 1H), 10.29 (s, 1H), 9.66 (br s, 1H), 8.83 (s, 1H), 8.51 (d, J= 8.8 Hz, 1H), 8.23 (d, J= 8.5 Hz, 1H), 8.08 - 8.03 (m, 4H), 7.76 (d, J= 8.8 Hz, 2H), 6.16 (ddt, J= 17.2, 10.3, 5.9 Hz, 1H), 6.05 (ddt, J= 17.2, 10.4, 5.6 Hz, 1H), 5.59 (br s, 1H), 5.56 (br s, 1H), 5.51 (dq, J = 17.1, 1.5 Hz, 1H), 5.44 - 5.38 (m, 2H), 5.33 - 5.27 (m, 2H), 5.12 (dd, J= 10.3, 1.6 Hz, 1H), 4.82 (dt, J= 5.6, 1.5 Hz, 2H), 4.75 (d, J= 5.8 Hz, 2H), 4.66 (hept, J= 6.1 Hz, 1H), 2.19 (q, J= 8.3 Hz, 1H), 1.52 (s, 9H), 1.42 (dd, J = 6.1, 2.0 Hz, 6H), 1.35 - 1.19 (m, 2H, overlay with impurity).13C NMR (176 MHz, CDC13): 8 = 168.4, 166.0, 163.0, 161.9, 157.7 (br s), 149.9, 144.7, 142.9, 139.6, 139.4, 138.1, 137.8, 133.2, 132.5, 132.5, 131.1, 127.5, 127.2, 125.4, 123.3, 121.3, 120.0, 119.3, 118.3, 118.3, 115.5, 82.1, 77.0, 75.0, 65.6, 43.1, 32.0, 29.1, 28.4, 22.7.

[0331] Step d: (kS',2R )-2-Ethenyl-l-r(6-H3-(prop-2-en-l-yloxy)-4-(f4-r(prop-2-en-l-yloxy)carbonyll phenyl } carbamoyl)-2-(propan-2-yloxy)phenyl]carbamoyl } pyridin-3 -y1carbamoy 1] cyclopropan-l-aminium chloride

[0332] Under argon atmosphere, the carbamate (26 mg, 1.0 eq.) was dissolved in a solution of HC1 in dioxane (4 M, 0.80 mL). The reaction mixture was stirred at rt while being continuously screened by TLC. After 30 min, all volatiles were removed under reduced pressure. The crude product was used without further purification. Off white solid, quant, yield.

[0333] Fragment B1 -10

[0334] Step a: tert-Butyl 4-(4-{5-r(lS,270-l-fr(terbutoxy)carbonyl]amino}-2-ethenylcyclopropane amido]pyridine-2-amido}-2-(prop-2-en-l-yloxy)-3-(propan-2-yloxy)benzamido)benzoate

[0335] The aniline (200 mg, 0.37 mmol) and (1S,2R?)-1-{[(tert-Butoxy)carbonyl]amino}-2- ethenylcyclopropane-1 -carboxylic acid (116 mg, 0.51 mmol, 1.40 equiv.) were dissolved in EtOAc (800 pL) and pyridine (90 pL, 1.10 mmol, 3.00 equiv.) was added. T3P (50% inEtOAc, 400 JJ.L, 0.66 mmol, 1.80 equiv.) was added at 0 °C and the mixture was stirred for 3 h while warming to rt. H2O was added and the aq. phase was extracted with EtOAc (2x). The combined organic phases were washed with a sat. NaHCOa solution, brine, dried over MgSO 4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Petroluem ether / EtOAc = 1 : 1) to furnish the product (186 mg, 0.25 mmol, 67%) as yellowish solid. ‘H-NMR (600 MHz, DMSO-d6) 8 = 10.70 (s, 1H), 10.48 (s, 1H), 10.36-10.25 (m, 1H), 9.03 (bs, 1H), 8.35-8.34 (d, J= 8.8 Hz, 2H), 8.17 (d, J= 8.8 Hz, 1H), 7.89 (d, J= 8.8 Hz, 2H), 7.83 (d, .j= 8.8 Hz, 2H), 7.54 (bs, 0.6H), 7.48 (d, J= 8.5 Hz, 1H), 7.23 (bs, 0.3H), 6.05-5.99 (m, 1H), 5.70-5.59 (m, 1H), 5.39 (dq, 1.6, 17.2 Hz, 1H), 5.25-5.20 (m, 2H), 5.05 (dd, J= 1.8, 10.4 Hz, 1H), 4.66 (sept, J= 6.1 Hz, 1H), 4.62 (d, J= 5.5 Hz, 2H), 2.34-2.29 (m, 1H), 1.80 (bs, 1H), 1.55 (s, 9H), 1.41-1.32 (m, 9H), 1.37 (dd, J= 2.6, 6.1 Hz, 6H), 1.26 (bs, 1H) ppm.13C-NMR (151 MHz, DMSO-d6) 5 = 169.5, 164.6, 164.3, 161.1, 155.6, 149.3, 143.3, 143.0, 140.0, 139.4, 138.8, 135.5, 134.3, 133.5, 130.1, 127.7, 126.0, 125.7, 124.6, 122.7, 118.8, 118.0, 117.2, 113.8, 80.3, 78.9, 76.3, 74.3, 42.4, 32.6, 28.1, 27.8, 22.3 (d, J= 2.7 Hz), 21.8 ppm. HRMS (ESI) calculated for CznHwNsCkNa [M+Na]+: 778.3428; found: 778.3441.

[0336] Step b: tert-Butyl 4-(4-f5-l(lS,27if)-l-amino-2-ethenylcyclopropaneamido]pyridine-2-amido}- 2-(prop-2-en- 1 -yloxy)-3-(propan-2-yloxy)benzamido)benzoate

[0337] The carbamate (177 mg, 0.23 mmol) was dissolved in HC1 (4 M in 1,4-dioxane, 5.90 mL, 23.4 mmol, 100 equiv.) at 0 °C. The mixture was warmed up to rt and stirred for 15 min. The solution was transferred to a stirred emulsion of EtOAc (150 mL) and sat. NaHCOa solution (150 mL). The aq. phase was extracted with EtOAc (3x) and the combined organic phases were washed with brine, dried over MgSO< and concentrated under reduced pressure. The crude product was used in the next step without further purification.

[0338] Fragment B1-11

[0339]

[0340] Step a: tert-Butyl 4-(4-(4-r(2Y37G-3-( / e / 7-butoxy)-2-( R(977-fluoren-9-yl)methoxy]carbonyl} amino)butanamido1benzamido}-2-(prop-2-en-l-yloxy)-3-(propan-2-yloxy)benzamido) benzoate

[0341] The aniline (0.37 mol) was coupled with (25,,37?)-3-(fer / -Butoxy)-2-({[(97 / -fluoren-9- yl)methoxy] carbonyl }amino)butanoic acid using General Procedure 5. Yellowish solid, 312.5 mg (92%). ‘H-NMR (700 MHz, CDC13, 300 K): δ (ppm) = 10.18 (s, 1H), 9.48 (br s, 1H), 8.76 (br s, 1H), 8.52 (d, 1H, J = 8.9 Hz), 8.09 (d, 1H, J = 8.9 Hz), 8.00 (d, 2H, J = 8.7 Hz), 7.92 (d, 2H, J = 8.7 Hz), 7.79 (d, 2H, J = 7.6 Hz), 7.75 (d, 2H, J = 8.7 Hz), 7.68 (d, 2H, J = 8.7 Hz), 7.64 (d, 2H, J = 7.3 Hz), 7.43 (t, 2H, J = 7.2 Hz), 7.34 (t, 2H, J = 7.8 Hz), 6.15 (ddt, 1H, J = 5.9 Hz, 10.4 Hz, 16.3 Hz), 6.04 (d, 1H, J = 5.0 Hz), 5.51 (dq, 1H, J = 1.4 Hz, 17.1 Hz), 5.42 (dq, 1H, J = 1.1 Hz, 10.4 Hz), 4.77 (hept., 1H, J = 6.2 Hz), 4.71 (dt, 2H, J = 1.2 Hz, 5.9 Hz), 4.46 (d, 2H, J = 7.0 Hz), 4.38 (t, 1H, J = 4.3 Hz), 4.32 - 4.29 (m, 1H), 4.27 (t, 1H, J = 7.1 Hz), 1.61 (s, 9H), 1.42 - 1.39 (m, 15H), 1.12 (d, 6H, J = 6.4 Hz).13C-NMR (176 MHz, CDCI3, 300 K): δ (ppm) = 168.2, 165.6, 164.3, 162.8, 156.2, 149.4, 144.0, 143.8, 142.3, 141.5, 141.3, 139.1, 137.7, 132.3, 130.8, 130.0, 128.4, 127.9, 127.7, 127.4, 127.2, 125.3, 121.7, 120.2, 120.2, 119.6, 119.2, 115.8, 80.9, 76.9, 75.1, 67.1, 59.3, 47.3, 28.6, 28.4, 23.0.

[0342] Step b: terZ-Butyl 4-(4-{4-r(2S,3R )-2-amino-3-(terA-butoxy)butanamidolbenzamido}-2-(prop- 2-en- 1 -yloxy)-3-(propan-2-yloxy)benzamido)benzoate

[0343] The amino acid derivative (99.6 pmol) was deprotected using General Procedure 6. The crude product was used without further purification.

[0344] Fragment Bl-12

[0345]

[0346] Step a: tert-Butyl 4-(4-f4-r(2£3S3-3-(te^butoxy)-2-({r(97 / -fhioren-9-yl)methoxy]carbonvH amino)butanamido]benzamido } -2-(prop-2-en- 1 -yloxy)-3 -(propan-2 -yloxy)benzamido) benzoate

[0347] The aniline (0.18 mol) was coupled with (2S,35')-3-(tert-butoxy)-2-({[(9 / 7-fluoren-9-yl) methoxy]carbonyl}amino)butanoic acid using General Procedure 5. Yellowish solid, 124.9 mg (74%). ‘H-NMR (700 MHz, CDC13, 300 K): 5 (ppm) = 10.17 (s, 1H), 8.74 (s, 1H), 8.50 (d, 1H, J = 8.9 Hz), 8.27 (br s, 1H), 8.07 (d, 1H, J - 8.9 Hz), 7.98 (d, 2H, J = 8.7 Hz), 7.90 (d, 2H, J = 8.7 Hz), 7.77 (dd, 2H, J = 2.7 Hz, 7.5 Hz), 7.73 (d, 2H, J = 8.8 Hz), 7.70 (d, 2H, J = 8.7 Hz), 7.61 - 7.58 (m, 2H), 7.40 (td, 2H, J = 2.7 Hz, 7.4 Hz), 7.30 (t, 2H, J = 7.3 Hz), 6.14 (ddt, 1H, J = 5.9 Hz, 10.4 Hz, 16.3 Hz), 5.49 (ddd, 1H, J = 1.4 Hz, 2.7 Hz, 17.1 Hz), 5.41 (ddd, 1H, J = 1.0 Hz, 2.1 Hz, 10.4 Hz), 4.76 (hept., 1H, J = 6.1 Hz), 4.69 (d, 2H, J = 5.9 Hz), 4.52 (dd, 1H, J = 7.0 Hz, 10.6 Hz), 4.46 - 4.42 (m, 1H), 4.24 (t, 1H, J = 6.8 Hz), 3.97 - 3.91 (m, 1H), 1.60 (s, 9H), 1.39 (dd, 6H, J = 1.6 Hz, 6.2 Hz), 1.19 (s, 9H).13C-NMR (176 MHz, CDCI3, 300 K): 8 (ppm) = 165.6, 164.3, 162.8, 149.4, 143.9, 143.8, 142.3, 141.5, 141.1, 139.1, 137.7, 132.3, 130.8, 130.1, 128.4, 127.9, 127.6, 127.4, 127.3, 125.1, 121.7, 120.2, 119.6, 119.2, 115.8, 80.9, 75.4, 75.1, 47.3, 28.6, 28.4, 23.0.

[0348] Step b: fer / -Butyl 4-(4-(4-r(2>S,.3S)-2-amino-3-(fert-butoxy)butanamidolbenzamido}-2-(prop- 2-en- 1 -yloxy)-3-(propan-2-yloxy)benzamido)benzoate

[0349] The amino acid derivative (129.3 pmol) was deprotected using General Procedure 6. The crude product was used without further purification.

[0350] Fragment B1-14

[0351]

[0352] Step a: 1,4-Dimethyl 2,3-dihydroxybenzene-l,4-dicarboxylate

[0353] 1 g 2,3-dihydroxyterephthalic acid (5.05 mmol, 1 eq) was added to a dry vial and further dried at high vacuum. 20 ml dry methanol (494.4 mmol, 98 eq.) was added under argon atmosphere and the solution was cooled down to 0 °C. 2 ml chlorotrimethylsilane (15.8 mmol, 3.1 eq.) was slowly added under argon atmosphere at 0 °C. The reaction was stirred overnight and controlled by LCMS. After completion, the solvent was removed under reduced pressure. The crude product was purified by flash chromatography. Colorless solid, 887 mg (78 %). ’H-NMR (500 MHz, CDC13, 300 K): 5 (ppm) = 10.92 (br s, 2H), 7.33 (br s, 2H), 3.98 (s, 6H).13C-NMR (126 MHz, CDCI3, 300 K): 5 (ppm) = 170.3, 151.7, 118.5, 116.0, 52.9.

[0354] Step b and c: 2-Hydroxy-4-(methoxycarbonyl -3-(propan-2-yloxy)benzoic acid

[0355] 400 mg dimethyl 2,3-dihydroxyterephthalate (1.77 mmol, 1 eq.) and 510 mg triphenylphosphine (1.94 mmol, 1.1 eq.) were added to a dry flask and further dried under high vacuum. 4.0 ml dry THF and 0.27 ml dry isopropanol (3.53 mmol, 2 eq.) were added under argon atmosphere and the solution was cooled down to 0 °C. 0.38 ml DIAD (1.93 mmol, 1.1 eq.) was added dropwise under argon atmosphere. The reaction was slowly warmed up to rt and stirred overnight. After completion, the reaction was concentrated under reduced pressure. The crude product was purified by flash chromatography.

[0356] 1,090 mg nicotinic acid (8.85 mmol, 5 eq.) and 246 mg potassium carbonate (1.78 mmol, 1 eq.) were added to a flask. 4.8 ml DMF was added and the mixture was stirred at 110 °C for 30 minutes. The crude diester (1 eq.) from the former reaction was dissolved in 3.7 ml DMF and added to the mixture. The reaction was stirred for 72 h at 110 °C and controlled by LCMS. After completion, 18 ml I M HC1 and 70 ml brine were added and extracted with 3 x 30 ml EtOAc. The combined organic layers were concentrated under reduced pressure. The crude product was purified by flash chromatography with Petroleum ether : EtOAc + 2 % AcOH. Yellowish solid, 240 mg (54% over 2 steps). *H-NMR (500 MHz, DMSO-de, 300 K): 5 (ppm) = 11.73 (br s, 1H), 7.56 (d, 1H, J = 8.3 Hz), 7.06 (d, 1H, J = 8.3 Hz), 4.53 (hept., 1H, J = 6.2 Hz), 3.82 (s, 3H), 1.19 (d, 6H, J = 6.2 Hz).13C-NMR (126 MHz, DMSO-d6, 300 K): 5 (ppm) = 171.9, 166.3, 155.6, 144.4, 131.7, 124.2, 118.4, 116.1, 75.2, 52.3, 22.2.

[0357] Step d: Methyl 4-({4-r(tert-butoxy)carbonyl1phenvncarbamoyl)-3-hydroxy-2-(propan-2- yloxy)benzoate

[0358] The benzoic acid (131 mg, 1.0 eq.) and tert-butyl 4-aminobenzoate (149 mg, 1.5 eq.) were suspended in dry toluene (1.3 mL) under argon atmosphere and P(OPh)3 (0.18 mL, 1.3 eq.) was added. The reaction was refluxed for 24 h and the mixture was directly purified by flash column chromatography (solid loading, Petroleum ether / EtOAc, 10% EtOAc-> 15% -> 20%). Yield: 168 mg (76%). *H NMR (500 MHz, CDC13): 8(ppm) = 9.27 (s, 1H), 9.22 (s, 1H), 8.00 (d, J = 9.0 Hz, 2H), 7.72 (d, J= 9.0 Hz, 2H), 7.71 (d, J= 8.5 Hz, 2H), 7.40 (d, J= 8.5 Hz, 1H), 4.54 (hept, J= 6A Hz, 1H), 3.94 (s, 3H), 1.60 (s, 9H), 1.36 (d, J= 6.1 Hz, 6H).13C NMR (126 MHz, CDCI3): 8(ppm) = 166.0, 165.4, 164.6, 151.7, 145.8, 141.3, 130.8, 130.2, 128.2, 123.3, 121.4, 120.3, 119.8, 81.2, 78.7, 52.6, 28.4, 22.5.

[0359] Step e: Methyl 4-(f4-r(tert-butoxy)carbonyl]phenyl}carbamoyl)-3-(prop-2-en-l-yloxy)-2- (propan-2-yloxy)benzoate

[0360] The phenol (162 mg, 1.0 eq.) and K2CO3 (104 mg, 2.0 eq.) were suspended in dry DMF (1.9 mL) under argon atmosphere. The suspension was stirred for 10 min before allyl bromide (36 pL, 1.1 eq.) was added and stirring was continued at rt while being screened with LCMS. After 5h, the reaction mixture was partitioned between EtOAc / HCl (0.1 M) (30 mL each) and the aqueous phase was extracted with EtOAc(2 x 20 mL). The organic phases were combined, dried over Na2SC>4 and the volatiles were removed under reduced pressure. The crude product was used without further purification. Yellowish oil, 186 mg.

[0361] Step f: 4-(f4-r(ferr-Butoxy)carbonyl1phenyl}carbamoyl)-3-(prop-2-en-l -yloxy)-2-(propan-2- yloxy)benzoic acid

[0362] The crude methyl ester and LiOH-FEO (63 mg, 4.0 eq.) were dissolved in a THF / H2O (1.3 mL each) forming a 2-phase system. The reaction was stirred at rt while being monitored by LCMS. After 3 h, the mixture was partitioned between EtOAc / HCl (0.1 M) (20 mL each) and the aqueous phase was extracted with EtOAc(2 x 20 mL). The organic phases were combined and dried over Na2SO4 before removing all volatiles under reduced pressure. The crude product was purified by flash column chromatography (solid loading, Petroleum ether / EtOAc / AcOH, 80 / 15 / 5). Colorless fluffy solid, 115 mg (67% over 2 steps). ’H NMR (500 MHz, Acetone): 8(ppm) = 11.50 (br s, 1H), 10.23 (s, 1H), 7.97 (d, J = 8.7 Hz, 2H), 7.87 (d, J = 9.0 Hz, 2H), 7.75 (d, J= 8.2 Hz, 1H), 7.69 (d, J= 8.2 Hz, 1H), 6.17 (ddt, J= 17.2, 10.4, 5.8 Hz, 1H), 5.51 (dq, J= 17.2, 1.6 Hz, 1H), 5.31 (dq, J= 10.4, 1.2 Hz, 1H), 4.76 (dt, J= 5.8, 1.4 Hz, 2H), 4.75 - 4.68 (m, 1H), 1.59 (s, 9H), 1.33 (d, J= 6.1 Hz, 6H).13C NMR (126 MHz, Acetone): 8(ppm) = 166.4, 165.6, 163.8, 151.5, 151.4, 143.5, 134.1, 133.4, 131.2, 131.1, 130.2, 128.2, 126.8, 125.5, 120.1, 119.9, 119.8, 119.3, 81.1, 78.4, 75.8, 28.3, 22.6.

[0363] Step g: tert-Butyl 4-{4-r(4-amino-2-fluorophenyl)carbamoyll-2-(prop-2-en-l-yloxy)-3- (propan-2-y loxy)benzamido } benzoate

[0364] The carboxylic acid (142.7 pmol) was coupled with 2-fluoro-4-nitroaniline using General Procedure 14 and reduced by General Procedure 15. Orange solid, 60.2 mg (75% over 2 steps). ‘H-NMR (500 MHz, ACN-d3, 300 K): δ (ppm) = 9.86 (br s, 1H), 9.73 (br s, 1H), 7.98 - 7.95 (m, 3H), 7.90 (d, 1H, J = 8.4 Hz), 7.80 - 7.76 (m, 3H), 6.52 (dd, 1H, J = 2.4 Hz, 13.2 Hz), 6.50 - 6.46 (m, 1H), 6.12 (ddt, 1H, J = 5.8 Hz, 10.5 Hz, 17.1 Hz), 5.46 (dq, 1H, J = 1.5 Hz, 17.2 Hz), 5.30 (ddd, 1H, J = 1.1 Hz, 2.6 Hz, 10.5 Hz), 4.88 (hept., 1H, J = 6.2 Hz), 4.71 (dt, 2H, J = 1.3 Hz, 5.8 Hz), 4.33 (br s, 2H), 1.57 (s, 9H), 1.35 (d, 6H, J = 6.2 Hz).13C-NMR (126 MHz, ACN- d3, 300 K): δ (ppm) = 166.0, 163.9, 163.1, 155.6 (d, J = 240.8 Hz), 151.2, 150.1, 147.4 (d, J = 11.1 Hz), 143.3, 134.0, 133.1, 132.7, 131.3, 128.4, 126.9, 126.1, 125.2 (d, J = 2.9 Hz), 120.1, 119.6, 116.5 (d, J = 11.3 Hz), 110.9 (d, J = 2.5 Hz), 102.0 (d, J = 23.1 Hz), 81.6, 79.0, 75.9, 28.3, 22.3.19F-NMR (470 MHz, ACN-d3, 300 K): 5 (ppm) = -128.3 - -128.4 (m).

[0365] Step h: fe / 7-Butyl 4-r4-({4-r(2&3R)-3-(terbutoxy)-2-(H(9H -fluoren-9-yl)methoxy]carbonyl} amino)butanamido]-2-fluorophenYl}carbamoyl)-2-(prop-2-en-l-yloxy)-3-(propan-2-yloxy) benzamidolbenzoate

[0366] The aniline (0.27 mol) was coupled with (2S,37?)-3-(ter / -butoxy)-2-({[(977-fluoren-9- yl)methoxy] carbonyl }amino)butanoic acid using General Procedure 5. Yellow solid, 227.0 mg (90%). ‘H-NMR (500 MHz, CDC13, 300 K): 5 (ppm) = 10.31 (d, 1H, J = 2.7 Hz), 10.19 (s, 1H), 9.27 (s, lH), 8.56 (t, 1H, J = 8.8 Hz), 8.14 (d, 1H, J = 8.5 Hz), 8.12 (d, 1H, J = 8.5 Hz), 8.00 (d, 2H, J = 8.8 Hz), 7.81 - 7.76 (m, 3H), 7.74 (d, 2H, J = 8.8 Hz), 7.63 (d, 2H, J = 7.5 Hz), 7.41 (t, 2H, J = 7.5 Hz), 7.33 (t, 2H, J = 7.4 Hz), 6.99 (dd, 1H, J = 1.1 Hz, 8.9 Hz), 6.16 (ddt, 1H, J = 5.9 Hz, 10.4 Hz, 16.3 Hz), 6.04 (d, 1H, J = 5.0 Hz), 5.52 (dq, 1H, J = 1.4 Hz, 17.1 Hz), 5.44 (dd, 1H, J = 1.1 Hz, 10.4 Hz), 4.90 (hept., 1H, J = 6.2 Hz), 4.75 (d, 2H, J = 5.9 Hz), 4.45 - 4.42 (m, 2H), 4.33 (t, 1H, J = 4.2 Hz), 4.26 (dd, 2H, J = 7.3 Hz, 14.7 Hz), 1.60 (s, 9H), 1.42 (dd, 6H, J = 2.6 Hz, 6.2 Hz), 1.38 (s, 9H), 1.10 (d, 3H, J = 6.4 Hz).13C-NMR (126 MHz, CDCI3, 300 K): δ (ppm) = 167.7, 165.4, 162.2, 162.0, 156.2, 152.6 (d, J = 242.9 Hz), 150.2, 149.2, 144.0, 143.8, 141.8, 141.5, 134.2 (d, J = 10.8 Hz), 132.1, 131.9, 131.1, 130.9, 130.6, 127.9, 127.3, 127.2, 126.8, 125.3 (d, J = 4.0 Hz), 122.2, 120.5, 120.2, 120.2, 119.3, 115.4 (d, J = 2.4 Hz), 107.3 (d, J = 24.7 Hz), 81.1, 79.0, 76.5, 75.7, 67.2, 67.1, 59.1, 47.3, 28.4, 28.3, 22.1, 17.0.19F- NMR (470 MHz, CDCI3, 300 K): δ (ppm) = - 127.25.

[0367] Step i: tert-butyl 4-(2-(allyloxy)-4-((4-((2S,3R)-2-amino-3-(tert-butoxy)butanamido)-2- fluorophenyl)carbamoyl)-3-isopropoxybenzamido)benzoate

[0368] The amino acid derivative (116.6 pmol) was deprotected using General Procedure 6. The crude product was used without further purification.

[0369] Fragment Bl-15

[0370]

[0371] Step a: fert-Butyl 4-r4-({4-r(25f)-2-((r(977-fluoren-9-yl)methoxy1carbonyl)amino)-3-

[0372] [ (triphenyhnethyl)carbamoyl1propanamido]-2-fluorophenyl } carbamoyl)-2-(prop-2-en- 1 - yloxy)-3 -( propan-2-y loxy)benzamido]benzoate

[0373] The aniline derivative (0.18 mol) was coupled with (25)-2-({[(977-fluoren-9-yl)methoxy] carbonyl}amino)-3-[(triphenylmethyl)carbamoyl]propanoic acid using General Procedure 16. Yellow solid, 187.2 mg (92%). 'H-NMR (500 MHz, CDC13, 300 K): δ (ppm) = 10.36 (d, 1H, J = 2.7 Hz), 10.21 (s, 1H), 8.92 (br s, 1H), 8.56 (t, 1H, J = 8.8 Hz), 8.17 (d, 1H, J = 8.5 Hz), 8.14 (d, 1H, J = 8.5 Hz), 8.03 (d, 2H, J = 8.7 Hz), 7.80 - 7.75 (m, 4H), 7.68 (dd, 1H, J = 2.2 Hz, 13.0 Hz), 7.60 (d, 2H, J = 7.4 Hz), 7.42 (t, 2H, J = 7.4 Hz), 7.35 - 7.29 (m, 3H), 7.22 - 7.17 (m, 7H), 6.18 (ddt, 1H, J = 5.9 Hz, 10.4 Hz, 16.3 Hz), 5.54 (dd, 1H, J = 1.3 Hz, 17.1 Hz), 5.46 (dd, 1H, J = 1.0 Hz, 10.4 Hz), 4.96 - 4.89 (m, 1H), 4.78 (d, 2H, J = 5.9 Hz), 4.23 (t, 1H, J = 5.9 Hz), 1.62 (s, 9H), 1.45 (dd, 6H, J = 3.6 Hz, 6.5 Hz).13C-NMR (126 MHz, CDCI3, 300 K): δ (ppm) = 167.7, 165.4, 162.2, 162.0, 156.2, 152.6 (d, J = 242.9 Hz), 150.2, 149.2, 144.0, 143.8, 141.8, 141.5, 134.2 (d, J = 10.8 Hz), 132.1, 131.9, 131.1, 130.9, 130.6, 127.9, 127.3, 127.2, 126.8, 125.3 (d, J = 4.0 Hz), 122.2, 120.5, 120.2, 120.2, 119.3, 115.4 (d, J = 2.4 Hz), 107.3 (d, J = 24.7 Hz), 81.1, 79.0, 76.5, 75.7, 67.2, 67.1, 47.3, 28.4, 28.3, 22.1.19F-NMR (470 MHz, CDCh, 300

[0374] K): δ (ppm) = - 127.84.

[0375] Step b: fert-Butyl 4-r4-G4-r(2S)-2-amino-3-r('triphenylmethyl)carbamoyl1propanamido]-2- fluorophenyl } carbamoyl)-2-(prop-2-en- 1 -y loxy)-3 -(propan-2-y loxylbenzamido] benzoate The amino acid derivative (79.5 pmol) was deprotected using General Procedure 6. The crude product was used without further purification. Fragment Bl-16

[0376] Step a: terf-Butyl 4-f4-r(4-nitrophenyl)carbamoyl]-2-(prop-2-en-l-yloxy)-3-(propaii-2-yloxy) benzamido } benzoate

[0377] The benzoic acid (402 mg, 1.0 eq.) and 4-nitro aniline (146 mg, 1.2 eq.) were dissolved in dry EtOAc(6.0 mL) under argon atmosphere and dry pyridine (0.21 mL, 3.0 eq.) was added. The solution was stirred for few minutes before adding T3P (sol. in EtOAc, 50%, 1.05 mL, 2.0 eq.) dropwise. The reaction was stirred at rt while being screened with LCMS. After 7 h, the reaction mixture was partitioned between EtOAc / HCl (0.1 M) (30 mL each) and the aqueous phase was extracted with EtOAc(2 x 20 mL). The organic phases were combined and dried over Na2SO4 before all volatiles were removed under reduced pressure. The crude product was used without further purification.

[0378] Step b: ferLButyl 4-14-[(4-aminophenyl)carbamoyl1-2-(prop-2-en-l-yloxy)-3-(propan-2- y loxy )benzamido } benzoate

[0379] The crude nitrobenzene was dissolved in THF / EtOH (7.0 mL each) and AcOH (1.01 mL, 20 eq.) and Zn powder (0.58 g, 10 eq.) were added. After 1.5 h, the mixture was partitioned between EtOAc / sat. NaHCO3 solution (40 mL each) and the aqueous phase was extracted with EtOAc(2 x 30 mL). The organic phases were combined and dried over Na2SCO4 before all volatiles were removed under reduced pressure. The product was purified by flash column chromatography (solid loading, Cyclohexane / EtOAc, 40% EtOAc-> 50%). To obtain a solid product, a coevaporation with MTBE / heptane (lx) was performed. Yellow solid, 450mg (93% over 2 steps). Stored under argon atmosphere wrapped in aluminium foil in a fridge. 1H NMR (500 MHz, CDC1): 5(ppm) = 10.18 (s, 1H), 9.68 (s, 1H), 8.09 (s, 2H), 8.00 (d, J = 8.9 Hz, 2H), 7.74 (d, J = 8.9 Hz, 2H), 7.50 (d, J = 8.9 Hz, 2H), 6.72 (d, J = 8.9 Hz, 2H), 6.16 (ddt, J = 17.1, 10.4, 6.0 Hz, 1H), 5.51 (dq, J = 17.1 , 1.4 Hz, 1H), 5.43 (dq, J = 10.4, 1.1 Hz, 1H), 4.83 (hept, J = 6.3 Hz, 1H), 4.73 (dt, J = 6.0, 1.3 Hz, 2H), 3.66 (s, 2H), 3.21 (s, 1H), 1.60 (s, 9H), 1.40 (d, J = 6.3 Hz, 6H).I3C NMR (126 MHz, CDCI3): 8(ppm) = 165.5, 162.2, 161.8, 150.2, 148.6, 143.6, 141.9, 132.9, 132.2, 130.8, 129.9, 129.5, 127.8, 127.2, 126.9, 121.7, 120.4, 119.3, 115.7, 81.1,

[0380] 78.3, 75.6, 28.4, 22.5.

[0381] Steb c: tert-Butyl 4-r4-({4-[(15,2R)-2-ethenyl-l-(H(9Hr-fluoren-9-yl)methoxy1carbonyl} amino)cyclopropaneamido]phenyl}carbamoyl)-2-(prop-2-en-l-yloxy)-3-(propan-2-yloxy) benzamido]benzoate

[0382] Aniline derivative (150 mg, 1 eq.) and (1S,2R )-2-ethenyl-l-({[(9 / Afluoren-9-yl)methoxy] carbonyl }amino)cyclopropane-l -carboxylic acid (106 mg, 1.1 eq.) were dissolved in dry EtOAc(2.0 mL) under argon atmosphere. Dry pyridine (67 pL, 3.0 eq.) was added and T3P (50% sol. in EtOAc, 0.32 mL, 2.0 eq.) was added dropwise before stirring the reaction for 2 h 45 min. The solution was dissolved between EtOAc / HCl (0.1 M) (40 mL each) and the aqueous phase was extracted with EtOAc(2 x 20 mL). Combined organic phases were dried over Na2SO4 before removing solvents under reduced pressure. The material was purified by flash column chromatography (solid loading, Cy / EtOAc, 30%EtOAc->40%) to give 203 mg, 84% (NMR: 80%) of a yellowish foam. *H NMR (500 MHz, CDCI3): 8(ppm) = 10.17 (s, 1H), 9.87 (s, 1H), 8.74 (d, J= 9.5 Hz, 1H), 8.10 (d, J= 2.0 Hz, 2H), 8.00 (d, J= 8.9 Hz, 2H), 7.81 - 7.71 (m, 4H), 7.67 (d, J= 9.0 Hz, 2H), 7.57 (dd, J= 7.6, 4.0 Hz, 2H), 7.48 (d, J= 8.9 Hz, 2H), 7.44 - 7.35 (m, 2H), 7.34 - 7.27 (m, 2H), 6.16 (ddt, J= 16.3, 10.4, 6.0 Hz, 1H), 5.64 (s, 1H), 5.52 (dq, J= 17.2, 1.5 Hz, 1H), 5.44 (dd, J= 10.4, 1.2 Hz, 1H), 5.28 (d, J= 17.1 Hz, 1H), 5.13 - 5.07 (m, 1H), 4.84 (hept, J= 6.0 Hz, 1H), 4.74 (dd, 5.9, 1.1 Hz, 2H), 4.64 - 4.54 (m, 2H), 4.22 (t, J = 6.0 Hz, 1H), 2.09 (q, 8.4 Hz, 1H), 2.05 (s, 2H), 1.93 - 1.87 (m, 1H), 1.60 (s,

[0383] 9H), 1.42 (s, 1H), 1.40 (t,J= 5.9 Hz, 6H).13C NMR (126 MHz, CDCI3): 8(ppm) = 167.2, 165.4, 162.1, 150.3, 148.7, 143.5, 141.8, 141.5, 134.3, 133.6, 132.5, 132.1, 130.9, 130.3, 128.0, 127.9,

[0384] 127.3, 127.2, 127.0, 124.9, 124.9, 121.0, 120.5, 120.4, 120.3, 119.3, 117.9, 81.1 , 78.5, 75.7, 67.2, 47.3, 42.8, 28.4, 27.0, 22.5, 22.4.

[0385] Step d: / ert-Butyl 4-[4-('{4-[('LS,2R )-1 -amino-2- carbamoyl)-2-(prop-2-en-l-yloxy)-3-(propan-2-yloxy)benzainido]benzoate Fmoc-protected amine (61 mg, 1 eq.) was dissolved in dry ACN (1.0 mL) under argon atmosphere and HNEt2 (0.11 mL, 15 eq.) was added. After 2h the mixture was diluted with ACN and solvents were removed under reduced pressure and by coevaporation with ACN (4x). The crude product was used without further purification.

[0386] CDE-Fragments

[0387] Fragment B2-1

[0388] Step a: terf-Butyl 4-{4-r(5-aminopyridin-2-yl)carbamoyl]-2-(prop-2-en-l-yloxy)-3-(propan-2- yloxy)benzamido } benzoate

[0389] 126 mg Benzoic acid (0.28 mmol, 1 eq.) and 62 mg 5-nitropyridin-2-amine (0.45 mmol, 1.6 eq.) were added to a dry flask and further dried under high vacuum. 67 pl dry pyridine (0.83 mmol, 3 eq.) and 2 ml dry CH2CI2 were added under argon atmosphere. The reaction was cooled to 0 °C and 27 pl phosphoiyl chloride (0.29 mmol, 1.05 eq.) was added to the mixture dropwise. The reaction was slowly warmed up to rt and controlled by TLC. After completion, 16 ml brine and 8 ml saturated NH4CI were added. The aqueous layer was extracted with 3 x 8 ml EtOAc. The combined organic layers were concentrated under reduced pressure. The product was purified by flash chromatography but still contained impurities.

[0390] 159 mg crude nitropyridine (0.28 mmol, 1 eq.) and 270 mg zinc dust (4.13 mmol, 15 eq.) were suspended in 1.2 ml THF and 1.0 ml ethanol and the mixture was cooled down to 0 °C. 0.24 ml acetic acid (4.19 mmol, 15.2 eq) was added dropwise to the stirring mixture over 1 hour while keeping it at 0 °C. The mixture was warmed up to rt and controlled by TLC and LCMS. After completion, the zinc dust was filtered off and washed with ethyl acetate, ethanol and THF. The solvent was concentrated under reduced pressure and the acetic acid was coevaporated with ethyl acetate. 14 ml saturated NaHCCh solution was added and the product was extracted with 3 x 8 ml ethyl acetate. The combined organic layers were concentrated under reduced pressure and the product was purified by flash chromatography but still contained impurities.

[0391] Fragment B2-2

[0392] Step a: 4-amino-A A^-bis(2,4-dimethoxybenzyl)benzenesulfonamide

[0393] To a dry flask, 150 mg bis(2,4-dimethoxybenzyl)amine (0.58 mmol, 1 eq) and 115 mg 4- nitrobenzenesulfonylchloride (0.52 mmol, 1.1 eq.) were added under argon atmosphere. 1.6 ml dry CH2CI2 was added under argon atmosphere. The mixture was cooled down to 0 °C and 0.2 ml dry triethylamine (1.43 mmol, 3 eq.) was added. The reaction was slowly warmed up to rt and stirred overnight. After completion, 3 ml 1 M HC1 and 19 ml brine were added. The aqueous layer was extracted with 3 x 8 ml CH2CI2. The combined organic layers were washed with sat. NaHCCh solution and the concentrated under reduced pressure. The crude product was directly used for further reactions.

[0394] 237 mg crude 7V,A-bis(2,4-dimethoxybenzyl)-4-nitrobenzenesulfonamide (0.47 mmol, 1 eq.) and 460 mg zinc dust (7.0 mmol, 14.9 eq.) were suspended in 2.0 ml THF and 1.7 ml ethanol and the mixture was cooled down to 0 °C. 0.4 ml acetic acid (7.0 mmol, 14.8 eq.) was added dropwise to the stirring mixture over 1 hour while keeping 0 °C. The mixture was warmed up to rt and controlled by TLC and LCMS. After completion, the zinc dust was filtered off and washed with EtOAc, ethanol and THF. The solution was concentrated under reduced pressure and the acetic acid was coevaporated with EtOAc and n-heptane. The crude product was purified by flash chromatography. Colorless solid, 179 mg (80% over 2 steps). ’H-NMR (500 MHz, CDCI3, 300 K): δ (ppm) = 7.52 (d, 2H, J = 8.8 Hz), 7.15 (d, 2H, J = 8.4 Hz), 6.66 (d, 2H, J = 8.7 Hz), 6.35 (dd, 2H, J = 2.4 Hz, 8.4 Hz), 6.26 (d, 2H, J = 2.4 Hz), 4.31 (s, 4H), 3.76 (s, 6H), 3.60 (s, 6H).13C-NMR (126 MHz, CDCI3, 300 K): 6 (ppm) = 160.2, 158.2, 130.7, 129.3, 117.5, 114.4, 103.8, 97.9, 55.5, 55.1, 46.1. Step b: 2-( allyloxy)-4-amino-N-(4-(A.A-bis(2,4-dimethoxybenzyrl)sulfamoyl)phenyl)-3- isopropoxybenzamide

[0395] 174 mg aniline derivative (0.37 mmol, 1 eq.) and 114 mg 2-(allyloxy)-3-isopropoxy-4- nitrobenzoic acid (0.41 mmol, 1.1 eq.) were added to a dry flask and further dried under high vacuum. 0.1 ml dry pyridine (1.24 mmol, 3.4 eq.) and 2.6 ml dry CH2CI2 were added under argon atmosphere. The reaction was cooled to 0 °C and 37 pl phosphoryl chloride (0.40 mmol, 1.1 eq.) was added to the stirring mixture dropwise. The reaction was slowly warmed up to rt and controlled by TLC. After completion, the reaction was quenched by 1 ml HC1 and 9 ml brine. The aqueous layer was extracted with 3 x 4 ml EtOAc. The combined organic layers were concentrated under reduced pressure and further dried under high vacuum. The crude product was used for further reactions.

[0396] 270 mg crude nitro benzene derivative (0.37 mmol, 1 eq.) and 350 mg zinc dust (5.35 mmol, 14.6 eq.) were added to a flask. 1.6 ml THF and 1.3 ml ethanol were added and the mixture was cooled down to 0 °C. 0.32 ml acetic acid (5.59 mmol, 15.2 eq.) was added over a time span of 1 hour while keeping 0 °C. The mixture was warmed up to rt and was controlled by LCMS. After completion, the zinc dust was filtered off and washed with THF and EtOAc. The solvent was concentrated under reduced pressure and the excess acetic acid was coevaporated with n- heptane. 20 ml sat. NaHCOs solution and 10 ml brine were added to the residue and the product was extracted with 3 x 12 ml EtOAc. The combined organic layers were concentrated under reduced pressure. The crude product was purified by flash chromatography. Yellow solid, 193 mg (74% over 2 steps). 'H-NMR (500 MHz, CDCI3, 300 K): δ (ppm) = 10.27 (s, 1H), 7.85 (d, 1H, J = 8.7 Hz), 7.70 (d, 2H, J = 9.0 Hz), 7.66 (d, 2H, J = 9.0 Hz), 7.16 (d, 2H, J = 8.4 Hz), 6.36 (dd, 2H, J = 2.4 Hz, 8.4 Hz), 6.26 (d, 2H, J = 2.4 Hz), 6.14 (ddt, 1H, J = 5.9 Hz, 10.4 Hz, 17.0 Hz), 5.49 (dq, 1H, J = 1.5 Hz, 17.1 Hz), 5.39 (ddd, 1H, J = 1.1 Hz, 2.3 Hz, 10.4 Hz), 4.70 (dt, 2H, J = 1.3 Hz, 5.9 Hz), 4.36 (s, 4H), 3.76 (s, 6H), 3.60 (s, 6H), 1.35 (d, 6H, J = 6.2 Hz).

[0397] Step c: 2-(allyloxy)-4-(4-aminobenzamido)- V-(4-(A,A?-bis(2,4-dimethoxybenzyl)sulfamoyl) phenyl)-3-isopropoxybenzamide

[0398] 186 mg aniline derivative (0.26 mmol, 1 eq.) and 54 mg 4-nitrobenzoyl chloride (0.29 mmol, 1.1 eq.) were added to a dry flask under argon atmosphere. 2.0 ml dry CH2CI2 was added and the mixture was cooled down to 0 °C. 70 pl dry pyridine (0.87 mmol, 3.3 eq.) was slowly added to the stirring mixture. The reaction was warmed up to rt and controlled by LCMS. After completion, the reaction was quenched with 2 ml 1 M HC1 and 12 ml brine. The aqueous layer was extracted with 3 x 8 ml EtOAc. The combined organic layers were concentrated under reduced pressure and the crude product was used in further reactions.

[0399] 225 mg crude nitro benzene derivative (0.26 mmol, 1 eq.) and 260 mg zinc dust (3.98 mmol, 15.1 eq.) were added to a flask. 1.1 ml THF and 0.9 ml ethanol were added and the mixture was cooled down to 0 °C. 0.23 ml acetic acid (4.02 mmol, 15.3 eq.) was added over a time span of 1 hour while keeping 0 °C. The mixture was warmed up rt and was controlled by LCMS. After completion, the zinc dust was filtered off and washed with THF and EtOAc. The solution was concentrated under reduced pressure and the excess acetic acid was coevaporated with n- heptane. 20 ml sat. NaHCCh solution and 10 ml brine were added to the residue and the product was extracted with 3 x 12 ml EtOAc. The combined organic layers were concentrated under reduced pressure. The crude product was purified by flash chromatography. Yellow solid, 149 mg (68% over 2 steps).!H-NMR (500 MHz, DMSO-d6, 300 K): 5 (ppm) = 10.57 (s, 1H), 9.08 (s, 1H), 7.95 (d, 1H, J = 8.5 Hz), 7.87 (d, 2H, J = 8.8 Hz), 7.72 - 7.69 (m, 4H), 7.40 (d, 1H, J = 8.5 Hz), 7.01 (d, 2H, J = 8.2 Hz), 6.63 (d, 2H, J = 8.7 Hz), 6.41 - 6.37 (m, 4H), 6.08 - 5.99 (m, 1H), 5.40 (dq, 1H, J = 1.7 Hz, 17.2 Hz), 5.22 (ddd, 1H, J = 1.3 Hz, 3.0 Hz, 10.5 Hz), 4.61 (d, 2H, J = 5.5 Hz), 4.53 (quint., 1H, J = 6.2 Hz), 4.20 (s, 4H), 3.71 (s, 6H), 3.59 (s, 6H), 1.28 (d, 6H, J = 6.2 Hz).13C-NMR (126 MHz, DMSO-d6, 300 K): 5 (ppm) = 164.7, 164.5, 160.0, 157.8, 152.7, 152.6, 149.4, 142.6, 141.4, 136.4, 134.1, 133.7, 129.9, 129.1, 128.0, 125.9, 123.9, 119.9, 119.2, 117.8, 117.6, 116.3, 112.9, 104.3, 97.8, 76.2, 74.3, 55.2, 55.1, 45.7, 22.4.

[0400] Fragment B2-3

[0401] See Fragment B 1 - 14

[0402] Fragment B2-4

[0403] See Fragment B 1 - 16

[0404] Final Compounds

[0405] 4-(4-{4-[(25)-2-{[4-(4-Cyanobenzamido)phenyl]formamido}pent-4- ynamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid (CN-CC- 861)

[0406]

[0407] The amino acid derivative (54.5 pmol) was coupled with the carboxylic acid using General Procedure 7. The product was obtained by deprotection with General Procedures 10 and 11. Yellowish solid, 10 mg (23% over 3 steps). ’H-NMR (700 MHz, DMSO-de, 300 K): δ (ppm) = 12.80 (br s, 1H), 12.30 (s, 1H), 10.71 (s, 1H), 10.58 (s, 1H), 9.40 (s, 1H), 8.77 (d, 1H, J = 7.5 Hz), 8.13 (d, 2H, J = 8.4 Hz), 8.05 (d, 2H, J = 8.4 Hz), 7.98 - 7.95 (m, 6H), 7.90 (d, 2H, J = 8.8 Hz), 7.87 - 7.84 (m, 3H), 7.83 (d, 2H, J = 8.8 Hz), 7.70 (d, 1H, J = 8.8 Hz), 4.81 (dd, 1H, J = 7.6 Hz, 14.7 Hz), 4.55 (hept., 1H, J = 6.1 Hz), 2.94 (t, 1H, J = 2.6 Hz), 2.79 (dddd, 2H, J = 2.6 Hz, 7.4 Hz, 11.1 Hz, 16.8 Hz), 1.27 (d, 6H, J = 6.1 Hz).13C-NMR (176 MHz, DMSO-d6, 300 K): δ (ppm) = 169.7, 168.5, 166.9, 166.0, 164.5, 164.2, 154.2, 142.2, 142.0, 141.7, 138.7, 137.0, 136.4, 132.5, 130.2, 128.9, 128.6, 128.5, 128.4, 128.4, 126.2, 122.8, 120.7, 119.5, 119.0, 118.3, 114.0, 112.1, 80.6, 74.8, 73.2, 53.5, 22.3, 21.4. HRMS (ESI) calculated 793.2622 [M+H+], 793.2617 found.

[0408] 4-(4-{4-[(25)-2-{[4-(4-Cyanobenzamido)-3-fluorophenyI]formamido}pent-4- ynamido] benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid (SS A293)

[0409] Step a: / e / V-Butyl 4-(4-{4-f(2S')-2-{r4-(4-cyanobenzamido)-3-fluorophenyllformamido}pent- 4-vnamido]benzamido}-2-(prop-2-en-l-yloxy)-3-(propan-2-yloxy)benzamido)benzoate To a solution of 4-(4-cyanobenzamido)-3-fluorobenzoic acid (28 mg, 0.099 mmol, 1.00 eq.) and the amine hydrochloride (67 mg, 0.099 mmol, 1.00 eq.) in DMF (1.0 mL) were added HATU (41 mg, 0.108 mmol, 1.10 eq.) and DIPEA (51 pL, 0.296 mmol, 3.00 eq.). After the resulting mixture was stirred for 1.75 h at rt, EtOAc (30 mL) was added, washed with HC1 solution (1 M, 10 mL), water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether / EtOAc). Off white solid, 78 mg (87%). *H-NMR (700 MHz, DMSO-d6, 298 K): 8 = 1.26 (d, 6H, J= 6.1 Hz), 1.54 (s, 9H), 2.73-2.86 (m), 2.95 (t, 1H, J - 2.6 Hz), 4.46-4.53 (m, 1H), 4.58-4.64 (m, 2H), 4.78-4.84 (m, 1H), 5.18-5.41 (m, 2H), 5.98-6.06 (m, 1H), 7.41 (d, 1H, J= 8.4 Hz), 7.77-7.93 (m, 12H), 7.99 (d, 2H, J- 8.8 Hz), 8.04 (d, 2H, J= 8.5 Hz), 8.14 (d, 2H, JHH = 8.5 Hz), 8.96 (d, 1H, J= 7.5 Hz), 9.53 (s, 1H), 10.53 (s, 1H), 10.58 (s, 1H) ppm.13C-NMR (176 MHz, DMSO-d6, 298 K): 8 = 21.4, 22.3, 27.9, 53.6, 73.2, 74.3, 76.3, 80.3, 80.6, 114.3, 115.1 (d, J= 21.7 Hz), 117.8, 118.3, 118.8, 118.9, 119.0, 123.6, 123.9, 125.9, 126.0, 127.1, 128.5, 128.5, 128.6, 128.8, 130.1, 132.0 (d, J= 6.0 Hz), 132.6, 133.6, 135.7, 137.8, 142.0, 142.6, 143.0, 149.5, 154.6 (d, J- 248.4 Hz), 164.3, 164.3, 164.5, 164.6, 164.9, 169.4 ppm.

[0410] Step b: tert-Butyl 4-(4-{4-F(25f)-2-{r4-(4-cvanobenzamido)-3-fluorophenyl]formamido}pent- 4-vnamido]benzamido}-2-hvdroxy-3-(propan-2-yloxy)benzamido)benzoate

[0411] To a solution of the allyl ether (78 mg, 0.086 mmol, 1.00 eq.) and Pd(PPh3)4 (10 mg, 0.10 eq.) in dry THF (1.0 mL) was added aniline (24 pL, 0.258 mmol, 3.00 eq.) at 0 °C and the resulting mixture was stirred at 0 °C for 4 h. After completion, HC1 solution (1 M, 1 drop) was added and all volatiles were removed under reduced pressure. The residue was purified by flash chromatography [petroleum ether / (EtOAc + 2% AcOH)]. Brown solid, quant, yield.

[0412] Step c:

[0413] To a solution of the tert-butyl ester (88 mg, 0.100 mmol, 1.00 eq.) in dry CH2CI2 (1.0 mL) was added TFA (1.0 mL, 13.0 mmol, 130 eq.) at 0 °C and the resulting solution was stirred for 1.25 h at 0 °C. After all volatiles were removed in vacuo the residue was purified by RP-HPLC (H2O with 10 mM NH4HCO3 / Acetonitrile) and freeze-dried. Off white solid, 24 mg (29%). ’H- NMR (700 MHz, DMSO-d6, 298 K): 8 = 1.25 (d, 6H, J= 6.1 Hz), 2.72-2.85 (m), 2.93 (t, 1H, J= 2.6 Hz), 4.53 (hept., 1H, J= 6.1 Hz), 4.76-4.83 (m, 1H), 7.68 (d, 1H, J= 8.8 Hz), 7.79- 7.88 (m, 8H), 7.93-7.99 (m, 4H), 8.03 (d, 2H, J- 8.6 Hz), 8.12 (d, 2H, J= 8.5 Hz), 8.96 (d, 1H, J= 7.5 Hz), 9.41 (s, 1H), 10.60 (s, 3H), 10.63 (br s, 1H), 10.58 (s, 1H) 12.57 (br s, 1H) ppm.13C-NMR (176 MHz, DMSO-d6, 298 K): 5 = 21.5, 22.4, 53.7, 73.4, 75.0, 80.6, 112.4, 112.7, 114.4, 115.2 (d, <7= 21.5 Hz), 118.4, 119.2, 120.9, 123.0, 124.0, 126.0, 126.4, 128.5, 128.6, 128.6, 128.7 128.9, 130.3, 132.1 (d, J = 6.6 Hz), 132.7, 136.5, 137.1, 137.9, 142.1, 142.2, 154.3, 154.8 (d, J= 248 Hz), 164.4, 165.5, 165.1, 167.1, 168.6, 169.6 ppm. HRMS (ESI) calculated 811.2528 [M+H+], 811.2548 found.

[0414] 4-(4-{4-[(25)-2-{[3-Chloro-4-(4-cyanobenzamido)phenyl]formamido}pent-4- ynamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid (DK710)

[0415] The amino acid derivative (17.8 pmol) was coupled with the carboxylic acid using General Procedure 7. The product was obtained by deprotection with General Procedures 9 and 12. Colorless solid, 8 mg (51% over 3 steps). 'H-NMR (700 MHz, DMSO-de, 300 K): 5 (ppm) = 10.48 (s, 1H), 10.47, 9.35 (s, 1H), 8.91 (d, 1H, J = 7.2 Hz), 8.15 (d, 2H, J = 8.4 Hz) 8.11 (d, 1H, J = 1 .9 Hz), 8.06 (d, 2H, J = 8.4 Hz), 7.96 - 7.93 (m, 4H), 7.92 (dd, 1H, J = 1.9 Hz, 8.4 Hz), 7.85 (d, 2H, J = 8.7 Hz), 7.83 - 7.80 (m, 3H), 7.78 (d, 1H, J = 8.4 Hz), 7.67 - 7.61 (m, 1H), 7.40 (s, 1H), 7.00 (s, 1H), 4.94 (dd, 1H, J = 7.4 Hz, 13.9 Hz), 4.59 (br s, 1H), 2.70 (qd, 2H, J = 7.1 Hz, 15.5 Hz), 1.26 (d, 6H, J = 6.1 Hz).13C-NMR (176 MHz, DMSO-d6, 300 K): δ (ppm) = 171.1, 170.5, 168.4, 166.9, 164.6, 164.2, 164.1, 142.4, 142.3, 137.7, 136.8, 136.5, 132.8, 132.6, 130.2, 128.8, 128.7, 128.6, 128.5, 128.2, 127.7, 126.9, 126.0, 122.9, 120.5, 119.0, 118.2, 114.3, 112.7, 74.4, 51.7, 36.7, 22.3. HRMS (ESI) calculated 846.2290 [M+H+], 846.2285 found.

[0416] 4-(4-{4-[(25)-2-{[3-(4-Cyanobenzainido)bicyclo[l.l.l]pentan-l-yl]formamido}pent-4- ynamido|benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid (DK444)

[0417]

[0418] The amino acid derivative (1.84 mmol) was coupled with the carboxylic acid using General Procedure 7. The product was obtained by deprotection with General Procedures 10 and 11. Colorless solid, 819 mg (57% over 3 steps). 'H-NMR (500 MHz, DMSO-d6, 300 K): δ (ppm) = 12.81 (br s, 1H), 12.29 (s, 1H), 10.60 (s, 1H), 10.52 (s, 1H), 9.40 (s, 1H), 9.30 (s, 1H), 8.21 (d, 1H, J = 7.8 Hz), 8.00 (d, 2H, J = 8.7 Hz), 7.98 - 7.94 (m, 6H), 7.87 - 7.84 (m, 3H), 7.80 (d, 2H, J = 8.8 Hz), 7.71 (d, 2H, J = 8.9 Hz), 4.62 (dd, 1H, J = 7.7 Hz, 14.8 Hz), 4.55 (hept., 1H, J = 6.2 Hz), 2.92 (t, 1H, J = 2.6 Hz), 2.65 (dddd, 2H, J = 2.6 Hz, 7.4 Hz, 10.6 Hz, 16.7 Hz), 2.32 (s, 6H), 1.27 (d, 6H, 6.2 Hz).13C-NMR (126 MHz, DMSO-d6, 300 K): δ (ppm) = 169.4, 168.7, 168.5, 166.9, 165.2, 164.2, 154.1, 142.1, 142.0, 138.1, 137.0, 136.3, 132.4, 130.2, 128.6, 128.4, 128.1, 126.3, 122.8, 120.7, 118.9, 118.3, 113.7, 112.4, 112.2, 80.3, 74.9, 73.2, 53.6, 52.6, 45.3, 37.3, 22.3, 21.4. HRMS (ESI) calculated 783.2779 [M+H+], 783.2774 found.

[0419] 4-(4-{4-[(25)-2-{[4-(4-Cyanobenzenethioamido)phenyl]formamido}pent-4-ynamido] benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid (KR167)

[0420] Step a: ter / -Butyl 4-(4-f4-I(2S)-2-f r4-(4-cyanobenzenethioamido)phenyl]formamido)pent-4- ynamidolbenzamido}-2-(prop-2-en-l-yloxy)-3-(propan-2-yloxy)benzamido)benzoate

[0421] DIPEA (148 pL, 0.87 mmol, 13.0 equiv.) was added dropwise to a stirred solution of HATU (63 mg, 0.16 mmol, 2.00 equiv.) and the carboxylic acid (43 mg, 0.06 mmol, 2.50 equiv.) in DMF (1.7 mL). The solution was stirred for 5 min and then transferred to a stirred solution of the free amine (43 mg, 0.06 mmol) in DMF (1.0 mL) at 0 °C. The reaction mixture was stirred for 16 h while warming to rt. The mixture was diluted with EtOAc and washed with a 0.1 M HC1 solution, brine, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (MeOH in CH2CI2 = 1%, 2%) to furnish the product (43 mg, 0.04 mmol, 71%) as yellow solid. 'H-NMR (400 MHz, DMSO) 5 = 12.19 (s, 1H), 10.57 (s, 1H), 10.53 (s, 1H), 9.53 (s, 1H), 8.89 (d, J = 7.5 Hz, 1H), 8.04-7.94 (m, 10H), 7.89 (d, J = 8.8 Hz, 2H), 7.85-7.78 (m, 5H), 7.41 (d, J = 8.5 Hz, 1H), 6.19-5.92 (m, 1H), 5.37 (dd, J = 17.2, 1.7 Hz, 1H), 5.20 (dd, J = 10.5, 1.6 Hz, 1H), 4.81 (q, J = 7.6 Hz, 1H), 4.61 (d, J =

[0422] 5.5 Hz, 1H), 4.49 (hept, J = 6.1 Hz, 1H), 2.94 (t, J = 2.6 Hz, 1H), 2.79 (ddd, J = 15.9, 7.5, 2.6 Hz, 2H), 1.55 (s, 9H), 1.26 (d, J = 6.1 Hz, 6H) ppm.13C-NMR (100 MHz, DMSO) 8 = 196.1, 169.6, 165.9, 164.6, 164.5, 164.3, 149.5, 146.3, 143.0, 142.6, 142.3, 142.1, 135.6, 133.7, 132.2, 131.4, 130.1, 128.6, 128.5, 128.2, 128.1, 127.1, 126.0, 123.6, 123.3, 119.0, 118.9, 118.8, 118.4,

[0423] 117.8, 112.9, 80.6, 80.3, 76.3, 74.3, 73.2, 53.5, 38.2, 27.9, 22.3 ppm. HRMS (ESI): m / z calculated for CsiH^NeOsS [M+H]+: 903.3176, found: 903.3154.

[0424] Step b: tert-Butyl 4-(4-f4-I(21S)-2-H4-(4-cvanobenzenethioamido)phenyl1formamido)pent-4- ynamido]benzamido } -2-hydroxy-3 -(propan-2 -yloxy)benzamido)benzoate

[0425] The allyl ether (27 mg, 0.03 mmol) was dissolved in THF (2.1 mL). Aniline (9 pL, 0.09 mmol, 3.30 equiv.) and Pd(PPh3)4 (3 mg, 3 pmol, O.lO equiv.) were added subsequently and the resulting mixture was stirred at rt for 90 min. The mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (MeOH in CH2CI2 = 2%, 3%) to furnish the product (18 mg, 0.02 mmol, 70%) as yellowish solid. 'H-NMR (400 MHz, DMSO) 8 = 12.30 (s, 1H), 12.19 (s, 1H), 10.65 (s, 1H), 10.59 (s, 1H), 9.41 (s, 1H), 8.90 (d, J =

[0426] 7.5 Hz, 1H), 8.07-7.90 (m, 10H), 7.88-7.77 (m, 6H), 7.70 (d, J = 8.9 Hz, 2H), 4.82 (q, J = 7.7 Hz, 1H), 4.55 (p, J = 6.1 Hz, 1H), 2.94 (t, J = 2.6 Hz, 1H), 2.81-2.79 (m, 2H), 1.55 (s, 9H), 1.27 (d, J = 6.1 Hz, 6H) ppm.13C-NMR (100 MHz, DMSO) 8 = 196.0, 169.6, 168.5, 165.9, 164.5, 164.2, 154.2, 146.3, 142.3, 142.2, 142.0, 137.0, 136.3, 132.2, 131.4, 129.9, 128.6, 128.4, 128.2, 128.1, 126.8, 123.3, 122.8, 120.7, 120.6, 119.0, 112.9, 112.4, 112.1, 80.5, 74.8, 73.2, 53.5, 38.2,

[0427] 27.8, 22.3 ppm. MS (ESI): m / z calculated for C51H43N6O8S [M+H]+: 863.3, found: 863.3.

[0428] Step c:

[0429] The tert-butyl ester (9 mg, 0.01 mmol) was dissolved in precooled TFA (607 pL) at 0 °C with stirring. The solution was warmed up to rt over 30 min. EtzO was added at 0 °C. The precipitate was filtered off, washed with excess of Et2O and dried in vacuo to furnish the product (6 mg, 0.01 mmol, 71%) as yellow solid. ‘H-NMR (400 MHz, DMSO) 8 = 12.82 (s, 1H), 12.29 (s, 1H), 12.19 (s, 1H), 10.60 (s, 1H), 10.59 (s, 1H), 9.41 (s, 1H), 8.90 (d, J = 7.5 Hz, 1H), 8.08- 7.93 (m, 10H), 7.95-7.74 (m, 6H), 7.70 (d, J = 8.8 Hz, 2H), 4.81 (q, J = 7.5 Hz, 1H), 4.54 (hept, J = 6.1 Hz, 1H), 2.94 (t, J = 2.7 Hz, 1H), 2.80-2.78 (m, 2H), 1.27 (d, J = 6.2 Hz, 6H) ppm.13C- NMR (100 MHz, DMSO) 8 = 196.5, 170.1, 169.0, 167.3, 166.4, 164.7, 154.6, 146.8, 142.8, 142.7, 142.4, 137.5, 136.8, 132.7, 131.9, 130.7, 129.0, 128.9, 128.7, 128.6, 126.7, 123.8, 123.3, 121.2, 119.4, 118.8, 113.3, 112.9, 112.7, 81.1, 75.3, 73.7, 54.0, 22.8, 21.9 ppm. MS (ESI): m / z calculated for C44H35N6O8S [M+H]+: 807.2, found: 807.2.

[0430] 4-(4-{4-[(25)-2-{[4-(4-Cyanobenzeneimidamido)phenyl]formamido}pent-4-ynamido] benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid (Hdo488) vnamidolbenzamido)-2-(prop-2-en-l-yloxy)-3-(propan-2-yloxy)benzamido)benzoate

[0431] To a solution of the crude carboxylic acid (71 mg, 0.186 mmol, 1.40 eq.) and the amine hydrochloride (90 mg, 0.133 mmol, 1.00 eq.) in DMF (514 mL) were added HATU (66 mg, 0.173 mmol, 1.30 eq.) and DIPEA (58 pL, 0.332 mmol, 2.50 eq.) at 0°C. After the resulting mixture was stirred for 30 min at 0 °C, stirring was continued at rt for 17 h. Upon completion, KOH solution (1 M, 10 mL) was added and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over NazSO4 and concentrated in vacuo. The residue was purified by flash chromatography (CHzCh / MeOH). Colorless solid, 75 mg (63%). 'H NMR (700 MHz, DMSO-D6): δ (ppm) = 1.26 (d, J= 6.1 Hz, 6H), 1.55 (s, 9H), 2.74 - 2.84 (m, 2H), 2.93 (t, J= 2.6 Hz, 1H), 4.50 (p, J= 6.1 Hz, 1H), 4.61 (d, J= 5.5 Hz, 2H), 4.78 - 4.83 (m, 1H), 5.20 (dq, J= 10.5Hz, 1.3 Hz, 1H), 5.37 (dq, J= 17.2 Hz, 1.7 Hz, 1H), 6.02 (ddt, J= 17.2 Hz, 10.7 Hz, 5.5 Hz, 1H), 6.96 (s, 2H), 7.41 (d, J= 8.4 Hz, 1H), 7.79 - 7.85 (m, 5H), 7.88 - 7.90 (m, 2H), 7.91 - 7.97 (m, 4H), 7.99 (d, J= 8.8 Hz, 2H), 8.14 (s, 2H), 8.65 (d, J= 6.6 Hz, 1H), 9.53 (s, 1H), 10.53 (s, 1H), 10.54 (s, 1H).13C NMR (176 MHz, DMSO-De): δ (ppm) = 21.4, 22.3, 27.9, 53.4, 73.1, 74.3, 76.3, 80.3, 80.8, 112.6, 117.8, 118.6, 118.8, 119.0, 121.3, 123.6, 126.0, 127.1, 128.1, 128.5, 128.5, 129.0, 130.1, 132.1, 133.7, 135.7, 139.9, 142.1, 142.6, 143.0, 149.5, 152.7, 164.3, 164.5, 164.6, 166.3, 169.8.

[0432] Step b: tert-Butyl 4-(4-(4-[(2»S,)-2-{r4-(4-cvanobenzeneimidamido)phenyl]formamidolpent-4- ynamidolbenzamido } -2 -hydroxy-3 -(propan-2 -yloxy)benzamido)benzoate

[0433] To a solution of the allyl ether (75 mg, 0.084 mmol, 1.00 eq.) in dry THF (634 pL) were added aniline (38 pL, 0.420 mmol, 5.00 eq.) and Pd(PPh3)4 (4 mg, 0.04 eq.) and the resulting mixture was stirred at rt for 3 h. After completion, water (10 mL) was added and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over NaiSCU and concentrated in vacuo. The residue was purified by flash chromatography (CHiCh / MeOH). Yellowish solid, 61 mg (86%). 'H NMR (500 MHz, DMSO- D6): δ (ppm) = 1.26 (d, J= 6.1 Hz, 6H), 1.55 (s, 9H), 2.73 - 2.85 (m, 2H), 2.94 (t, J= 2.6 Hz, 1H), 4.55 (p, J= 6.1 Hz, 1H), 4.81 (q, J= 7.3 Hz, 1H), 6.99 (s, 2H), 7.68 (d, J= 8.8 Hz, 1H), 7.81 - 7.86 (m, 5H), 7.94 (dd, J= 19.0 / 8.8 Hz, 9H), 8.14 (s, 2H), 8.68 (d, J= 7.0 Hz, 1H), 9.40 (s, 1H), 10.58 (s, 1H), 10.82 (s, 1H).13C NMR (126 MHz, DMSO-D6): δ (ppm) = 21.4, 22.4, 27.9, 53.5, 73.2, 74.8, 80.5, 80.8, 111.9, 112.6, 112.7, 118.6, 118.9, 120.6, 121.4, 122.9, 126.7, 127.3, 128.1, 128.4, 128.6, 129.0, 130.0, 132.2, 136.4, 137.0, 139.7, 142.1, 142.3, 144.1, 153.3, 154.6, 164.2, 164.6, 166.3, 168.5, 169.9.

[0434] Step c:

[0435] To a solution of the tert-butyl ester (72 mg, 0.085 mmol, 1.00 eq.) in dry CH2CI2 (922 pL) was added TFA (360 pL, 4.67 mmol, 55.0 eq.) at 0 °C and the resulting solution was stirred for 3 h at 0 °C. After all volatiles were removed in vacuo the residue was purified by RP-HPLC (H2O / ACN with 0.1% HCOOH) and freeze-dried. Colorless solid, 40 mg (60%). *HNMR (500 MHz, DMSO-D6): δ (ppm) = 1.26 (d, J= 6.1 Hz, 6H), 2.73 - 2.85 (m, 2H), 2.94 (t, J= 2.6 Hz, 1H), 4.55 (p, J= 6.1 Hz, 1H), 4.80 (q, J= 7.5 Hz, 1H), 6.97 (s, 2H), 7.68 (d, J= 8.8 Hz, 1H), 7.81 - 7.87 (m, 5H), 7.92 - 7.98 (m, 8H), 8.13 (d, J= 7.7 Hz, 2H), 8.68 (d, J= 7.2 Hz, 1H), 9.41 (s, 1H), 10.58 (s, 1H), 10.80 (s, 1H).13C NMR (126 MHz, DMSO-D6): δ (ppm) = 21.4, 22.4, 53.5, 73.2, 74.8, 80.8, 111.9, 112.6, 112.7, 118.6, 119.0, 120.7, 121.4, 122.9, 126.2, 127.4, 128.2, 128.4, 128.6, 129.0, 130.3, 132.2, 136.5, 137.0, 139.7, 142.1, 142.3, 153.2, 154.6, 164.2,

[0436] 166.3, 167.0, 168.5, 169.9. HRMS (ESI) calculated 792.2776 [M+H+], 792.2755 found.

[0437] 4-(4-{4-[(2>S)-2-({4-[(4-Cyanophenyl)carbamoyl]phenyI}formamido)pent-4-ynamido] benzamido}-2-hydroxy-3-(propan-2-yIoxy)benzamido)benzoic acid (DK610)

[0438] The amino acid derivative (46.8 pmol) was coupled with the carboxylic acid using General Procedure 8. The product was obtained by deprotection with General Procedures 10 and 11. Colorless solid, 14 mg (38% over 3 steps). 'H-NMR (500 MHz, DMSO-d6, 300 K): δ (ppm) = 12.80 (br s, 1H), 12.30 (br s, 1H), 10.76 (s, 1H), 10.63 - 10.59 (m, 2H), 9.41 (br s, 1H), 9.05 (d, 1H, J = 7.5 Hz), 8.08 (s, 4H), 8.01 (d, 2H, J = 8.9 Hz), 7.99 - 7.95 (m, 4H), 7.88 - 7.81 (m, 7H), 7.71 (d, 1H, J = 8.9 Hz), 4.84 (dd, 1H, J = 7.8 Hz, 14.6 Hz), 4.55 (hept., 1H, J = 6.1 Hz), 2.95 (t, 1H, J = 2.6 Hz), 2.88 - 2.75 (m, 2H), 1.27 (d, 6H, J = 6.2 Hz).13C-NMR (126 MHz, DMSO-dg, 300 K): δ (ppm) = 169.5, 168.5, 166.9, 165.8, 165.5, 164.2, 154.1, 143.3, 142.1, 142.0, 137.0, 136.8, 136.6, 136.3, 133.2, 130.2, 128.6, 128.4, 127.9, 127.7, 126.3, 122.8, 120.7, 120.3, 119.0, 119.0, 112.4, 112.2, 105.6, 80.5, 74.9, 73.2, 53.6, 22.3, 21.4. HRMS (ESI) calculated 793.2622 [M+H+], 793.2615 found.

[0439] 4-(4-{4-[(25)-2-({3-ChIoro-4-[(4-cyanophenyl)carbamoyl]phenyl}formamido)pent-4- ynamido] benzamido}-2-hydroxy-3-(propan-2-y loxy)benzamido)benzoic acid (DK732) The amino acid derivative (88.6 pmol) was coupled with the carboxylic acid using General Procedure 8. The product was obtained by deprotection with General Procedures 10 and 11. Off-white solid, 36 mg (49% over 3 steps). 'H-NMR (700 MHz, DMSO-d6, 300 K): δ (ppm) = 12.82 (br s, 1H), 12.29 (br s, 1H), 11.05 (s, 1H), 10.70 - 10.58 (m, 2H), 9.41 (s, 1H), 9.15 (d, 1H, J = 7.5 Hz), 8.14 (d, 1H, J = 1.6 Hz), 8.00 (dd, 1H, J = 1.6 Hz, 8.0 Hz), 7.98 - 7.96 (m, 4H), 7.91 (d, 2H, J = 8.8 Hz), 7.87 - 7.84 (m, 5H), 7.82 (d, 2H, J = 8.8 Hz), 7.78 (d, 1H, J = 7.9 Hz), 7.69 (d, 1H, J = 8.8 Hz), 4.83 (dd, 1H, J = 7.6 Hz, 14.8 Hz), 4.55 (hept., 1H, J = 6.1 Hz), 2.95 (t, 1H, J = 2.6 Hz), 2.80 (dddd, 2H, J = 2.6 Hz, 7.5 Hz, 11.5 Hz, 16.8 Hz), 1.27 (d, 6H, J = 6.1 Hz).13C-NMR (176 MHz, DMSO-d6, 300 K): δ (ppm) = 169.3, 168.5, 166.9, 165.0, 164.5, 164.2, 142.8, 142.1, 142.0, 138.6, 137.0, 136.4, 136.3, 133.4, 130.2, 130.1, 129.1, 128.6, 128.4, 126.6, 126.2, 122.8, 120.7, 119.7, 119.0, 119.0, 112.5, 112.1, 105.9, 80.5, 74.8, 73.3, 53.6, 22.3, 21.4. HRMS (ESI) calculated 827.2227 [M+H+], 827.2220 found.

[0440] 4-(4-{4-[(2S)-2-({4-[(4-CyanophenyI)carbamoyl]bicycIo[2.2.2]octan-l-yl}formamido) pent-4-ynamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid

[0441] Step a: tert-Butyl 4-(4-{4-r(2S)-2-({4-r(4-cyanophenyl)carbamoyl]bicyclor2.2.2]octan-l-yH formamido)pent-4-ynamido1benzamido}-2-(prop-2-en-l-yloxy)-3-(propan-2-yloxy) benzamido)benzoate

[0442] To a solution of the crude carboxylic acid (30 mg, 0.101 mmol, 1.00 eq.) and the amine hydrochloride (68 mg, 0.101 mmol, 1.00 eq.) in DMF (0.5 mL) were added HATU (42 mg, 0.111 mmol, 1.10 eq.) and DIPEA (53 pL, 0.302 mmol, 3.00 eq.). After the resulting mixture was stirred for 2.25 h at rt, EtOAc (30 mL) was added, washed with HC1 solution (1 M, 10 mL), water (10 mL) and brine (10 mL), dried over Na2SO 4 and concentrated in vacuo. The resulting residue was coevaporated with n-heptane (3x) and with EtOAc / n-heptane (2x). The crude product was used without further purification. Yellow / orange solid. Step b: / erZ-Butyl 4-(4-[4-[('21S,)-2-({4-[(4-cyanophenyl)carbamoyl]bicvclo[2.2.21octan-l-yn formamido)pent-4-ynamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoate To a solution of the crude allyl ether and Pd(PPh3)4 (12 mg, 0.10 eq.) in dry THF (1.0 mL) was added aniline (27 pL, 0.300 mmol, 3.00 eq.) at 0 °C and the resulting mixture was stirred at 0 °C for 3 h. After completion, all volatiles were removed under reduced pressure. The residue was purified by flash chromatography [petroleum ether / (EtOAc + 2% AcOH)]. The crude product was used in the next reaction. Yellow solid.

[0443] Step c:

[0444] To a solution of the tert-butyl ester (88 mg, 0.100 mmol, 1.00 eq.) in dry CH2Q2 (1.0 mL) was added TFA (1.0 mL, 13.0 mmol, 130 eq.) at 0 °C and the resulting solution was stirred for 2.25 h at 0 °C. After all volatiles were removed in vacuo the residue was purified by RP-HPLC and freeze-dried. Off white solid, 40 mg (49 % over 3 steps). *H-NMR (700 MHz, DMSO- d6): 5 = 1.27 (d, 6H, J= 6.1 Hz), 1.73-1.80 (m, 6H), 1.80-1.87 (m, 6H), 2.61-2.75 (m, 2H), 2.90 (t, 1H, J= 2.6 Hz), 4.53-4.58 (m, 1H), 4.58-4.63 (m, 1H), 7.66 (d, 1H), 7.70 (d, 1H, 8.9

[0445] Hz), 7.74 (d, 2H, J= 8.7 Hz), 7.79 (d, 2H, J= 8.8 Hz), 7.85 (d, 2H, J= 8.6 Hz), 7.84-7.89 (m, 4H), 7.94-7.99 (m, 4H), 9.39 (br s, 1H), 9.58, (s, 1H), 10.43 (s, 1H), 10.7 (br s, 1H), 12.30 (br s, 1H), 12.81 (br s, 1H) ppm.13C-NMR (176 MHz, DMSO-d6, 298 K): 5 = 21.4, 22.3, 27.4, 27.7, 38.3, 39.7, 52.5, 73.1, 74.8, 80.4, 104.9, 112.0 (br), 112.5, 118.9, 119.1, 119.9, 120.7,

[0446] 122.9, 126.2, (br), 128.4, 130.2, 128.5, 133.0, 136.3, 137.0, 142.0, 142.2, 143.6, 154.3, 164.2,

[0447] 166.9, 168.5, 169.7, 176.5, 176.8 ppm. HRMS (ESI) calculated 825.3249 [M+H+], 825.3261 found.

[0448] 4-(4-{4-[(25')-2-({8-[(4-Cyanophenyl)carbamoyl]cuban-l-yI}formamido)pent-4-ynamido| benzamido}-2-hydroxy-3-(propan-2-yIoxy)benzamido)benzoic acid (DK700) 22 mg carboxylic acid (58 pmol, 1.1 eq.) was added to a dry flask and further dried under high vacuum. 0.5 ml Dry DMF, 36 pl DIPEA (3.1 eq.) and 29 mg HATU (76 pmol, 1.1 eq.) were added under argon atmosphere. The solution was stirred for 30 minutes. The solution was referred as [1]. 41 mg free amine (68 pmol, 1 eq) was dissolved in 0.3 ml dry DMF under argon atmosphere and cooled down to 0 °C. Solution [1] was added to the flask and the mixture was stirred at 0 °C. The reaction was controlled by LCMS. After the reaction was completed, the reaction was directly purified by flash chromatography but still contained impurities.

[0449] 74 mg crude rt-butyl ester (84.6 pmol, 1 eq.) was added to a dry flask and further dried at the vacuum pump. 0.8 ml Dry CH2Q2 was added under nitrogen atmosphere and the solution was cooled down to 0 °C. 0.35 ml TFA (4.5 mmol, 53.7 eq.) was added under nitrogen atmosphere. The solution was stirred for 3 hours at 0 °C and controlled by LCMS. After the reaction was completed, the solvent was removed under reduced pressure. The crude product was purified by RP-HPLC. Off-white solid, 25 mg (34%). 'H-NMR (700 MHz, DMSO-d6, 300 K): δ (ppm) = 12.82 (br s, 1H), 12.30 (br s, 1H), 10.61 (br s, 1H), 10.52 (s, 1H), 10.08 (s, 1H), 9.41 (s, 1H), 8.26 (d, 1H, J = 7.8 Hz), 7.98 - 7.95 (m, 4H), 7.88 - 7.84 (m, 5H), 7.81 (d, 2H, J = 8.8 Hz), 7.77 (d, 2H, J = 8.8 Hz), 7.71 (d, 1H, J = 8.8 Hz), 4.65 (dd, 1H, J = 7.8 Hz, 14.8 Hz), 4.55 (hept., 1H, J = 6.1 Hz), 4.26 - 4.23 (m, 3H), 4.19 - 4.16 (m, 3H), 2.93 (t, 1H, J = 2.6 Hz), 2.66 (dddd, 2H, J = 2.6 Hz, 7.4 Hz, 10.7 Hz, 16.7 Hz), 1.27 (d, 6H, J = 6.1 Hz).13C-NMR (126 MHz, DMSO-d6, 300 K): δ (ppm) = 170.9, 170.5, 169.6, 168.5, 166.9, 164.2, 154.2, 143.4, 142.1, 142.0, 137.0, 136.3, 133.1, 130.2, 128.6, 128.4, 126.3, 122.8, 120.7, 119.5, 119.1, 119.0, 112.5, 112.2, 104.9, 80.5, 74.9, 73.2, 57.6, 56.6, 52.5, 46.4, 46.2, 22.3, 21.5. HRMS (ESI) calculated 819.2773 [M+H+], 819.2778 found.

[0450] 4-(4-{4-[2-({3-[(4-Cyanophenyl)carbamoyI]bicyclo[l.l.l]pentan-l-yI}formamido)-3- methyl-3-nitrobutanamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido) Step a: tert-Butyl 4-(4-f4-r2-(f3-r(4-cvanophenyl)carbamoyl1bicyclori.l.l1pentan-l-yl} formamido)-3-methyl-3-nitrobutanamido1benzamido}-2-(prop-2-en-l-yloxy)-3-(propan-2- yloxy)benzamido)benzoate

[0451] DIPEA (35 pL, 0.20 mmol, 3.00 equiv.) was added dropwise to a stirred solution of HATU (30.2 mg, 0.08 mmol, 1.20 equiv.) and the carboxylic acid (20.3 mg, 0.08 mmol, 1.20 equiv.) in DMF (1.6 mL). The solution was stirred for 5 min and then transferred to a stirred solution of the amine (45.6 mg, 0.07 mmol) in DMF (1.0 mL) at 0 °C. The reaction mixture was stirred for 18 h while warming to rt. The mixture was diluted with EtOAc and washed with a 0.1 M HC1 solution, brine, dried over MgSC>4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (MeOH in CH2CI2 = 1%, 2%) to furnish the product (45.0 mg, 0.05 mmol, 73%) as beige solid. 'H-NMR (600 MHz, DMSO-de) = 10.70 (s, 1H), 10.53 (s, 1H), 9.98 (s, 1H), 9.56 (s, 1H), 8.39 (d, J= 9.9 Hz, 1H), 8.00 (d, J= 8.8 Hz, 2H), 7.89 (d, J= 8.7 Hz, 2H), 7.86 (d, J= 8.9 Hz, 2H), 7.84-7.77 (m, 7H), 7.41 (d, J= 8.4 Hz, 1H), 6.05-5.98 (m, 1H), 5.48 (d, J= 9.6 Hz, 1H), 5.37 (dq, J= 1.6, 17.2 Hz, 1H), 5.20 (dq, J= 1.6, 10.5 Hz, 1H), 4.61 (d, J= 5.4 Hz, 2H), 4.49 (sept, J= 6.1 Hz, 1H), 2.32 (s, 6H), 1.68 (s, 3H), 1.61 (s, 3H), 1.55 (s, 9H), 1.26-1.25 (d, J= 6.1 Hz, 6H) ppm.13C-NMR (151 MHz, DMSO- d6) = 169.3, 168.5, 166.4, 166.1, 164.6, 164.2, 149.5, 143.0, 142.9, 142.6, 135.6, 133.6, 133.1, 130.1, 129.1, 128.4, 127.2, 126.0, 123.6, 119.7, 119.6, 119.4, 119.1, 118.8, 117.8, 105.3, 88.9, 80.3, 76.2, 74.3, 57.6, 51.8, 40.3, 38.0, 27.9, 22.9, 22.7, 22.3 ppm. HRMS (ESI) calculated for C5oH53N7OiiNa [M+Na]+: 950.3701; found: 950.3692.

[0452] Step b: tert-Butyl 4-(4-f4-r2- [(4-cvanophenyl)carbamoyl1bicyclori.l.l1pentan-l-yl} formamido)-3-methyl-3-nitrobutanamidolbenzamido}-2-hydroxy-3-(propan-2-yloxy) benzamido)benzoate

[0453] The allyl ether (43.2 mg, 0.05 mmol) was dissolved in THF (2.1 mL). Aniline (14 pL, 0.15 mmol, 3.30 equiv.) and Pd(PPh3)4 (5.4 mg, 5 pmol, 0.10 equiv.) were added subsequently and the resulting mixture was stirred at rt for 2 h. The mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (dry load, MeOH in CH2Ch = 1%, 3%) to furnish the product (36.5 mg, 0.04 mmol, 88%) as yellowish solid. ’H-NMR (600 MHz, DMSO-d6) = 12.28 (s, 1H), 10.71 (s, 1H), 10.62 (bs, 1H), 9.98 (s, 1H), 9.41 (s, 1H), 8.40 (d, J= 9.6 Hz, 1H), 7.97-7.96 (d, J= 8.6 Hz, 2H), 7.92 (d, J= 8.6 Hz, 2H), 7.87-7.84 (m, 5H), 7.80 (d, J= 8.7 Hz, 2H), 7.78 (d, J= 8.7 Hz, 2H), 7.66 (bs, 1H), 5.48 (d, J= 9.6 Hz, 1H), 4.56 (bs, 1H), 2.32 (s, 6H), 1.68 (s, 3H), 1.61 (s, 3H), 1.55 (s, 9H), 1.26 (d, J= 6A Hz, 6H) ppm.13C-NMR (151 MHz, DMSO-d6) = 169.3, 168.5, 168.4, 166.4, 164.6, 164.1, 142.9, 141.5, 136.9, 136.5, 133.1, 129.9, 129.2, 128.3, 122.9, 120.5, 119.7, 119.5, 119.0,

[0454] 112.6. 112.2. 105.3, 88.9, 80.4, 57.6, 51.8, 40.4, 38.0, 27.8, 22.9, 22.7, 22.3 ppm. HRMS (ESI) calculated for C47H49N70iiNa [M+Na]+: 910.3388; found: 910.3389.

[0455] Step c:

[0456] The tert-butyl ester (35.1 mg, 0.04 mmol) was dissolved in precooled TFA (2 mL) at 0 °C with stirring. The solution was warmed up to rt over 30 min. EtiO was added at 0 °C. The precipitate was filtered off, washed with excess of EtiO and dried in vacuo to furnish the product (25.5 mg, 0.03 mmol, 78%) as colorless solid. 'H-NMR (600 MHz, DMSO-d6) = 12.82 (s, 1H), 12.29 (s, 1H), 10.71 (s, 1H), 10.60 (s, 1H), 9.98 (s, 1H), 9.43 (s, 1H), 8.39 (d, J= 9.9 Hz, 1H), 7.98-7.96 (m, 4H), 7.87-7.85 (m, 5H), 7.81 (d, J= 8.8 Hz, 2H), 7.78 (d, J= 8.8 Hz, 2H), 7.69 (d, J= 8.9 Hz, 1H), 5.48 (d, J= 9.6 Hz, 1H), 4.54 (sept, J= 6.1 Hz, 1H), 2.32 (s, 6H), 1.68 (s, 3H), 1.61 (s, 3H), 1.27 (d, J= 6.1 Hz, 6H) ppm.I3C-NMR (151 MHz, DMSO-d6) = 169.3, 168.5, 168.5, 166.9, 166.4, 164.1, 154.1, 142.9, 141.9, 141.5, 137.0, 136.4, 133.1, 130.2, 129.1, 128.4,

[0457] 126.3, 122.8, 120.7, 119.7, 119.5, 119.0, 112.5, 112.3, 105.3, 88.9, 74.9, 57.6, 51.8, 40.4, 38.0, 22.9, 22.7, 22.3 ppm. HRMS (ESI) calculated for C43H41N7O11 [M-H]': 830.2786; found: 830.2771.

[0458] 4-(4-{4-[(2S)-2-{[4-(5-Cyano-l-methyl-l / f-l,3-beiizodiazol-2-yl)pheiiyl]formamido}peiit-

[0459] 4-ynamido] benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid (SS A295)

[0460] Step a: tert-Butyl 4-(4-{4- -2-f r4-(5-cyano-l-methyl-l / / -E3-benzodiazol-2-yl)phenyll formamido } pent-4-ynamido]benzamido } -2-(prop-2-en- 1 -yloxy)-3 -(propan-2-yloxy) benzamido)benzoate To a solution of the crude carboxylic acid (28 mg, 0.101 mmol, 1.00 eq.) and the amine hydrochloride (68 mg, 0.101 mmol, 1.00 eq.) in DMF (0.5 mL) were added HATU (42 mg, 0.111 mmol, 1.10 eq.) and DIPEA (53 pL, 0.302 mmol, 3.00 eq.). After the resulting mixture was stirred for 3 h at rt, EtOAc (30 mL) was added, washed with sat. NaHCOa solution (10 mL), water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (petroleum ether / EtOAc). The crude product was used without further purification. Yellow solid.

[0461] Step b: tert-Butyl 4-(4-{4-r(21Sr)-2-{[4-(5-cvano-l-methyl-177-L3-benzodiazol-2-yl)phenyl1 formamido } pent-4-ynamido]benzamido } -2-hydroxy-3 -(propan-2-yloxy)benzamido)benzoate To a solution of the allyl ether (41 mg, 0.046 mmol, 1.00 eq.) and Pd(PPh3)4 (5 mg, 0.10 eq.) in dry THF (3.0 mL) was added aniline (25 pL, 0.273 mmol, 6.00 eq.) at 0 °C and the resulting mixture was stirred at 0 °C for 1.5 h. After completion, HC1 solution (1 M, 1 drop) and EtOAc (30 mL) were added, the organic layer was washed with sat. NaHCOa solution (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography [petroleum ether / (EtOAc + 2% AcOH)]. The crude product was used without further purification. Brown solid.

[0462] Step c:

[0463] To a solution of the crude tert-butyl ester (40 mg, 0.047 mmol, 1.00 eq.) in dry CH2CI2 (2.0 mL) was added TFA (1.0 mL, 13.0 mmol, 280 eq.) at 0 °C and the resulting solution was stirred for 1.5 h at 0 °C. After all volatiles were removed in vacuo the residue was purified by RP-HPLC (H2O with 10 mM NFLHCOs / Acetonitrile) and freeze-dried. Off white solid, 12 mg (32 % over 3 steps). ’H-NMR (700 MHz, DMSO-d6, 298 K): 8 = 1.27 (d, 6H, J= 6.1 Hz), 2.77-2.89 (m), 2.94 (t, 1H, J= 2.6 Hz), 3.97 (s, 3H), 4.54 (hept., 1H, J= 6.1 Hz), 4.82-4.88 (m, 1H), 7.69 (d, 1H, J= 8.8 Hz), 7.74 (dd, 1H, J= 8.4 Hz, J= 1.5 Hz), 7.81-7.87 (m, 5H), 7.89 (d, 1H, J= 8.2 Hz), 7.95-7.99 (m, 4H), 8.03 (d, 2H, J= 8.4 Hz), 8.14 (d, 2H, J= 8.4 Hz), 8.27 (dd, 1H, J= 1.4 Hz, J= 0.5 Hz), 9.08 (d, 1H, J= 7.8 Hz), 9.43 (s, 1H), 10.63 (s, 1H), 10.65 (br s, 1H), 12.28 (br s, 1H) ppm.13C-NMR (176 MHz, DMSO-d6, 298 K): 8 = 21.5, 22.4, 53.7, 73.3, 75.1, 80.7, 104.6, 112.4, 112.7, 119.9, 120.0, 120.2, 123.0, 124.1, 126.2, 126.4, 128.1, 128.5, 128.7, 129.6, 130.3, 131.9, 135.2, 136.5, 137.1, 139.5, 141.6, 142.1, 142.3, 154.2, 155.0, 164.4, 166.2, 167.1, 168.6, 169.6 ppm. HRMS (ESI) calculated 804.2782 [M+H+], 804.2766 found. 4-(4-{4-[(25)-2-{[4-(5-Cyano-l-ethyI-1jHr-1,3-benzodiazol-2-yl)phenyI]formamido}pent-4- ynamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid (MLe6)

[0464] Step a and b: / erf -Butyl 4-(4-f4-r(2S)-2-(r4-(5-cyano-l-ethyl-177-l,3-benzodiazol-2-yl) phenyl]formamido } pent-4-ynamido]benzamido } -2-hydroxy-3-(propan-2-yloxy)benzamido) benzoate

[0465] To a solution of the crude carboxylate (40 mg, 0.12 mmol, 1.17 eq.) and amine hydrochloride (70 mg, 0.10 mmol, 1.00 eq.) in DMF (0.4 mL) were added HATU (43 mg, 0.11 mmol, 1.09 eq.) and DIPEA (76 pL, 0.44 mmol, 4.20 eq.) at 0°C. Upon completion, aniline (30 pL, 0.33 mmol, 3.20 eq.), Pd(PPh3)4 (6 mg, 0.05 eq.) and THF (0.7 pL) were added and stirring was continued at 0 °C. After complete deally lation, all volatiles were removed in vacuo. The remaining residue was coevaporated with H-heptane and purified by flash chromatography(petroleum ether / EtOAcCh / MeOH) to furnish the product (73 mg, 81%).

[0466] Step c:

[0467] To a solution of the / er / -butyl ester (73 mg, 0.083 mmol, 1.00 eq.) in dry CH2CI2 (650 pL) was added TFA (350 pL, 4.54 mmol, 54.5 eq.) at 0 °C and the resulting solution was stirred for 20 min at 0 °C before stirring was continued at rt for 1 h. After all volatiles were removed in vacuo the residue was purified by RP-HPLC and freeze-dried. Beige solid, 28 mg (41%). *H NMR (700 MHz, DMSO-D6) 5 12.79 (s, 1H), 12.30 (s, 1H), 10.61 (s, 1H), 9.38 (s, 1H), 9.08 (d, J = 7.5 Hz, 1H), 8.28 (d, J = 1.4 Hz, 1H), 8.14 (d, J = 8.1 Hz, 2H), 8.01 - 7.90 (m, 7H), 7.84 (dd, J = 12.1, 8.6 Hz, 5H), 7.75 - 7.71 (m 1H), 7.66 (d, J = 8.8 Hz, 1H), 4.85 (td, J = 8.1, 6.3 Hz, 1H), 4.58 (hept, J = 6.0 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 2.96 (t, J = 2.6 Hz, 1H), 2.87 - 2.76 (m, 2H), 1.33 (t, J = 7.2 Hz, 3H), 1.26 (d, J = 6.1 Hz, 6H).13C NMR (176 MHz, DMSO- D6) 8 173.3, 169.5, 168.4, 166.9, 166.0, 164.1, 154.6, 143.4, 142.2, 142.1, 138.4, 136.8, 136.4, 135.1, 132.3, 130.2, 129.2, 128.7, 128.3, 128.1, 126.0, 124.3, 122.9, 120.5, 119.9, 119.4, 119.0, 112.7, 112.5, 104.4, 80.6, 74.6, 73.2, 53.6, 39.7, 22.3, 21.4, 14.9. HRMS (ESI) calculated 818.2933 [M+H+], 818.2922 found.

[0468] 4-(4-{4-[(15',22f)-l-[4-(5-Cyano-l-methyl-1Hr-l,3-benzodiazoI-2-yl)benzamido]-2-ethenyl- cyclopropaneamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid

[0469] Step a: tert-Butyl 4-(4-f4-r(lS,,2J?)-l-r4-(5-cvano-l-methyl-l / / -L3-benzodiazol-2-yl) benzamido]-2-ethenylcvclopropaneamido1benzamido}-2-(prop-2-en-l-yloxy)-3-(propan-2- yloxy)benzamido)benzoate

[0470] DIPEA (89 pL, 0.51 mmol, 3.00 equiy.) was added dropwise to a stirred solution of HATU (77.4 mg, 0.20 mmol, 1.20 equiv.) and the carboxylic acid (56.4 mg, 0.20 mmol, 1.20 equiv.) in DMF (4.2 mL). The solution was stirred for 5 min and then transferred to a stirred solution of the amine hydrochloride (111 mg, 0.17 mmol) in DMF (2.4 mL) at 0 °C. The reaction mixture was stirred for 18 h while warming to rt. The mixture was diluted with EtOAc and washed with a 1 M HC1 solution, brine, dried over MgSCL and concentrated under reduced pressure. The crude residue was purified by column chromatography (MeOH in CH2CI2 = 1%, 2%) to furnish the product (83 mg) as off-white solid, which contained minor impurities. The product was used in the next step without further purification.

[0471] Step b: tert- Butyl 4-(4-{4-r(1S,2R )-l-f4-(5-cyano-l-methyl-l / Tl,3-benzodiazol-2-yl) benzamidol-2-ethenylcvclopropaneamido]benzamido}-2-hydroxy-3-(propan-2-yloxy) benzamido) benzoate

[0472] The allyl ether (83.0 mg, 0.09 mmol) was dissolved in THF (4.5 mL). Aniline (27 pL, 0.30 mmol, 3.30 equiv.) and Pd(PPh3)4 (10.5 mg, 0.01 mmol, 0.10 equiv.) were added subsequently and the resulting mixture was stirred at rt for 3 h. The mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (dry load, MeOH in CH2CI2 = 1%, 2%) to furnish the product (47.3 mg, 0.05 mmol, 32% over two steps) as yellowish solid. 'H-NMR (600 MHz, DMSO-d6) 8 = 12.27 (s, 1H), 10.61 (bs, 1H), 10.02 (s, 1H), 9.39 (s, 1H), 9.27 (s, 1H), 8.29 (dd, J= 0.6, 1.5 Hz, 1H), 8.19 (d, 7= 8.6 Hz, 2H), 8.04 (d, 7= 8.6 Hz, 2H), 7.95-7.89 (m, 5H), 7.86-7.84 (m, 3H), 7.80 (d, .7= 8.9 Hz, 2H), 7.74 (dd, J= 1.5, 8.4 Hz, 2H), 7.68 (bs, 1H), 5.75-5.69 (m, 1H), 5.33 (d, J= 17.1 Hz, 1H), 5.11 (d, J= 10.5 Hz, 1H), 4.55 (bs, 1H), 3.97 (s, 3H), 1.97-1.94 (m, 1H), 1.55 (s, 9H), 1.39-1.36 (m, 1H), 1.26 (dd, 7= 3.9, 6.1 Hz, 6H), 1.23 (m, lH) ppm.13C-NMR (126 MHz, DMSO-d6) 8 = 168.4, 168.3, 166.8, 164.6, 164.2, 154.9, 142.2, 141.9, 139.5, 136.9, 136.3, 135.1, 134.6, 132.0, 129.9, 129.3, 128.6, 128.2, 128.1, 125.9, 124.1, 122.9, 120.6, 119.9, 119.7, 119.4, 117.2, 112.4, 104.3, 80.5, 74.8, 42.4, 32.2, 27.8, 22.3, 21.6 ppm. HRMS (ESI) calculated for C5oH47N708Na [M+Na]+: 896.3384; found: 896.3384.

[0473] Step c:

[0474] The te / Y-butyl ester (41.4 mg, 0.05 mmol) was dissolved in precooled TFA (2.4 mL) at 0 °C with stirring. The solution was warmed up to rt over 30 min. Et20 was added at 0 °C. The precipitate was filtered off, washed with excess of Et2O and dried in vacuo to furnish the product (16.4 mg, 0.02 mmol, 42%) as colorless solid. 'H-NMR (600 MHz, DMSO-de) 8 = 12.83 (bs, 1H), 12.28 (s, 1H), 10.60 (s, 1H), 10.02 (s, 1H), 9.41 (s, 1H), 9.27 (s, 1H), 8.28 (dd, 7= 0.6, 1.5 Hz, 1H), 8.19 (d, 7= 8.5 Hz, 2H), 8.03 (d, 7= 8.6 Hz, 2H), 7.97 (d, 7= 8.7 Hz, 2H), 7.95 (d, 7= 8.9 Hz, 2H), 7.90 (dd, J= 0.5, 8.6 Hz, 2H), 7.86-7.84 (m, 3H), 7.80 (d, 7= 8.9 Hz, 2H), 7.74 (dd, 7= 1.5, 8.4 Hz, 2H), 7.70 (d, 7= 8.9 Hz, 2H), 5.75-5.69 (m, 1H), 5.32 (d, 7= 17.1 Hz, 1H), 5.12 (d, 7= 12.1 Hz, 1H), 4.54 (sept, 7= 6.1 Hz, 1H), 3.98 (s, 3H), 1.97-1.94 (m, 1H), 1.39-1.36 (m, 1H), 1.30-1.23 (m, 1H), 1.26 (dd, 7= 3.8, 6.1 Hz, 6H) ppm.13C-NMR (126 MHz, DMSO-d6) 8 = 168.5, 168.3, 166.9, 166.9, 164.2, 154.9, 154.1, 142.2, 142.0, 141.9, 139.5, 137.0, 136.3, 135.1, 134.6, 132.0, 130.2, 129.3, 128.5, 128.2, 128.1, 126.3, 126.0, 124.1, 122.8, 120.7, 119.9, 119.7, 119.5, 117.0, 112.4, 112.2, 104.4, 74.6, 42.4, 32.2, 22.3 (d, 7= 2.3 Hz), 21.6 ppm. HRMS (ESI) calculated for C46H39N7O8 [M+Na]+: 840.2758; found: 840.2769. 4-{4-[4-(2-{[4-(5-Cyano-l-methyl-1H-1,3-benzodiazol-2-yI)phenyl]formamido}-3-methyl-

[0475] 3-nitrobutanamido)benzamido]-2-hydroxy-3-(propan-2-yloxy)benzamido}benzoic acid

[0476] Step a: tert-Butyl 4-{4-[4-(2-l r4-(5-cyano-l-methyl-177-l,3-benzodiazol-2-yl)phenyl1 formamido}-3-methyl-3-nitrobutanamido)benzamido]-2-(prop-2-en-l-yloxy)-3-(propan-2- yloxy)benzamido } benzoate

[0477] DIPEA (35 pL, 0.20 mmol, 3.00 equiv.) was added dropwise to a stirred solution of HATU (30.2 mg, 0.08 mmol, 1.20 equiv.) and fragment A4-1 (22.0 mg, 0.08 mmol, 1.20 equiv.) in DMF (1.6 mL). The solution was stirred for 5 min and then transferred to a stirred solution of the amine (45.6 mg, 0.07 mmol) in DMF (1.0 mL) at 0 °C. The reaction mixture was stirred for 17 h while warming to rt. The mixture was diluted with EtOAc and washed with a 1 M HC1 solution, brine, dried over MgSCU and concentrated under reduced pressure. The crude residue was purified by column chromatography (MeOH in CH2CI2 = 1%, 3%) to furnish the product (41.7 mg, 0.04 mmol, 66%) as orange solid.lH-NMR (600 MHz, DMSO-d6) = 8 10.72 (s, 1H), 10.52 (bs, 1H), 9.56 (s, 1H), 9.14 (d, J= 9.2 Hz, 1H), 8.28 (s, 1H), 8.11 (d, J= 8.4 Hz, 2H), 8.03 (d, J= 8.5 Hz, 2H), 8.00 (d, J= 8.8 Hz, 2H), 7.90-7.88 (m, 3H), 7.83-7.79 (m, 5H), 7.74 (dd, J= 1.5, 8.4 Hz, 1H), 7.41 (d, J= 8.5 Hz, 1H), 6.05-5.98 (m, 1H), 5.74 (d, J= 9.2 Hz, 1H), 5.37 (dq, J= 1.7, 17.2 Hz, 1H), 5.20 (dq, J= 1.5, 10.5 Hz, 1H), 4.61 (d, J= 5.5 Hz, 1H), 4.48 (sept, 9.2 Hz, 1H), 3.97 (s, 3H), 1.78 (s, 3H), 1.72 (s, 3H), 1.55 (s, 9H), 1.25 (d, J= 6. l Hz, 6H) ppm.13C-NMR (151 MHz, DMSO-d6) = 8 166.9, 166.2, 164.6, 164.5, 164.2, 154.9, 149.5,

[0478] 142.6. 141.9. 140.4. 139.5. 135.6. 134.9. 133.6. 132.2. 130.1. 129.3. 129.1. 128.4. 128.4. 127.2, 127.0, 126.7, 126.0, 126.0, 125.4, 124.2, 119.8, 119.6, 118.8, 117.8, 112.4, 104.3, 89.0, 80.3,

[0479] 76.2, 74.3, 58.5, 32.2, 27.9, 23.4, 22.8, 22.3 ppm. HRMS (ESI) calculated for C52H52N8OioNa [M+Na]+: 971.3704; found: 971.3693. Step b: tert-Butyl 4-{4-r4-(2-ir4-(5-cvano-l-methyl-177-L3-benzodiazol-2-yl)phenyll formamido ) -3 -methyl-3 -nitrobutanamido)benzamido]-2-hydroxy-3 -(propan-2 -yloxy) benzamido ) benzoate

[0480] The allyl ether (40.0 mg, 0.04 mmol) was dissolved in THF (1.9 mL). Aniline (13 pL, 0.14 mmol, 3.30 equiv.) and Pd(PPh3)4 (4.9 mg, 4 μmol , 0.10 equiv.) were added subsequently and the resulting mixture was stirred at rt for 2 h. The mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (dry load, MeOH in CH2CI2 = 1%, 2%, 3%) to furnish the product (31.3 mg, 0.03 mmol, 82%) as yellow solid.1H-NMR (600 MHz, DMSO-d6) = 5 12.28 (s, 1H), 10.73 (s, 1H), 10.61 (bs, 1H), 9.43 (bs, 1H), 9.14 (d, J= 9.2 Hz, 1H), 8.28 (s, 1H), 8.11 (d, J= 8.4 Hz, 2H), 8.03 (d, J= 8.4 Hz, 2H), 7.98 (d, J= 8.7 Hz, 2H), 7.93 (d, J= 8.7 Hz, 2H), 7.90 (d, J= 8.7 Hz, 1H), 7.86-7.82 (m, 5H), 7.74 (dd, J= 1.5, 8.4 Hz, 1H), 7.70-7.64 (m, 1H), 5.75 (d, J= 9.2 Hz, 1H), 4.55 (m, 1H), 3.97 (s, 3H), 1.78 (s, 3H), 1.72 (s, 3H), 1.55 (s, 9H), 1.26 (d, J= 6.1 Hz, 6H) ppm.13C-NMR (151 MHz, DMSO-de) = 8 168.4, 166.9, 166.6, 164.6, 164.1, 154.9, 141.9, 141.6, 139.5, 134.9, 132.2,

[0481] 129.9, 129.3, 128.4, 128.3, 125.9, 124.2, 122.9, 120.6, 119.9, 119.6, 112.4, 112.3, 89.0, 80.5, 74.7, 58.5, 32.2, 27.8, 23.3, 22.8, 22.3 ppm. HRMS (ESI) calculated for C49H48N8OioNa [M+Na]+: 931.3391; found: 931.3417.

[0482] Step c:

[0483] The ZcrZ-butyl ester (30.1 mg, 0.03 mmol) was dissolved in precooled TFA (1.7 mL) at 0 °C with stirring. The solution was warmed up to rt over 30 min. EtzO was added at 0 °C. The precipitate was filtered off, washed with excess of EtzO and dried in vacuo to furnish the product (14.9 mg, 0.02 mmol, 53%) as colorless solid. 'H-NMR (600 MFIz, DMSO-de) 8 = 12.82 (bs, 1H), 12.28 (s, 1H), 10.74 (s, 1H), 10.60 (s, 1H), 9.44 (s, 1H), 9.14 (d, J= 9.2 Hz, 1H), 8.28 (s, 1H), 8.11 (d, J= 8.4 Hz, 2H), 8.03 (d, J= 8.4 Hz, 2H), 7.99-7.96 (m, 4H), 7.90 (d, J= 8.5 Hz, 2H), 7.86-7.82 (m, 5H), 7.74 (dd, J= 1.4, 8.4 Hz, 1H), 7.69 (d, J= 8.9 Hz, 1H), 5.75 (d, J= 9.2 Hz, 1H), 4.54 (sept, 6.1 Hz, 1H), 3.97 (s, 3H), 1.78 (s, 3H), 1.72 (s, 3H), 1.27 (d, J= 6.1 Hz, 6H) ppm.I3C-NMR (151 MHz, DMSO-de) 8 = 168.5, 166.9, 166.9, 166.6, 164.2, 154.9, 154.1, 141.9, 141.9, 141.6, 139.5, 137.0, 136.4, 134.9, 132.2, 130.2, 129.3, 129.1, 128.4, 128.3, 126.3, 126.0, 124.1, 122.8, 120.7, 119.9, 119.6, 112.5, 112.4, 112.3, 104.3, 89.0,

[0484] 74.9, 58.5, 32.2, 23.3, 22.8, 22.3 ppm. HRMS (ESI) calculated for C45H39N8O10 [M-H]': 851.2789; found: 851.2789. 4-(4-{4-[(lS',27f)-l-[3-(5-Cyano-l-methyl-l / 7-l,3-benzodiazol-2-yl)bicyclo[l.l.l]pentane- l-amido]-2-etIienyicyclopropaneamido]benzamido}-2-hydroxy-3-(propan-2-yioxy) benzamido)benzoic acid (Hdo308)

[0485] Step a: terZ-Butyl 4-(4-{4-[fl£,27?)-l-[3-(5-cyano-l-methyl-l. / 7-L3-benzodiazol-2-yl)bicyclo [1.1.1 Ipentane- 1 -amido]-2-ethenylcyclopropaneamidolbenzamido } -2-(prop-2-en- 1 -yloxy)-3- (propan-2-yloxy)benzamido)benzoate

[0486] To a solution of the crude carboxylic acid (51 mg, 0.191 mmol, 1.10 eq.) and the amine hydrochloride (120 mg, 0.174 mmol, 1.00 eq.) in DMF (1.90 mL) were added HATU (79 mg, 0.208 mmol, 1.20 eq.) and DIPEA (121 pL, 0.694 mmol, 4.00 eq.) at 0°C. After the resulting mixture was stirred for 30 min at 0 °C, stirring was continued at rt for 17 h. Upon completion, sat. NaHCO3 solution (10 mL) was added and extracted with EtOAc (3 x l0 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2 / MeOH). Colorless solid, 74 mg (47%). 1H NMR (500 MHz, DMSO-D6): δ (ppm) = 1.25 (dd, J= 6.3 / 3.6 Hz, 7H), 1.54 (s, 9H), 1.87 (dd, J= 7.6 / 5.3 Hz, 1H), 2.32 (q, J= 8.7 Hz, 1H), 2.56 (s, 6H), 3.89 (s, 3H), 4.48 (p, J= 6.1 Hz, 1H), 4.61 (d, J= 5.5 Hz, 2H), 5.06 - 5.10 (m, 1H), 5.20 (dq, J= 10.5 / 1.4 Hz, 1H), 5.29 (dd, J= 17.1 / 1.9 Hz, 1H), 5.37 (dq, J= 17.1 / 1.7 Hz, 1H), 5.57 (ddd, J= 17.2 / 10.5 / 9.2 Hz, 1H), 6.01 (ddt, J= 17.3 / 10.7 / 5.5 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.65 (dd, J= 8.4 / 1.5 Hz, 1H), 7.76 (dd, J= 8.7 / 1.7 Hz, 3H), 7.79 - 7.85 (m, 3H), 7.89 (d, J= 8.8 Hz, 2H), 7.98 - 8.02 (m, 2H), 8.14 (d, J= 1.5 Hz, 1H), 8.60 (s, 1H), 9.58 (s, 1H), 9.87 (s, 1H), 10.56 (s, 1H).13C NMR (176 MHz, DMSO-D6): δ (ppm) = 22.3, 27.8, 30.9, 31.5, 34.9, 40.8, 41.9, 53.1, 53.5, 74.3, 76.2, 80.3, 103.7, 111.6, 117.2, 117.8, 118.8, 119.0, 119.3, 120.0, 123.6, 125.5, 126.0, 127.1, 128.4, 128.6, 130.1, 133.6, 134.4, 135.6, 139.0, 141.4, 141.9, 142.5, 143.0, 149.5, 154.2, 164.3, 164.5, 164.6, 167.9, 170.1. Step b: tert-Butyl 4-(4-{4-r(1S',27R)-l-r3-(5-cvano-l-methyl-177-L3-benzodiazol-2-yl)bicyclo fl .1.1 Ipentane- 1 -amidol-2-ethenylcyclopropaneamidolbenzamido } -2 -hydroxy-3 -(propan-2 - yloxy)benzamido)benzoate

[0487] To a solution of the allyl ether (70 mg, 0.077 mmol, 1.00 eq.) in dry THF (584 pL) were added aniline (28 pL, 0.310 mmol, 4.00 eq.) and Pd(PPh3)4 (4 mg, 0.04 eq.) and the resulting mixture was stirred at rt for 3 h. After completion, water (10 mL) was added and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (CH2Ch / MeOH). Colorless solid, 57 mg (85%). *H NMR (500 MHz, DMSO- D6): δ (ppm) = 1.26 (dd, J= 6.1 / 3.2 Hz, 7H), 1.55 (s, 9H), 1.87 (dd, J= 7.6 / 5.3 Hz, 1H), 2.32 (q, J= 8.7 Hz, 1H), 2.56 (s, 6H), 3.89 (s, 3H), 4.53 (p, J= 6.2 Hz, 1H), 5.06 - 5.10 (m, 1H), 5.29 (dd, J= 17.1 / 1.9 Hz, 1H), 5.57 (ddd, J= 17.1 / 10.5 / 9.1 Hz, 1H), 7.65 (dd, J= 8.4 / 1.6 Hz, 1H), 7.70 (d, J= 8.8 Hz, 1H), 7.76 (t, J = 8.2 Hz, 3H), 7.84 - 7.88 (m, 3H), 7.91 - 7.94 (m, 2H), 7.95 - 7.99 (m, 2H), 8.14 (d, J= 1.4 Hz, 1H), 8.61 (s, 1H), 9.45 (s, 1H), 9.88 (s, 1H), 10.63 (s, 1H), 12.30 (d, J= 1.2 Hz, 1H).13C NMR (126 MHz, DMSO-D6): δ (ppm) = 20.7, 22.4, 27.9, 30.9, 31.6, 35.0, 40.9, 41.9, 53.2, 74.9, 80.6, 103.8, 111.7, 112.4, 112.5, 117.3, 119.4, 120.1, 120.7, 122.9, 123.7, 125.6, 126.9, 128.4, 128.6, 130.0, 134.5, 136.4, 137.1, 139.1, 141.3, 142.1, 142.1, 154.2, 154.2, 164.3, 164.6, 168.0, 168.5, 170.1.

[0488] Step c:

[0489] To a solution of the tert-butyl ester (51 mg, 0.059 mmol, 1.00 eq.) in dry CH2CI2 (641 pL) was added TFA (250 pL, 3.25 mmol, 55.0 eq.) at 0 °C and the resulting solution was stirred for 3 h at 0 °C. After all volatiles were removed in vacuo the residue was purified by RP-HPLC (H2O with 10 mM NPLHCOa / Acetonitrile) and freeze-dried. Colorless solid, 32 mg (67%). ’H NMR (500 MHz, DMSO-D6): δ (ppm) = 1.26 (dd, J= 6.1 / 3.3 Hz, 7H), 1.87 (dd, J= 7.6 / 5.3 Hz, 1H), 2.32 (q, J= 8.7 Hz, 1H), 2.56 (s, 6H), 3.89 (s, 3H), 4.55 (p, J= 6.1 Hz, 1H), 5.05 - 5.11 (m, 1H), 5.29 (dd, J= 17.0 / 1.8 Hz, 1H), 5.57 (ddd, J= 17.1 / 10.5 / 9.1 Hz, 1H), 7.63 - 7.69 (m, 2H), 7.76 (dd, J= 8.6 / 6.S Hz, 3H), 7.84 (t, J= 8.7 Hz, 3H), 7.94 - 7.98 (m, 4H), 8.14 (d, J= 1.5 Hz, 1H), 8.61 (s, 1H), 9.43 (s, 1H), 9.88 (s, 1H), 10.80 (s, 1H), 12.33 (s, 1H), 12.84 (s, 1H).13C NMR (176 MHz, DMSO-D6): δ (ppm) = 20.5, 22.3, 30.7, 30.9, 31.5, 34.9, 40.8, 41.9, 53.1, 74.7, 103.8, 111.6, 112.6, 117.3, 119.4, 120.0, 120.6, 122.9, 123.7, 125.6, 126.2, 128.3, 128.7, 130.2, 134.4, 136.4, 136.9, 139.0, 141.4, 142.1, 154.2, 164.2, 166.9, 168.0, 168.5, 170.1. HRMS (ESI) calculated 808.3089 [M+H+], 808.3087 found.

[0490] 4-(4-{4-[(2S')-2-{f4-(5-Cyano-l-methyl-l / / -l,3-henzodiazol-2-yl)bicyclo[2.2.2]octan-l-yI] formamido}pent-4-ynamido]benzamido}-2-hydroxy-3-(propan-2-yioxy)benzamido) benzoic acid (Hdol66)

[0491] Step a: ferf-Butyl 4-(4-f4-r(25)-2-H4-(5-cyano-l-methyl-17 / -l,3-benzodiazol-2-yl)bicvclo r2.2.2]octan-l-yl1formamido}pent-4-ynamido1benzamido}-2-(prop-2-en-l-yloxy)-3-(propan- 2-yloxy)benzamido)benzoate

[0492] To a solution of the crude carboxylic acid (151 mg, 0.487 mmol, 1.50 eq.) and the amine hydrochloride (220 mg, 0.325 mmol, 1.00 eq.) in DMF (2.52 mL) were added HATU (185 mg, 0.487 mmol, 1.50 eq.) and DIPEA (226 pL, 1.30 mmol, 4.00 eq.) at 0°C. After the resulting mixture was stirred for 30 min at 0 °C, stirring was continued at rt for 17 h. Upon completion, water (20 mL) was added and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SCO4 and concentrated in vacuo. The residue was purified by flash chromatography (CFLCh / MeOH). Colorless solid, 172 mg (57%). ‘H NMR (500 MHz, DMSO-D6): 5 (ppm) = 1.26 (d, J= 6.2 Hz, 6H), 1.55 (s, 9H), 1.89 (dd, J= 93 / 6.2 Hz, 6H), 2.10 (dd, J= 9.6 / 6.0 Hz, 6H), 2.66 (ddd, J= 16.9 / 8A / 2.5 Hz, 1H), 2.72 (ddd, J= 16.6 / 6.1 / 2.5 Hz, 1H), 2.91 (t, J= 2.6 Hz, 1H), 3.97 (s, 3H), 4.50 (hept, J= 6.1 Hz, 1H), 4.59 - 4.65 (m, 3H), 5.20 (dq, 10.5 / 1.3 Hz, 1H), 5.38 (dq, J= 17.2 / 1.6 Hz, 1H), 6.02 (ddt, J= 17.1 / 10.7 / 5.5 Hz, 1H), 7.41 (d, J= 8.5 Hz, 1H), 7.61 (dd, J= 8.4 / 1.5 Hz, 1H), 7.68 (d, J= 7.7 Hz, 1H), 7.70 - 7.73 (m, 1H), 7.78 (d, J= 8.8 Hz, 2H), 7.83 (dd, J= 8.6 / 4.2 Hz, 3H), 7.89 (d, 8.8 Hz, 2H), 7.99 (d, J= 8.8 Hz, 2H), 8.10 (dd, J= 1.5 / 0.5 Hz, 1H), 9.53

[0493] (s, 1H), 10.42 (s, 1H), 10.53 (s, 1H).13C NMR (126 MHz, DMSO-D6): δ (ppm) = 21.5, 22.3, 27.6, 27.9, 28.5, 32.9, 34.3, 38.2, 52.5, 59.8, 73.1, 74.3, 76.3, 80.3, 80.5, 103.4, 111.3, 117.8, 118.7 - 118.9 (m), 119.0, 120.1, 123.4, 123.6, 125.2, 126.0, 127.1, 128.4 - 128.5 (m), 130.1, 133.6, 135.6, 140.2, 140.8, 142.1, 142.5, 143.0, 149.5, 162.3, 164.3, 164.5, 164.6, 169.6, 176.8.

[0494] Step b: ter / -Butyl 4-(4- 14- [(25'1-2-1 [4-(5-cvano-l-methyl- l,3-benzodiazol-2-yl)bicyclo r2.2.2]octan-l-yl1formamido}pent-4-vnamido1benzamido)-2-hydroxy-3-(propan-2-yloxy) benzamidolbenzoate

[0495] To a solution of the allyl ether (268 mg, 0.288 mmol, 1.00 eq.) in dry THF (2.17 mL) were added aniline (105 pL, 1.15 mmol, 4.00 eq.) and Pd(PPh3)4 (13 mg, 0.04 eq.) and the resulting mixture was stirred at rt for 3 h. After completion, water (20 mL) was added and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2 / MeOH). Colorless solid, 154 mg (60%). ’H NMR (500 MHz, DMSO-D6): δ (ppm) = 1.27 (d, J= 6.1 Hz, 6H), 1.55 (s, 9H), 1.85 - 1.91 (m, 6H), 2.10 (dd, J= 9.5 / 6.0 Hz, 6H), 2.63 - 2.69 (m, 1H), 2.72 (ddd, J= 16.5 / 6.1 / 2.6 Hz, 1H), 2.91 (t, J= 2.6 Hz, 1H), 3.97 (s, 3H), 4.55 (p, J = 6.1 Hz, 1H), 4.62 (q, J= 7.7 Hz, 1H), 7.61 (dd, J = 8.4 / 1.5 Hz, 1H), 7.68 (d, J= 7.7 Hz, 1H), 7.71 (dd, J= 8.5 / 2.9 Hz, 2H), 7.79 (d, J= 8.8 Hz, 2H), 7.86 (d, J= 8.9 Hz, 3H), 7.91 - 7.94 (m, 2H), 7.96 (d, J= 8.8 Hz, 2H), 8.10 (dd, J = 1.4 / 0.6 Hz, 1H), 9.41 (s, 1H), 10.44 (s, 1H), 10.61 (s, 1H), 12.29 (s, 1H).13C NMR (126 MHz, DMSO-D6): δ (ppm) = 21.5, 22.3, 27.6, 27.8, 28.5, 32.9, 34.3, 38.2, 52.5, 73.1, 74.9, 80.4, 80.5, 103.4, 111.3, 112.1, 118.9, 120.1, 120.7, 122.8, 123.4, 125.2, 126.8, 128.4, 128.5, 129.9, 136.3, 137.0, 140.2, 140.7, 142.0, 142.2, 154.1, 162.3, 164.2, 164.5, 168.5, 169.6, 176.8.

[0496] Step c:

[0497] To a solution of the ter -butyl ester (154 mg, 0.173 mmol, 1.00 eq.) in dry CH2C12(1.87 mL) was added TFA (732 pL, 9.50 mmol, 55.0 eq.) at 0 °C and the resulting solution was stirred for 3 h at 0 °C. After all volatiles were removed in vacuo the residue was purified by RP-HPLC (H2O with 10 mMNHiHCCh / Acetonitrile) and freeze-dried. Colorless solid, 117 mg (81%). 'H NMR (500 MHz, DMSO-D6): δ (ppm) = 1.27 (d, J= 6.1 Hz, 6H), 1.86 - 1.91 (m, 6H), 2.08 - 2.13 (m, 6H), 2.62 - 2.75 (m, 2H), 2.91 (t, J= 2.6 Hz, 1H), 3.97 (s, 3H), 4.55 (p, J= 6.1 Hz, 1H), 4.62 (td, J= 1.9 / 62 Hz, 1H), 7.61 (dd, J= 8.4 / 1.5 Hz, 1H), 7.66 - 7.73 (m, 3H), 7.78 - 7.81 (m, 2H), 7.84 - 7.87 (m, 3H), 7.95 - 7.99 (m, 4H), 8.10 (d, 1.6 Hz, 1H), 9.41 (s, 1H),

[0498] 10.44 (s, 1H), 10.60 (s, 1H), 12.29 (s, 1H), 12.83 (s, 1H).13C NMR (126 MHz, DMSO-D6): 8 (ppm) = 21.5, 22.3, 27.6, 28.5, 32.9, 34.3, 38.2, 52.5, 73.1, 74.9, 80.5, 103.4, 111.4, 112.2, 112.5, 118.9, 120.1, 120.7, 122.8, 123.4, 125.3, 126.3, 128.4, 128.5, 130.2, 136.3, 137.0, 140.2, 140.7, 142.0, 142.2, 154.1, 162.3, 164.2, 166.9, 168.5, 169.7, 176.8. HRMS (ESI) calculated 836.3402 [M+H+], 836.3405 found.

[0499] 4-(4-{4-[(15,21?)-l-[4-(5-Cyano-l-methyl-1jH-1,3-benzodiazol-2-yl)bicyclo[2.2.2]octane-l- amido]-2-ethenylcyclopropaneamido]benzamido}-2-hydroxy-3-(propan-2-yloxy) benzamido)benzoic acid (Hdo294)

[0500] Step a: / ert-Butyl 4-(4-f4-r(l1S',27?)-1-r4-(5-cvano-l-methyl-lH-l,3-benzodiazol-2-yl)bicvclo I2.2.2]octane- 1 -amido]-2-ethenylcyclopropaneamido]benzamido }-2-(prop-2-en- 1 -yloxy)-3- (propan-2-yloxy)benzamido)benzoate

[0501] To a solution of the crude carboxylic acid (58 mg, 0.188 mmol, 1.00 eq.) and the amine hydrochloride (130 mg, 0.188 mmol, 1.00 eq.) in DMF (1.46 mL) were added HATU (79 mg, 0.207 mmol, 1.10 eq.) and DIPEA (131 pL, 0.752 mmol, 4.00 eq.) at 0°C. After the resulting mixture was stirred for 30 min at 0 °C, stirring was continued at rt for 19 h. Upon completion, sat. NaHCO3 solution (10 mL) was added and extracted with EtOAc (1 x 20 mL, 2 x 10 mL). The combined organic layers were washed with sat. NaHCO3 solution (10 mL) and brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (CH2C12MeOH). Colorless solid, 52 mg (29%).1H NMR (500 MHz, DMSO- D6): δ (ppm) = 1.25 - 1.27 (m, 6H), 1.54 (s, 9H), 1.76 - 1.92 (m, 8H), 2.06 - 2.12 (m, 6H), 3.97 (s, 3H), 4.45 - 4.50 (m, 1H), 4.60 (d, J= 5.5 Hz, 2H), 5.07 (d, J= 12.1 Hz, 1H), 5.20 (dt, J= 9.1 / 1.6 Hz, 1H), 5.24 - 5.30 (m, 1H), 5.37 (dt, J= 17.2 / 1.7 Hz, 1H), 5.49 - 5.58 (m, 1H), 6.01 (ddd, J= 11.6 / 10.5 / 5.2 Hz, 1H), 7.62 (dd, J= 8.4 / 1.5 Hz, 1H), 7.73 (dd, J= Hz, 2H), 7.76 - 7.84 (m, 5H), 7.89 (d, J= 8.8 Hz, 3H), 7.96 - 8.00 (m, 3H), 8.13 (s, 1H), 9.57 (s, 1H), 9.73 (s, 1H), 10.56 (s, 1H).13C NMR (176 MHz, DMSO-D6): δ (ppm) = 20.5, 22.3, 22.9, 27.3, 27.9, 28.5, 34.3, 38.2, 42.3, 59.8, 74.3, 76.3, 80.3, 103.4, 111.4, 117.1, 117.8, 118.8, 120.1, 123.4, 123.7, 125.3, 126.0, 127.1, 128.2, 128.5, 130.1, 133.7, 134.6, 135.6, 140.8, 142.0, 142.5, 143.0, 149.5, 162.3, 164.3, 164.6, 164.6, 168.2, 178.3.

[0502] Step b: tert-Butyl 4-(4-(4-r(lS,2R’)-l-[4-(5-cvano-l-methyl-lH-L3-benzodiazol-2-yl')bicyclo r2.2.2]octane-l-amido]-2-ethenylcyclopropaneamido]benzamido}-2-(prop-2-en-l-yloxy)-3- (propan-2 -yloxy)benzamido)benzoate

[0503] To a solution of the allyl ether (48 mg, 0.051 mmol, 1.00 eq.) in dry THF (383 pL) were added aniline (18 pL, 0.203 mmol, 4.00 eq.) and Pd(PPh3)4 (2 mg, 0.04 eq.) and the resulting mixture was stirred at rt for 3 h. After completion, sat. NH4CI solution (10 mL) was added and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was used without further purification.

[0504] Step c:

[0505] To a solution of the crude tert-butyl ester in dry CH2CI2 (551 pL) was added TFA (215 pL, 2.79 mmol, 55.0 eq.) at 0 °C and the resulting solution was stirred for 3 h at 0 °C. After all volatiles were removed in vacuo the residue was purified by RP-HPLC (H2O with 10 mM NFLHCCL / Acetonitrile) and freeze-dried. Colorless solid, 20 mg (46%). *H NMR (500 MHz, DMSO-D6): 5 (ppm) = 1.12 - 1.17 (m, 1H), 1.26 (dd, J= 6.1 / 2.7 Hz, 6H), 1.86 (dt, J= 17.5 / 7.8 Hz, 7H), 2.09 (t, J= 7.8 Hz, 6H), 2.32 (q, J= 8.7 Hz, 1H), 3.97 (s, 3H), 4.53 (hept, J= 6.1 Hz, 1H), 5.04 - 5.08 (m, 1H), 5.27 (dd, J= Y1AIX.9 Hz, 1H), 5.49 - 5.57 (m, 1H), 7.61 (dd, J = 8.4 / 1.5 Hz, 1H), 7.68 - 7.76 (m, 4H), 7.86 (dt, J= 9.1 / 2.2 Hz, 3H), 7.94 - 7.99 (m, 4H), 8.08 - 8.16 (m, 2H), 9.44 (s, 1H), 9.74 (s, 1H), 10.63 (s, 1H), 12.31 (s, 1H), 12.87 (s, 1H).13C NMR (176 MHz, DMSO-D6): 5 (ppm) = 20.5, 22.3, 27.3, 28.4, 31.6, 32.9, 34.3, 38.2, 42.4, 74.9, 103.7, 111.5, 112.1, 112.4, 117.1, 118.9, 120.0, 120.7, 122.8, 123.2, 125.4, 126.3, 128.1, 128.4, 128.4, 130.2, 134.6, 136.3, 137.0, 140.0, 142.0, 142.1, 154.1, 162.2, 164.2, 166.9, 168.2, 168.5, 178.3. HRMS (ESI) calculated 850.3559 [M+H+], 850.3570 found.

[0506] 4-(4-{4-[(2A)-2-{[4-(6-Cyano-l-methyl-17 / -l,3-benzodiazoI-2-yI)phenyi|forinamido}pent- 4-ynamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid (DK980)

[0507]

[0508] The amino acid derivative (103.4 pmol) was coupled with the carboxylic acid using General Procedure 8. The product was obtained by deprotection with General Procedures 10 and 11. Colorless solid, 47 mg (57% over 3 steps). ’H-NMR (500 MHz, DMSO-de, 300 K): δ (ppm) = 12.83 (br s, 1H), 12.30 (br s, 1H), 10.66 (s, 1H), 9.42 (s, 1H), 9.10 (d, 1H, J = 7.5 Hz), 8.36 (d, 1H, J = 0.9 Hz), 8.14 (d, 2H, J = 8.6 Hz), 8.05 (d, 2H, J = 8.5 Hz), 7.99 - 7.95 (m, 4H), 7.88 (dd, 1H, J = 0.4 Hz, 8.4 Hz), 7.87 - 7.82 (m, 5H), 7.70 - 7.65 (m, 2H), 4.85 (dd, 1H, J = 7.8 Hz, 14.6 Hz), 4.55 (hept., 1H, J = 6.1 Hz), 3.99 (s, 3H), 2.97 (t, 1H, J = 2.6 Hz), 2.88 - 2.76 (m, 2H), 1.26 (d, 6H, J = 6.2 Hz).13C-NMR (126 MHz, DMSO-d6, 300 K): δ (ppm) = 169.5, 168.5, 166.9, 165.9, 164.2, 155.6, 154.3, 145.3, 142.2, 142.1, 137.0, 136.4, 136.4, 135.1, 132.0, 130.2, 129.5, 128.6, 128.4, 128.0, 126.2, 125.5, 122.8, 120.7, 120.2, 119.9, 116.3, 112.5, 112.0, 104.3, 80.6, 74.8, 73.2, 53.6, 32.2, 22.3, 21.4. HRMS (ESI) calculated 804.2776 [M+H+], 804.2767 found.

[0509] 4-(4-{4-[(2S)-2-{[4-(6-Cyano-l-ethyl-1H-1,3-benzodiazol-2-yI)phenyl]formamido}pent-4- ynamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid (MLel7)

[0510] Step a: ZerZ-Butyl 4-(4-(4-r(2Sr)-2-fr4-(6-cyano-l-ethyl-l / 7-l,3-benzodiazol-2-yl)phenyl1 formamido}pent-4-ynamido]benzamido}-2-(prop-2-en-l-yloxy)-3-(propan-2-yloxy) benzamido)benzoate To a solution of the crude carboxylate (40 mg, 0.12 mmol, 1.17 eq.) and amine hydrochloride (70 mg, 0.10 mmol, 1.00 eq.) in DMF (1.0 mL) were added HATU (60 mg, 0.16 mmol, 1 .52 eq.) and DIPEA (760 pL, 0.44 mmol, 42.2 eq.) at 0°C. Upon completion, HC1 solution (1 M, 50 mL) was added and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over Na2SCO4 and concentrated in vacuo. The crude product was used without further purification.

[0511] Step b: tert-Butyl 4-(4-{4-r(2S)-2-fr4-(6-cyano-l-ethyl-lZ / -L3-benzodiazol-2-yl)phenyl1 formamido}pent-4-vnamido1benzamidol-2-hvdroxy-3-(proDan-2-yloxy)benzamido)benzoate To a solution of the crude allyl ether in dry THF (1 mL) were added aniline (30 pL, 0.33 mmol, 3.20 eq.) and Pd(PPh3)4 (6 mg, 0.05 eq.) at 0 °C overnight. After completion, all volatiles were removed in vacuo. The remaining residue was coevaporated with n-heptane and purified by flash chromatography (petroleum ether / EtOAcC1 / MeOH) to furnish the product (90 mg, quant, yield). LC-MS: m / z = 874.3 (calcd. 874.36 for C5oH48N708+[M+H+]).

[0512] Step c:

[0513] To a solution of the tert-butyl ester (90 mg, 0.103 mmol, 1.00 eq.) in dry CH2CI2 (860 pL) was added TFA (432 pL, 5.61 mmol, 54.5 eq.) at 0 °C and the resulting solution was stirred for 20 min at 0 °C before stirring was continued at rt for 1 h. After all volatiles were removed in vacuo the residue was purified by RP-HPLC (H2O with 10 mM NH4HCO3 / Acetonitrile) and freeze-dried. Off-white solid, 34 mg (40%). 'H NMR (700 MHz, DMSO-De) S(ppm) 12.77 (s, 1H), 12.30 (s, 1H), 10.60 (s, 1H), 9.36 (s, 1H), 9.08 (d, J = 7.6 Hz, 1H), 8.40 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.99 - 7.93 (m, 6H), 7.88 (d, J = 8.4 Hz, 1H), 7.87 - 7.78 (m, 5H), 4.85 (q, J = 7.5 Hz, 1H), 4.60 (s, 1H), 4.43 (q, J = 7.2 Hz), 2.96 (t, J = 2.6 Hz, 1H), 2.88 - 2.75 (m), 1.34 (t, J = 7.2 Hz), 1.26 (d, J = 6.1 Hz).13C NMR (176 MHz, DMSO-D6) 5(ppm) 169.6, 168.4, 166.9, 166.0, 164.1, 155.2, 145.5, 142.3, 142.1, 136.7, 136.5, 135.2, 132.2, 130.2, 129.2, 128.7, 128.3, 128.1, 125.6, 122.9, 120.5, 120.4, 119.9, 119.4, 119.0, 116.4, 112.8, 112.8, 104.4, 80.6, 74.4, 73.2, 53.6, 39.7, 22.421.4, 15.0. HRMS (ESI) calculated 818.2933 [M+H+], 818.2932 found.

[0514] 4-(4-{4-[(1S',27?)-1-[3-(6-Cyano-l-methyl-1.H--1,3-benzodiazol-2-yl)bicycIo[l.l.l]pentane-

[0515] 1 -amido] -2-ethenylcyclopropaneamido] benzamido}-2-hy droxy-3-(propan-2-yloxy) benzamido)benzoic acid (Hdo425)

[0516]

[0517] Step a: terZ-Butyl 4-(4-{4-[(l<S',2R)-l-[3-(6-cvano-l-methyl-l / 7-L3-benzodiazol-2-yl)bicvclo [1.1.1 Ipentane- 1 -amido]-2-ethenylcvclopropaneamido]benzamido}-2-(prop-2-en- 1 -yloxy)-3- (propan-2-yloxy)benzamido)benzoate

[0518] To a solution of the crude carboxylate (48 mg, 0.158 mmol, 1.00 eq.) and the amine hydrochloride (109 mg, 0.158 mmol, 1.00 eq.) in DMF (610 qL) were added HATU (72 mg, 0.189 mmol, 1.20 eq.) and DIPEA (110 qL, 0.631 mmol, 4.00 eq.) at 0°C. After the resulting mixture was stirred for 30 min at 0 °C, stirring was continued at rt for 16 h. Upon completion, sat. NaHCO3 solution (10 mL) was added and extracted with EtOAc (3 x l0 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2 / MeOH). Colorless solid, 68 mg (47%). 1H NMR (700 MHz, DMSO-D6): δ (ppm) = 1.25 - 1.27 (m, 7H), 1.55 (s, 9H), 1.85 - 1.89 (m, 1H), 2.31 (q, J= 8.8 Hz, 1H), 2.56 (s, 6H), 3.90 (s, 3H), 4.50 (p, J= 6.1 Hz, 1H), 4.61 (d, . / = 5.4 Hz, 2H), 5.08 (d, J= 11.8 Hz, 1H), 5.19 - 5.22 (m, 1H), 5.29 (d, J= 17.1 Hz, 1H), 5.37 (dd, J= 17.2 / 1.5 Hz, 1H), 5.58 (dt, J= 17.2 / 9.4 Hz, 1H), 6.02 (ddt, J= 16.1 / 10.8 / 5.5 Hz, 1H), 7.41 (d, J= 8.4 Hz, 1H), 7.57 (dd, J= 8.3 / 1.4 Hz, 1H), 7.75 (dd, J= 8.4Z6.9 Hz, 3H), 7.82 (t, J= 8.5 Hz, 3H), 7.89 (d, J= 8.7 Hz, 2H), 7.99 (d, J = 8.7 Hz, 2H), 8.20 (s, 1H), 8.58 (s, 1H), 9.53 (s, 1H), 9.84 (s, 1H), 10.53 (s, 1H).13C NMR (176 MHz, DMSO-D6): δ (ppm) = 22.3, 27.9, 30.9, 31.5, 34.9, 40.8, 41.9, 53.1, 53.6, 74.3, 76.3, 80.3, 103.8, 115.5, 117.2, 117.8, 118.8, 119.0, 119.3, 119.8, 120.0, 123.6, 125.0, 126.0, 127.1, 128.4, 128.6, 130.1, 133.7, 134.4, 135.6, 135.8, 141.9, 142.5, 143.0, 144.8, 149.5, 154.9, 164.3, 164.5, 164.6, 167.9, 170.0.

[0519] Step b: fert-Butyl 4-(4-14-[(15l.2R)-l-r3-(6-cvano-l-methyl- l,3-benzodiazol-2-yl)bicyclo [1.1.1 Ipentane- 1 -amidol^-ethenylcyclopropaneamidolbenzamido) ^-hydroxy-S-lpropan^- yloxylbenzamidoIbenzoate To a solution of the allyl ether (65 mg, 0.072 mmol, 1.00 eq.) in diy THF (542 μL ) were added aniline (26 pL, 0.288 mmol, 4.00 eq.) and Pd(PPh3)4 (3 mg, 0.04 eq.) and the resulting mixture was stirred at rt for 3 h. After completion, water (10 mL) was added and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO 4 and concentrated in vacuo. The residue was purified by flash chromatography (CH2C12MeOH). Colorless solid, 55 mg (89%). 'H NMR (700 MHz, DMSO- D6): 5 (ppm) = 1.25 - 1.28 (m, 7H), 1.55 (s, 9H), 1.86 - 1.89 (m, 1H), 2.31 (q, J= 8.8 Hz, 1H), 2.56 (s, 6H), 3.89 (s, 3H), 4.55 (p, J= 6.1 Hz, 1H), 5.08 (d, J= 12.0 Hz, 1H), 5.29 (d, J= 17.1 Hz, 1H), 5.54 - 5.61 (m, 1H), 7.57 (dd, J= 8.3 / 1.4 Hz, 1H), 7.71 (d, J= 8.8 Hz, 1H), 7.74 (d,

[0520] 8.3 Hz, 1H), 7.76 (d, J= 8.7 Hz, 2H), 7.85 (d, J = 8.8 Hz, 3H), 7.93 (d, J= 8.7 Hz, 2H), 7.96 (d, 8.7 Hz, 2H), 8.20 (s, 1H), 8.59 (s, 1H), 9.41 (s, 1H), 9.85 (s, 1H), 10.61 (s, 1H),

[0521] 12.29 (s, 1H).13C NMR (126 MHz, DMSO-D6): δ (ppm) = 22.4, 27.9, 30.9, 31.6, 35.0, 40.9, 41.9, 53.2, 74.9, 80.6, 103.8, 112.3, 112.5, 115.6, 117.3, 119.4, 119.9, 120.1, 120.7, 122.9, 125.1, 126.8, 128.4, 128.6, 130.0, 134.5, 135.8, 136.4, 137.1, 142.0, 142.1, 144.8, 154.2, 155.0, 164.2, 164.6, 168.0, 168.5, 170.1.

[0522] Step c:

[0523] To a solution of the terf-butyl ester (45 mg, 0.052 mmol, 1.00 eq.) in dry CH2CI2 (565 pL) was added TFA (221 pL, 2.87 mmol, 55.0 eq.) at 0 °C and the resulting solution was stirred for 3 h at 0 °C. After all volatiles were removed in vacuo the residue was purified by RP-HPLC (H2O / ACN with 0.1% HCOOH) and freeze-dried. Colorless solid, 27 mg (64%).!H NMR (700 MHz, DMSO-D6): 3 (ppm) = 1.25 - 1.28 (m, 7H), 1.85 - 1.88 (m, 1H), 2.31 (q, J = 8.8 Hz, 1H), 2.56 (s, 6H), 3.89 (s, 3H), 4.55 (hept, J= 6.1 Hz, 1H), 5.08 (d, J= 12.0 Hz, 1H), 5.29 (d, J= 17.1 Hz, 1H), 5.54 - 5.61 (m, 1H), 7.57 (dd, 8.3 / 1.4 Hz, 1H), 7.71 (d, J= 8.8 Hz, 1H), 7.74 (d, 7 = 8.3 Hz, 1H), 7.76 (d, J= 8.7 Hz, 2H), 7.84 - 7.87 (m, 3H), 7.95 - 7.98 (m, 4H), 8.19 (s, 1H), 8.59 (s, 1H), 9.41 (s, 1H), 9.85 (s, 1H), 10.60 (s, 1H), 12.30 (s, 1H).13C NMR (176 MHz, DMSO-D6): δ (ppm) = 20.6, 22.3, 22.3, 30.9, 31.6, 35.0, 40.9, 41.9, 53.2, 74.9, 103.9, 112.2, 112.5, 115.5, 117.3, 119.4, 119.8, 120.0, 120.8, 122.9, 125.1, 126.3, 128.3, 128.6, 130.2, 134.4, 135.8, 136.3, 137.1, 142.0, 142.1, 144.7, 154.1, 155.0, 164.2, 166.9, 168.0, 168.5, 170.1. HRMS (ESI) calculated 808.3089 [M+H+], 808.3114 found. 4-(4-{4-[(15’,2R )-l-[3-(6-Cyano-l-ethyl-1H ,3-benizodiazol-2-yl)bicyclo[l.l.l]pentane-l- amido|-2-ethenylcyclopropaneanudo]benzamido}-2-hydroxy-3-(propan-2-yloxy) benzamido)benzoic acid (MLel8)

[0524] Step a and b: tert-Butyl 4-(4-f4-r(lS,2R)-l-r3-(6-cvano-l-ethyl-l / 7-L3-benzodiazol-2-yl) bicyclo 1.1.1 (pentane- 1 -amido]-2-ethenylcvclopropaneamido]benzamido 1 -2 -hydroxy-3 - (propan-2 -yloxy)benzamido)benzoate

[0525] To a solution of the crude carboxylate (40 mg, 0.13 mmol, 1.17 eq.) and amine (70 mg, 0.11 mmol, 1.00 eq.) in DMF (1.0 mL) were added HATU (43 mg, 0.11 mmol, 1.07 eq.) and DIPEA (76 pL, 0.44 mmol, 4.10 eq.) at 0°C. Upon completion, aniline (30 pL, 0.33 mmol, 3.10 eq.), Pd(PPha)4 (6 mg, 0.05 eq.) and THF (1.0 mL) were added and stirring was continued at 0 °C. After complete deally lation, all volatiles were removed in vacuo. The remaining residue was coevaporated with n-heptane and purified by flash chromatography(petroleum ether / EtOAcCh / MeOH) to furnish the product (89 mg, 95%).

[0526] Step c:

[0527] To a solution of the tert-butyl ester (89 mg, 0.10 mmol, 1.00 eq.) in dry CH2O2 (790 pL) was added TFA (426 pL, 5.52 mmol,- 54.5 eq.) at 0 °C and- the resulting solution was stirred for 20 min at 0 °C before stirring was continued at rt for 1 h. After all volatiles were removed in vacuo the residue was purified by RP-HPLC (H2O with 10 mM NHfrdCCh / Acetonitrile) and freeze-dried. Off-white solid, 34 mg (41%). *H NMR (500 MHz, DMSO-d6) 5(ppm) 12.57 (s, 2H), 9.85 (s, 1H), 9.15 (s, 1H), 8.63 (s, 1H), 8.24 (d, J = 1.4 Hz, 1H), 7.95 - 7.86 (m, 4H), 7.85 - 7.78 (m, 2H), 7.75 (dd, J = 8.6, 1.8 Hz, 3H), 7.64 (s, 1H), 7.58 (dd, J = 8.4, 1.5 Hz, 1H), 7.37 (d, J = 15.2 Hz, 1H), 5.58 (ddd, J = 17.1, 10.4, 9.1 Hz, 1H), 5.29 (dd, J = 17.1, 1.9 Hz, 1H), 5.14 - 5.02 (m, 1H), 4.79 (s, 1H), 4.39 (q, J = 7.2 Hz, 2H), 2.57 (s, 6H), 2.30 (q, J = 8.7 Hz, 1H), 1.87 (dd, J = 7.6, 5.3 Hz, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.28 - 1.25 (m, 1H), 1.23 (dd, J = 6.2, 3.3 Hz, 6H).13CNMR (126 MHz, DMSO) 5(ppm) 170.0, 168.0, 167.9, 167.1, 163.7, 163.4, 154.4, 145.0, 141.9, 141.8, 137.0, 134.7, 134.5, 130.4, 129.2, 128.0, 125.2, 123.3, 120.0, 120.0, 119.5, 117.3, 115.5, 103.9, 72.6, 53.4, 41.9, 40.6, 38.9, 34.9, 31.6, 22.5, 20.6, 15.5. HRMS (ESI) calculated 822. 3246 [M+H+], 822.3239 found.

[0528] 4-{4-[4-(2-{[4-(4-Cyanobenzamido)phenyl]formamido}-3-methyI-3-iiitrobutanamido) benzamido]-2-hydroxy-3-(propan-2-yloxy)benzamido}benzoic acid (TSF14)

[0529] Step a: fert-Butyl 4-f4-I4-(2-(r4-(4-cyanobenzamido)phenyl1formamido}-3-methyl-3- nitrobutanamido)benzamido1-2-(prop-2-en-l-yloxy)-3-(propan-2-yloxy)benzamidolbenzoate DIPEA (230 pL, 1.32 mmol, 3.00 equiv.) was added dropwise to a stirred solution of HATU (200 mg, 0.53 mmol, 1.20 equiv.) and the carboxylic acid (140 mg, 0.53 mmol, 1.20 equiv.) in DMF (11 mL). The solution was stirred for 5 min and then transferred to a stirred solution of the amine (303 mg, 0.44 mmol) in DMF (6 mL) at 0 °C. The reaction mixture was stirred at 20 h while warming to rt. The mixture was diluted with EtOAc and washed with a 1 M HC1 solution, brine, dried over MgSCL and concentrated under reduced pressure. The crude residue was purified by column chromatography (2% MeOH in CH2CI2) to furnish the product (315 mg, 0.34 mmol, 77%) as orange amorphous solid. 'H-NMR (500 MHz, DMSO-de) 3 = 10.71 (s, 1H), 10.70 (s, 1H), 10.53 (s, 1H), 9.56 (s, 1H), 8.77 (d, J= 9.2 Hz, 1H), 8.13 (d, J= 8.5 Hz, 2H), 8.05 (d, J= 8.5 Hz, 2H), 7.99 (d, J= 8.8 Hz, 2H), 7.96 (d, 8.8 Hz, 2H), 7.91-7.88 (m,

[0530] 4H), 7.84-7.79 (m, 5H), 7.41 (d, J= 8.4 Hz, 1H), 6.05-5.98 (m, 1H), 5.70 (d, J= 9.3 Hz, 1H), 5.37 (dq, J= 1.6, 17.2 Hz, 1H), 5.20 (dq, J= 1.5, 10.5 Hz, 1H), 4.61 (d, J= 5.4 Hz, 2H), 4.49 (sept, J= 6.1 Hz, 1H), 1.76 (s, 3H), 1.69 (s, 3H), 1.55 (s, 9H), 1.26 (d, J= 6.1 Hz, 6H) ppm.13C-NMR (126 MHZ, DMSO-d6) 8 = 168.6, 166.8, 166.7, 164.6, 164.5, 164.2, 149.5, 143.0, 142.6, 141.9, 141.5, 138.6, 135.6, 133.7, 132.5, 130.1, 129.1, 128.9, 128.7, 128.6, 128.4, 127.6, 127.2, 126.0, 123.6, 119.9, 119.5, 119.4, 118.8, 117.8, 114.1, 89.0, 80.3, 76.2, 74.3, 58.5, 27.9, 23.2, 22.9, 22.3 ppm. HRMS (ESI) calculated for CsiHsiNyOnNa [M+Na]+: 960.3544; found: 960.3557. Step b: ferZ-Butyl 4-f4-[4-(2-f [4-(4-cyanobenzamido)phenyl1formamido}-3-methyl-3- nitrobutanamido)benzamidol-2-hvdroxy-3-(propan-2-vIoxy)benzamido}benzoate

[0531] The allyl ether (56.8 mg, 0.06 mmol) was dissolved in THF (2.7 mL). Aniline (18 pL, 0.20 mmol, 3.30 equiv.) and Pd(PPh3)4 (7.0 mg, 6 pmol, 0.10 equiv.) were added subsequently and the resulting mixture was stirred at rt for 90 min. The mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (dry load, 2% MeOH in CH2CI2) to furnish the product (57.3 mg, 0.05 mmol, 84%) as yellow solid, which was of 80% purity. The compound was used in the next step without further purification. HRMS (ESI) calculated for C48H46N7O11 [M-H]’: 896.3255; found: 896.3212.

[0532] Step c:

[0533] The tert-butyl ester (19.8 mg, 0.02 mmol) was dissolved in precooled TFA (1.1 mL) at 0 °C with stirring. The solution was warmed up to rt over 30 min. Et2O was added at 0 °C. The precipitate was filtered off, washed with excess of Et2O and dried in vacuo to furnish the product (11.4 mg, 0.01 mmol, 61%) as colorless solid. *H-NMR (500 MHz, DMSO-de) 8 = 12.82 (s, 1H), 12.28 (s, 1H), 10.71 (bs, 2H), 10.60 (s, 1H), 9.44 (s, 1H), 8.77 (d, J= 9.3 Hz, 1H), 8.13 (d, J= 8.6 Hz, 2H), 8.05 (d, J= 8.6 Hz, 2H), 7.98-7.94 (m, 6H), 7.91 (d, J= 8.9 Hz, 2H), 7.86-7.84 (m, 3H), 7.81 (d, J= 8.8 Hz, 2H), 7.69 (d, J= 8.9 Hz, 1H), 5.70 (d, 9.3 Hz,

[0534] 1H), 4.53 (sept, J= 6.1 Hz, 1H), 1.76 (s, 3H), 1.70 (s, 3H), 1.26 (d, J= 6.1 Hz, 6H) ppm.I3C-NMR (126 MHz, DMSO-de) 8 = 168.5, 166.9, 166.8, 166.7, 164.5, 164.2, 154.1, 142.0, 141.9, 141.6, 138.6, 137.0, 136.4, 132.5, 130.2, 129.1, 128.9, 128.7, 128.6, 128.3, 126.3, 122.8, 120.7, 119.6, 119.4, 118.3, 114.1, 112.5, 112.3, 89.0, 74.9, 58.5, 23.2, 22.9, 22.3 ppm. HRMS (ESI) calculated for C44H38N7O11 [M-H]': 840.2629; found: 840.2632.

[0535] 4-(4-{4-[(15,,2 / ?)-l-[4-(4-Cyanobenzamido)benzamido]-2-ethenylcycIopropaneamido] benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid (Hdol27)

[0536]

[0537] Step a: 4-(4-(4-[(l>S',27?)-l-r4-(4-Cyanobenzamido)benzamido1-2 -ethenylcyclopropaneamidol benzamido } -2-(prop-2-en- 1 -yloxy)-3 -(propan-2- yloxy )benzamido)benzoic acid

[0538] To a solution of the carboxylic acid (47 mg, 0.177 mmol, 1.25 eq.) in dry DMF (518 pL) were added HATU (54 mg, 0.142 mmol, 1.00 eq.) and DIPEA (99 pL, 0.567 mmol, 4.00 eq.) at O °C. After 30 min, the amin hydrochloride (90 mg, 0.142 mmol, 1.00 eq.) dissolved in dry DMF (518 pL) was added and stirring was continued at 0 °C for 30 min before the mixture was stirred overnight at rt. HC1 solution (0.5 M, 10 mL) was added to the reaction mixture and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with HC1 solution (0.5 M, 10 mL), water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (CFhCh / MeOH). Colorless solid, 47 mg (39%). ‘H NMR (700 MHz, DMSO-D6): δ (ppm) = 1.25 (dd, J= 6.1 / 4.3 Hz, 6H), 1.31 - 1.35 (m, 1H), 1.91 - 1.94 (m, 1H), 2.44 (q, J= 8.8 Hz, 1H), 4.49 (hept, J= 6.2 Hz, 1H), 4.61 (d, J= 5.5 Hz, 2H), 5.08 - 5.11 (m, 1H), 5.20 (dq, J= 10.4 / 1.5 Hz, 1H), 5.31 (d, J= 17.1 Hz, 1H), 5.37 (dq, J = 17.2 / 1.7 Hz, 1H), 5.68 (dt, J= 17.2 / 9.7 Hz, 1H), 6.02 (ddt, J= 16.1 / 10.7 / 5.5 Hz, 1H), 7.40 (d, J= 8.4 Hz, 1H), 7.77 (d, J= 8.5 Hz, 2H), 7.82 (dd, J= 14.1 / 8.5 Hz, 3H), 7.90 (d, J= 8.6 Hz, 2H), 7.93 (d, J= 8.6 Hz, 2H), 7.96 (d, J= 8.7 Hz, 2H), 7.99 (d, J= 8.6 Hz, 2H), 8.03 - 8.06 (m, 2H), 8.13 (d, J= 8.4 Hz, 2H), 9.03 (s, 1H), 9.51 (s, 1H), 10.00 (s, 1H), 10.52 (s, 1H), 10.71 (s, 1H), 12.45 (s, 1H).I3C NMR (176 MHZ, DMSO-D6): δ (ppm) = 21.1, 21.4, 22.4, 42.4, 74.3, 76.3, 114.1, 117.1, 117.8, 118.3, 118.9, 119.0, 119.5, 120.7, 123.7, 125.5, 127.2, 128.3, 128.5, 128.7, 128.8, 129.1, 130.4, 132.6, 133.7, 134.7, 135.7, 138.7, 141.8, 142.2, 142.6, 143.1, 149.6,

[0539] 164.3, 164.5, 164.6, 166.9 - 167.1 (m), 168.4, 172.1.

[0540] Step b:

[0541] To a solution of the allyl ether (41 mg, 0.048 mmol, 1.00 eq.) in dry THF (365 pL) were added aniline (18 pL, 0.194 mmol, 4.00 eq.) and Pd(PPh3)4 (2 mg, 0.04 eq.) and the resulting mixture was stirred at rt for 3 h. After completion, HC1 solution (0.5 M, 10 mL) was added and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with HC1 solution (0.5 M, 10 mL) and brine (10 mL), dried over Na2SC>4 and concentrated in vacuo. The residue was purified by RP-HPLC (H2O with 10 mM NH4HCO3 / Acetonitrile) and freeze-dried. Colorless solid, 21 mg (54%). ’H NMR (700 MHz, DMSO-D6): δ (ppm) = 1.24 - 1.26 (m, 6H), 1.31 - 1.35 (m, 1H), 1.92 (t, 1H), 2.44 (q, J = 8.7 Hz, 1H), 4.54 (hept, J= 6.1 Hz, 1H), 5.10 (d, J= 12.1 Hz, 1H), 5.31 (d, J= 17.1 Hz, 1H), 5.67 (dt, J= 17.1 / 9.7 Hz, 1H), 7.68 (d, J= 8.8 Hz, 1H), 7.78 (d, J= 8.6 Hz, 2H), 7.82 - 7.87 (m, 3H), 7.90 (d, J= 8.6 Hz, 2H), 7.93 (d, J= 8.8 Hz, 2H), 7.95 - 7.97 (m, 2H), 7.99 (d, J= 8.6 Hz, 2H), 8.03 - 8.06 (m, 2H), 8.11 - 8.15 (m, 2H), 9.03 (s, 1H), 9.39 (s, 1H), 10.01 (s, 1H), 10.67 (s, 1H), 10.71 (s, 1H), 12.28 (s, 1H), 12.80 (s, 1H).13C NMR (176 MHZ, DMSO-D6): δ (ppm) = 21.4, 22.3, 32.2, 42.4, 74.8, 111.9, 112.5, 114.1, 117.2, 118.3, 119.5, 119.6, 120.7, 122.9, 126.3, 128.2, 128.5, 128.7, 129.1, 130.2, 132.6, 134.7, 136.4, 137.0, 138.7, 141.8, 142.1, 142.3, 154.2, 164.2, 164.5, 166.9, 167.0, 168.5, 168.5. HRMS (ESI) calculated 807.2773 [M+H+], 807.2752 found.

[0542] 4-(4-{4-|(l / ?,2A)-l-[4-(4-Cyanobenzamido)benzamido]-2-ethenylcyclopropaneamido] benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid (Hdol33)

[0543] Step a: 4-(4-f4-l(lR,2.S)-l-r4-(4-Cyanobenzamido)benzamido]-2-ethenylcvclopronaneamido] benzamido } -2-(prop-2-en- 1 -yloxy)-3 -(propan-2 -yloxy)benzamido)benzoic acid

[0544] To a solution of the carboxylic acid (58 mg, 0.216 mmol, 1.25 eq.) in dry DMF (300 pL) were added HATU (66 mg, 0.173 mmol, 1.00 eq.) and DIPEA (121 pL, 0.693 mmol, 4.00 eq.) at 0 °C. After 30 min, the amine hydrochloride (110 mg, 0.173 mmol, 1.00 eq.) dissolved in dry DMF (650 pL) was added and stirring was continued at 0 °C for 30 min before the mixture was stirred overnight at rt. HC1 solution (0.5 M, 10 mL) was added to the reaction mixture and extracted with EtOAc (3 x l0 mL). The combined organic layers were washed with HC1 solution (0.5 M, 10 mL), water (10 mL) and brine (10 mL), dried overNa2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (CIHhCh / MeOH). Colorless solid, 61 mg (41%). *H NMR (500 MHz, DMSO-D6): 5 (ppm) = 1.25 (dd, J= 6A / 3A Hz, 6H), 1.31

[0545] - 1.35 (m, 1H), 1.93 (dd, J= 7.7 / 5 A Hz, 1H), 2.45 (q, J= 8.7 Hz, 1H), 4.48 (p, 6.2 Hz, 1H),

[0546] 4.59 - 4.63 (m, 2H), 5.06 - 5.12 (m, 1H), 5.20 (dq, 10.5 / 1.4 Hz, 1H), 5.28 - 5.40 (m, 2H), 5.68 (ddd, J= 17.1 / 10.5 / 9.1 Hz, 1H), 5.97 - 6.07 (m, 1H), 7.40 (d, J= 8.5 Hz, 1H), 7.76 - 7.84 (m, 5H), 7.88 - 8.00 (m, 8H), 8.04 - 8.06 (m, 2H), 8.11 - 8.15 (m, 2H), 9.03 (s, 1H), 9.52 (s, 1H), 10.00 (s, 1H), 10.53 (s, 1H), 10.71 (s, 1H), 12.72 (s, 1H).13C NMR (126 MHz, DMSO- D6): δ (ppm) = 21.4, 22.2 - 22.4 (m), 32.2, 42.4, 74.3, 76.3, 114.1, 117.1, 117.8, 118.3, 118.9, 119.0, 119.4 - 119.6 (m), 120.7, 123.6, 125.5, 127.2, 128.3, 128.5, 128.7, 128.9, 129.1, 130.4, 132.6, 133.7, 134.7, 135.6, 138.6, 141.8, 142.1, 142.6, 143.0, 151.1, 164.3, 164.5, 164.6, 166.9, 167.0, 168.4. LC-MS: m / z = 847.5 (calcd. 847.31 for C48H43N6O9+[M+H+]).

[0547] Step b:

[0548] To a solution of the allyl ether (48 mg, 0.057 mmol, 1.00 eq.) in dry THF (428 pL) were added aniline (21 pL, 0.227 mmol, 4.00 eq.) and Pd(PPh3)4 (3 mg, 0.04 eq.) and the resulting mixture was stirred at rt for 3 h. After completion, HC1 solution (0.5 M, 10 mL) was added and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with HC1 solution (0.5 M, 10 mL) and brine (10 mL), dried over Na SCU and concentrated in vacuo. The residue was purified by RP-HPLC (H2O with 10 mM NH4HCO3 / Acetonitrile) and freeze-dried. Colorless solid, 24 mg (51%). *HNMR (700 MHz, DMSO-D6): δ (ppm) = 1.25 - 1.27 (m, 6H), 1.34 (dt, J= 9.4 / 4.2 Hz, 1H), 1.91 - 1.94 (m, 1H), 2.44 (q, J= 8.7 Hz, 1H), 4.54 (hept, J= 6.1 Hz, 1H), 5.08 - 5.11 (m, 1H), 5.31 (dd, J= 17.1 / 1.8 Hz, 1H), 5.64 - 5.71 (m, 1H), 7.69 (d, J= 8.9 Hz, 1H), 7.77 - 7.80 (m, 2H), 7.83 - 7.87 (m, 3H), 7.89 - 7.92 (m, 2H), 7.92 - 7.95 (m, 2H), 7.96

[0549] - 7.98 (m, 2H), 7.98 - 8.01 (m, 2H), 8.04 - 8.06 (m, 2H), 8.12 - 8.15 (m, 2H), 9.04 (s, 1H), 9.39 (s, 1H), 10.02 (s, 1H), 10.64 (s, 1H), 10.71 (s, 1H), 12.29 (s, 1H), 12.82 (s, 1H).13C NMR (176 MHz, DMSO-D6): δ (ppm) = 21.4, 22.3 - 22.3 (m), 32.2, 42.4, 74.8, 112.1, 112.5, 114.1, 117.1, 118.3, 119.5, 119.6, 120.7, 122.9, 126.3, 128.2, 128.5, 128.6, 129.1, 130.2, 132.5, 134.7, 136.3, 137.0, 138.6, 141.8, 142.0, 142.3, 154.2, 164.2, 164.5, 166.9, 167.0, 168.4, 168.5. HRMS (ESI) calculated 807.2773 [M+H+], 807.2791 found. 4-(4-{4-[(15',2 / f)-l-[3-(4-Cyanobenzamido)bicyclo[l.l.l]pentane-l-amido]-2-ethenyl- cyclopropaneamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid (HdolSO)

[0550] Step a: fer / -Butyl 4-(4-14-r(l£2.R)-1-[3-(4-cyanobenzamido)bicvclo[T.Ll]pentane-l-amido]- 2-ethenylcyclopropaneamido]benzamido}-2-(prop-2-en-l-yloxy)-3-(propan-2- yloxy)benzamido)benzoate

[0551] To a solution of the carboxylic acid (26 mg, 0.102 mmol, 1.20 eq.) in dry DMF (336 pL) were added HATU (39 mg, 0.102 mmol, 1.20 eq.) and DIPEA (59 pL, 0.341 mmol, 4.00 eq.) at O °C. After 30 min, the amine hydrochloride (59 mg, 0.085 mmol, 1.00 eq.) dissolved in dry DMF (600 pL) was added and stirring was continued at 0 °C for 30 min. Sat. NaHCO3 solution (10 mL) was added to the reaction mixture and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with HC1 solution (0.5 M, 10 mL), water (10 mL) and brine (10 mL), dried over NaiSCL and concentrated in vacuo. The residue was purified by flash chromatography (CFLCh / MeOH). Colorless solid, 45 mg (59%). 'H NMR (700 MHz, DMSO- D6): δ (ppm) = 1.26 (dd, J= 62 / 4.3 Hz, 6H), 1.54 (s, 9H), 1.84 (dd, J= 1.6 / 5.3 Hz, 1H), 2.29 (q, J= 8.7 Hz, 1H), 2.33 (s, 6H), 4.50 (p, 6.1 Hz, 1H), 4.61 (d, J= 5.5 Hz, 2H), 5.07 (dd, J

[0552] = 10.3 / 1.9 Hz, 1H), 5.20 (dq, J= 10.5 / 1.5 Hz, 1H), 5.27 (dd, J= 17.1 / 1.8 Hz, 1H), 5.37 (dq, J = 172 / 1.7 Hz, 1H), 5.56 (dt, J= 17.1 / 9.7 Hz, 1H), 6.02 (ddt, J= 16.3 / 10.7 / 5.5 Hz, 1H), 7.41 (d, J= 8.4 Hz, 1H), 7.74 (d, J= 8.4 Hz, 2H), 7.83 (dd, J= 9.5 / 72 Hz, 3H), 7.89 (d, J= 8.6 Hz, 2H), 7.95 - 8.00 (m, 7H), 8.45 (s, 1H), 9.31 (s, 1H), 9.53 (s, 1H), 9.81 (s, 1H), 10.53 (s, 1H).I3C NMR (176 MHz, DMSO-d6): δ (ppm) = 20.5, 22.3, 27.9, 31.5, 37.5, 42.0, 45.4, 53.6, 74.3, 76.3, 80.3, 113.8, 117.2, 117.8, 118.3, 118.9, 119.0, 119.2, 123.7, 126.0, 127.1, 128.1, 128.4, 128.6, 130.1, 132.5, 133.7, 134.5, 135.7, 138.1, 142.0, 142.5, 143.0, 149.6, 162.3, 164.3, 164.6, 165.2, 168.0, 170.2. Step b: ferf-Butyl 4-(4-{4-f(l.S',2R)-l-r3-(4-cvanobenzamido)bicvclori.l.l]pentane-l-amido]- 2-ethenylcvclopropaneamido]benzamido}-2-hvdroxy-3-(propan-2-yloxy)benzamido)benzoate To a solution of the allyl ether (35 mg, 0.039 mmol, 1.00 eq.) in dry THF (296 pL) were added aniline (14 pL, 0.157 mmol, 4.00 eq.) and Pd(PPh3)4 (2 mg, 0.04 eq.) and the resulting mixture was stirred at rt for 3 h. After completion, HC1 solution (0.5 M, 10 mL) was added and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with HC1 solution (0.5 M, 10 mL) and brine (10 mL), dried over NaiSCU and concentrated in vacuo. The crude product was used without further purification. Pale yellow solid, 32 mg (97%).

[0553] Step c:

[0554] To a solution of the ZerLbutyl ester (35 mg, 0.041 mmol, 1.00 eq.) in dry CH2CI2 (445 pL) was added TFA (174 pL, 2.26 mmol, 55.0 eq.) at 0 °C and the resulting solution was stirred for 3 h at 0 °C. After all volatiles were removed in vacuo the residue was purified by RP-HPLC (H2O with 10 mM NFLiHCCh / Acetonitrile) and freeze-dried. Colorless solid, 20 mg (62%). ’H NMR (700 MHz, DMSO-D6): δ (ppm) = 1.23 (q, J= 5.4 Hz, 1H), 1.26 (dd, J= 62 / 3.9 Hz, 6H), 1.84 (dd, J= 7.6 / 5.3 Hz, 1H), 2.29 (q, J= 8.7 Hz, 1H), 2.33 (s, 6H), 4.55 (p, J= 6.1 Hz, 1H), 5.05 - 5.08 (m, 1H), 5.27 (dd, J= YIA / X.Z Hz, 1H), 5.55 (ddd, J= 17.2 / 10.5 / 9.1 Hz, 1H), 7.70 (d, J= 8.8 Hz, 1H), 7.73 - 7.76 (m, 2H), 7.83 - 7.87 (m, 3H), 7.94 - 7.98 (m, 6H), 8.00 (d, J= 8.5 Hz, 2H), 8.45 (s, 1H), 9.31 (s, 1H), 9.40 (s, 1H), 9.82 (s, 1H), 10.63 (s, 1H), 12.29 (s, 1H), 12.81 (s, 1H).13C NMR (176 MHz, DMSO-D6): δ (ppm) = 20.5, 22.3, 31.5, 37.5, 42.0, 45.4, 53.6, 74.8, 112.1, 112.5, 113.8, 117.2, 118.3, 119.3, 120.7, 122.9, 126.3, 128.1, 128.3, 128.6, 130.2, 132.5, 134.5, 136.3, 137.0, 138.1, 142.1, 154.3, 164.2, 165.2, 166.9, 168.0, 168.5, 170.2. HRMS (ESI) calculated 797.2930 [M+H+], 797.2935 found.

[0555] 4-(4-{4-[(1S',2R )-l-{3-[(4-Cyanopheiiyl)carbamoyl]bicyclo[l.l.l]pentane-l-amido}-2- ethenyI-cyclopropaneamido]benzamido}-2-hydroxy-3-(propan-2- yloxy)benzamido)benzoic acid (Hdo247)

[0556]

[0557] Step a: / erZ-Butyl 4-(4-f4-r(l&270-l-13-r(4-cyanophenyl)carbamoyl]bicyclori.l.l]pentane-l- amido } -2-ethenylcyclopropaneamidolbenzamido } -2-(prop-2-en- 1 -yloxy)-3 -(propan-2-yloxy) benzamido)benzoate

[0558] To a solution of the crude carboxylic acid (44 mg, 0.174 mmol, 1.00 eq.) and the amine hydrochloride (120 mg, 0.174 mmol, 1.00 eq.) in DMF (2.02 mL) were added HATU (86 mg, 0.226 mmol, 1.30 eq.) and DIPEA (121 pL, 0.694 mmol, 4.00 eq.) at 0°C. After the resulting mixture was stirred for 30 min at 0 °C, stirring was continued at rt for 18 h. Upon completion, sat. NaHCCE solution (10 mL) / water (30 mL) were added and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with HC1 solution (0.5 M, 10 mL), water (10 mL) and brine (10 mL), dried over NazSO4 and concentrated in vacuo. The crude product was used without further purification. Brown solid.

[0559] Step b: ferZ-Butyl 4-(4-f4-[(l1Sl,2 / ?)-l-(3-r(4-cvanophenyl)carbamoyl]bicvclori.L11pentane-l- amido}-2-ethenylcvclopropaneamidolbenzamido}-2-hydroxy-3-(propan-2- yloxy)benzamido)benzoate

[0560] To a solution of the crude allyl ether (1.00 eq.) in dry THF (1.34 mL) were added aniline (64 pL, 0.708 mmol, 4.00 eq.) and Pd(PPh3)4 (8 mg, 0.04 eq.) and the resulting mixture was stirred at rt for 3 h. After completion, HC1 solution (0.5 M, 10 mL) was added and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (CH2Ch / MeOH). Colorless solid, 68 mg (45%). 1HNMR (500 MHz, DMSO- D6): δ (ppm) = 1.22 - 1.28 (m, 7H), 1.55 (s, 9H), 1.83 - 1.88 (m, 1H), 2.26 (t, J= 3.5 Hz, 1H), 2.29 (s, 6H), 4.54 (hept, J= 6.1 Hz, 1H), 5.07 (d, J= 12.1 Hz, 1H), 5.25 - 5.31 (m, 1H), 5.51 - 5.60 (m, 1H), 7.70 (d, J = 8.9 Hz, 1H), 7.76 (dd, J= 15.8 / 8.8 Hz, 4H), 7.84 - 7.88 (m, 5H), 7.94 (dd, J= 15.6 / 8.8 Hz, 4H), 8.50 (s, 1H), 9.41 (s, 1H), 9.82 (s, 1H), 10.01 (s, 1H), 10.62 (s, 1H), 12.29 (s, 1H).13C NMR (176 MHz, DMSO-D6): δ (ppm) = 20.5, 22.3, 27.9, 31.5, 38.1, 39.0, 41.9, 51.8, 74.9, 80.5, 105.3, 112.2, 112.4, 117.2, 119.0, 119.3, 119.8, 120.7, 122.9, 126.8, 128.3, 128.6, 129.9, 133.1, 134.4, 136.3, 137.0, 142.0, 142.0, 142.9, 154.1, 164.2, 164.6, 167.9, 168.5, 168.5, 170.3.

[0561] Step c:

[0562] To a solution of the tert-butyl ester (64 mg, 0.075 mmol, 1.00 eq.) in dry CH2Q2 (815 pL) was added TFA (318 pL, 4.13 mmol, 55.0 eq.) at 0 °C and the resulting solution was stirred for 3 h at 0 °C. After all volatiles were removed in vacuo the residue was purified by RP-HPLC (H2O with 10 mM N^HCOs / Acetonitrile) and freeze-dried. Colorless solid, 20 mg (34%). 'H NMR (700 MHz, DMSO-D6): δ (ppm) = 1.22 - 1.24 (m, 1H), 1.26 (dd, J= 6.1 / 3.8 Hz, 6H), 1.85 (dd, J= 7.7 / 5.3 Hz, 1H), 2.25 - 2.31 (m, 7H), 4.55 (hept, J = 6.3 Hz, 1H), 5.05 - 5.09 (m, 1H), 5.28 (dd, J= 17.1 / 1.8 Hz, 1H), 5.55 (dt, J= 17.1 / 9.7 Hz, 1H), 7.68 (d, J= 8.8 Hz, 1H), 7.74 (d, J= 8.6 Hz, 2H), 7.76 - 7.79 (m, 2H), 7.82 - 7.88 (m, 5H), 7.93 - 7.98 (m, 4H), 8.51 (s, 1H), 9.40 (s, 1H), 9.83 (s, 1H), 10.02 (s, 1H), 10.69 (s, 1H), 12.29 (s, 1H).13C NMR (176 MHz, DMSO- D6): δ (ppm) = 20.5, 22.4, 31.5, 38.1, 39.0, 42.0, 51.8, 74.8, 105.4, 112.0, 112.6, 117.3, 119.1, 119.3, 119.8, 120.7, 122.9, 126.1, 128.4, 128.7, 130.3, 133.2, 134.4, 136.4, 137.0, 142.1, 143.0, 153.4, 164.2, 167.0, 168.0, 168.5, 168.6, 170.4. HRMS (ESI) calculated 797.2930 [M+H+], 797.2917 found.

[0563] 4-(4-{4-[(15,2i?)-l-[3-(4-Cyanobenzamido)bicyclo[l.l.l]pentane-l-amido]-2-ethynyl- cyclopropaneamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid

[0564] Step a: tert-Butyl 4-(4-f4-r(lS,2R)-l-r3-(4-cyanobenzamido)bicyclo pentane-l-amido]-

[0565] 2-ethvnylcvclopropaneamidolbenzamido}-2-(prop-2-en-l-yloxy)-3-(propan-2-yloxy) benzamido)benzoate To a solution of the crude carboxylic acid (35 mg, 0.136 mmol, 1.30 eq.) and the amine hydrochloride (72 mg, 0.104 mmol, 1.00 eq.) in DMF (809 pL) were added HATU (56 mg, 0.146 mmol, 1.40 eq.) and DIPEA (73 pL, 0.418 mmol, 4.00 eq.) at 0°C. After the resulting mixture was stirred for 30 min at 0 °C, stirring was continued at rt for 17 h. Upon completion, sat. NaHCO3 solution (10 mL) was added and extracted with EtOAc (3 x l0 mL). The combined organic layers were washed with sat. NaHCO3 solution (10 mL) and brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was used without further purification. Brown solid.

[0566] Step b: terf-Butyl 4-(4-{4-l(llS',27?)-l-r3-(4-cyanobenzamido)bicvclorLl.llpentane-l-amido]- 2-ethynylcyclopropaneamido]benzamido)-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoate To a solution of the crude allyl ether (63 mg, 0.071 mmol, 1.00 eq.) in dry THF (533 pL) were added aniline (26 pL, 0.283 mmol, 4.00 eq.) and Pd(PPli3)4 (3 mg, 0.04 eq.) and the resulting mixture was stirred at rt for 3 h. After completion, HC1 solution (0.5 M, 10 mL) was added and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (CH2C12MeOH). Brownish solid, 33 mg (55%). ’H NMR (700 MHz, DMSO-D6): 5 (ppm) = 1.27 (dd, J = 6.1 / 3.1 Hz, 6H), 1.55 (s, 9H), 1.98 (q, J = 5.274.5 Hz, 1H), 2.21 (ddd, J= 9.6 / 7.5 / 2.3 Hz, 1H), 2.31 (s, 6H), 2.44 (s, 1H), 2.86 (d, J= 2.2 Hz, 1H), 4.53 - 4.57 (m, 1H), 7.71 (d, .7 = 8.8 Hz, 1H), 7.75 - 7.79 (m, 2H), 7.84 - 7.87 (m, 4H), 7.92 - 7.94 (m, 2H), 7.95 - 8.00 (m, 7H), 9.30 (s, 1H), 9.93 (s, 1H), 10.61 (s, 1H), 12.29 (s, 1H).13C NMR (176 MHz, DMSO-D6): δ (ppm) = 15.7, 20.7, 22.3, 27.8, 37.4, 40.0, 42.0, 45.4, 53.5, 71.3, 74.9, 80.5, 80.9, 112.2, 112.4, 113.8, 118.3, 119.3, 120.7, 122.8, 126.4, 126.8, 128.1, 128.4, 129.9, 132.5, 136.3, 137.1, 138.1, 142.0, 142.1, 154.1, 164.2, 164.6, 165.2, 166.5, 168.5, 170.2.

[0567] Step c:

[0568] To a solution of the fer / -butyl ester (30 mg, 0.035 mmol, 1.00 eq.) in dry CH2CI2 (383 pL) was added TFA (149 pL, 1.94 mmol, 55.0 eq.) at 0 °C and the resulting solution was stirred for 3 h at 0 °C. After all volatiles were removed in vacuo the residue was purified by RP-HPLC (H2O with 10 mM NHiHCCh / Acetonitrile) and freeze-dried. Colorless solid, 3.5 mg (13%). 1H NMR (700 MHz, DMSO-D6): δ (ppm) = 1.26 - 1.28 (m, 6H), 1.95 - 1.99 (m, 1H), 2.18 - 2.23 (m, 1H), 2.31 (s, 6H), 2.52 (d, J= 1.9 Hz, 1H), 2.86 (d, J= 2.2 Hz, 1H), 4.52 - 4.58 (m, 1H), 7.70 (d, J= 8.7 Hz, 1H), 7.77 (d, J= 8.7 Hz, 2H), 7.85 (dd, J= 9.7 / 33 Hz, 3H), 7.94 - 8.00 (m, 8H), 8.52 (s, 1H), 9.31 (s, 1H), 9.42 (s, 1H), 9.92 (s, 1H), 10.61 (s, 1H), 12.29 (s, 1H).!3C NMR (176 MHz, DMSO-D6): 5 (ppm) = 15.7, 20.7, 22.3, 37.4, 40.0, 42.0, 45.4, 53.6, 71.3, 75.0, 80.9, 112.6, 113.7, 115.0, 118.2, 119.3, 120.7, 122.9, 126.1, 128.1, 128.4, 128.8, 130.2, 132.5, 138.1, 141.9, 142.1, 150.1, 164.2, 165.2, 166.5, 166.9, 168.5, 170.2.

[0569] 4-[4-({4-[(2Y)-2-{[4-(4-Cyanobenzamido)phenyl|formamido}pent-4-ynamido]phenyl} carbarn oyI)-2-hydroxy-3-(propan-2-yloxy)benzamido] benzoic acid (MST264)

[0570] Step a: tert-Butyl 4-r4-fl4-l -2-ir4-(4-cvanobenzamido)phenyl]formamido}pent-4- ynamidolphenyl } carbamoyl)-2-(prop-2-en- 1 -yloxy)-3 -(propan-2 -yloxy)benzamido1benzoate The primary aromatic amine (68.8 mg, 1.0 eq.) and the carboxylic acid (52 mg, 1.15 eq.) were suspended in dry EtOAc(2.0 mL) and pyridine (51 pL, 5.0 eq.) was added. T3P (sol. in EtOAc 50%, 0.15 mL, 2.0 eq.) was added and the reaction was stirred at rt while being monitored with LCMS. After 2 h, the mixture was partitioned between EtOAc / HCl (0.1 M) (20 mL each) and the aqueous phase was extracted with EtOAc(2 x 15 mL) before drying the combined organic phases over Na2SO4 and removing all volatiles under reduced pressure. The crude product was used without further purification. Yellow solid.

[0571] Step b: Butyl 4-14-({4-r(21S,)-2-H4-(4-cyanobenzamido)phenyl]formamido}pent-4- ynamidolphenyl } carbamoyl)-2-hydroxy-3 -(propan-2-yloxy)benzamido]benzoate

[0572] The crude allyl ether, fresh Pd(PPh3)4 (7.3m g, 0.05 eq.) and aniline (35 pL, 3.0 eq.) were dissolved in dry THF (1.9 mL) under argon atmosphere and the reaction was stirred at rt while being monitored with LCMS. After 1 .5 h, the solvent was removed under reduced pressure and the product was isolated by flash chromatography (petroleum ether / EtOAc / AcOH, 50 / 50 / 2 -> 40 / 60 / 2 -> 60 / 40 / 10). Brownish solid, 94 mg (88% over 2 steps). *H NMR (500 MHz, Acetone): 8(ppm) = 10.24 (br s, 1H), 10.04 (s, 1H), 9.98 (s, 1H), 9.66 (s, 1H), 8.20 - 8.15 (m, 2H), 8.03 - 7.85 (m, 13H), 7.81 - 7.75 (m, 2H), 7.71 (dd, J = 8.8, 1.9 Hz, 2H), 7.44 (d, J = 8.5 Hz, 1H), 4.98 (td, J = 7.6, 6.3 Hz, 1H), 4.86 - 4.78 (m, 1H), 2.99 - 2.84 (m, 2H), 2.51 (t, J = 2.7 Hz, 1H), 1.59 (s, 9H), 1.33 (d, J = 6.1 Hz, 6H).I3C NMR (126 MHz, Acetone): 8(ppm) = 172.2, 169.4, 167.2, 165.5, 165.2, 163.5, 156.4, 145.1, 142.9, 142.5, 139.7, 135.7, 135.5, 133.6,

[0573] 133.2. 132.7. 132.7. 130.9. 130.2. 129.6. 129.5. 129.5, 129.3, 129.2, 128.9, 128.9, 122.7, 121.4, 121.2, 121.1, 120.9, 120.8, 120.5, 120.4, 120.3, 119.8, 118.7, 115.8, 81.2, 80.8, 77.2, 72.4, 54.3,

[0574] 32.5, 28.3, 23.3, 22.5, 22.4.

[0575] Step c:

[0576] The tert-butyl ester (86 mg, 1.0 eq.) was dissolved in dry CH2Q2 (1.5 mL) and TFA (0.39 mL, 50 eq.) was added dropwise. The reaction was stirred at rt for 1.5 h while being monitored by LCMS. All volatiles were removed under reduced pressure and by coevaporation with CH2CI2 (4x). The crude product was purified by RP-HPLC (H2O with 10 mM NH4HCO3 / Acetonitrile) and freeze-dried. Colorless fluffy solid, 46 mg (57%). *H NMR (500 MHz, DMSO): 8(ppm) = 12.87 (br s, 1H), 12.01 (br s, 1H), 10.89 (br s, 1H), 10.72 (s, 1H), 10.30 (s, 1H), 10.26 (s, 1H), 8.73 (d, J= 7.8 Hz, 1H), 8.13 (d, J= 8.7 Hz, 2H), 8.05 (d, J= 8.7 Hz, 2H), 8.01 - 7.94 (m, 4H), 7.92 - 7.81 (m, 5H), 7.68 (d, J= 9.2 Hz, 2H), 7.62 (d, J= 9.2 Hz, 2H), 7.13 (d, J= 8.2 Hz, 1H), 4.81 - 4.75 (m, 1H), 4.53 - 4.44 (m, 1H), 2.93 (t, J= 2.6 Hz, 1H), 2.83 - 2.68 (m, 2H), 1.21 (d, J = 6.1 Hz, 6H).13C NMR (126 MHz, DMSO): 5(ppm) = 168.9, 167.8, 166.9, 165.9, 164.5, 164.0, 154.2, 143.5, 142.0, 141.7, 138.7, 135.1, 134.7, 134.6, 132.6, 130.3, 129.1, 128.7, 128.5, 126.3, 122.9, 120.6, 119.9, 119.5, 118.6, 118.4, 117.8 (2x), 114.1, 80.9, 75.9, 73.1, 53.3, 22.2

[0577] 4-|4-({4-J(25)-2-{[4-(4-Cyanobenzamido)phenyI]f'ormamido}pent-4-ynamido|-2- fluorophenyl}carbamoyl)-2-hydroxy-3~(propan-2-yloxy)benzamido]benzoic acid

[0578] (DK971) The amine derivative (97.6 pmol) was coupled with the carboxylic acid and the allyl ether deprotected using General Procedure 13. The product was obtained by deprotection with General Procedure 11. Off-white solid, 26 mg (33% over 3 steps). 'H-NMR (700 MHz, DMSO- d6, 300 K): 5 (ppm) = 12.81 (br s, 1H), 12.09 (br s, 1H), 10.70 (s, 1H), 10.47 (s, 1H), 10.30 (br s, 1H), 8.74 (d, 1H, J = 7.6 Hz), 8.13 (d, 2H, J = 8.4 Hz), 8.08 (t, 1H, J = 8.7 Hz), 8.05 (d, 2H, J = 8.3 Hz), 7.98 - 7.95 (m, 4H), 7.90 (d, 2H, J = 8.8 Hz), 7.87 - 7.82 (m, 3H), 7.77 (dd, 1H, J = 2.1 Hz, 13.3 Hz), 7.40 - 7.37 (m, 1H), 7.31 (d, 1H, J = 5.8 Hz), 4.79 - 4.74 (m, 2H), 2.93 (t, 1H, J = 2.6 Hz), 2.77 (dddd, 2H, J = 2.6 Hz, 7.4 Hz, 11.1 Hz, 16.7 Hz), 1.28 (d, 6H, J = 6.2 Hz).13C-NMR (176 MHz, DMSO-d6, 300 K): 5 (ppm) = 169.3, 167.7, 166.9, 165.9, 164.5, 163.3, 153.0 (d, J = 153.0 Hz), 144.3, 142.2, 141.7, 138.7, 136.1 (d, J = 9.7 Hz), 132.5, 130.3, 129.0, 128.6, 128.4, 126.2, 123.5, 122.9, 121.1 (d, J = 11.0 Hz), 120.5, 119.8, 119.5, 118.3, 115.2, 114.0, 106.6 (d, J = 24.5 Hz), 80.7, 75.6, 73.2, 53.3, 21.8, 21.5.19F-NMR (470 MHz, DMSO- d6, 300 K): 5 (ppm) = -73.4. HRMS (ESI) calculated 811.2522 [M+H+], 811.2518 found.

[0579] 4- [4-( {5-[(2S)-2- { [4-(4-Cyanobenzamido)phenyl] formamido}pent-4-ynamido] pyridin-2- yI}carbamoyI)-2-hydroxy-3-(propan-2-yloxy)benzamido]benzoic acid (DK895)

[0580] The amine derivative (82.3 pmol) was coupled with the carboxylic acid and the allyl ether was deprotected using General Procedure 13. The product was obtained by deprotection with General Procedure 11. Off-white solid, 20 mg (30% over 3 steps). *H-NMR (700 MHz, DMSO- d6, 300 K): δ (ppm) = 12.80 (br s, 1H), 12.06 (br s, 1H), 10.81 (br s, 1H), 10.70 (s, 1H), 10.46 (s, 1H), 8.76 (d, 1H, J = 7.6 Hz), 8.63 (d, 1H, J = 2.4 Hz), 8.23 (d, 1H, J = 8.9 Hz), 8.13 (d, 2H, J = 8.4 Hz), 8.10 (dd, 1H, J = 2.5 Hz, 9.0 Hz), 8.05 (d, 2H, J = 8.3 Hz), 7.98 - 7.95 (4H, m), 7.90 (d, 2H, J = 8.8 Hz), 7.86 (d, 2H, J = 8.7 Hz), 7.83 (d, 1H, J = 8.4 Hz), 7.36 - 7.30 (m, 1H), 4.82 - 4.73 (m, 2H), 2.93 (t, 1H, J = 2.6 Hz), 2.78 (dddd, 2H, J = 2.6 Hz, 7.4 Hz, 1 1.1 Hz, 16.7 Hz), 1.29 (d, 6H, J = 6.2 Hz).I3C-NMR (176 MHz, DMSO-d6, 300 K): δ (ppm) = 169.4, 167.6, 166.9, 165.9, 164.5, 163.2, 147.1, 142.3, 141.7, 139.6, 138.7, 132.5, 132.0, 130.3, 129.3, 129.0, 128.6, 128.4, 126.1, 123.0, 120.4, 120.1, 119.5, 118.3, 114.0, 113.6, 80.7, 75.7, 73.1, 53.2, 21.9, 21.5. HRMS (ESI) calculated 794.2569 [M+H+], 794.2562 found.

[0581] 4-(4-{5-[(25)-2-({3-[(4-Cyanophenyl)carbamoyl]bicyclo[l.l.l]pentan-l-yl}formamido)-3- cycIopropylpropanamido]pyridine-2-amido}-2-hydroxy-3-(propan-2-yIoxy)benzamido) formamido)-3-cvclopropylpropanamido]pyridine-2-amido}-2-(prop-2-en-l-yloxy)-3-(propan-

[0582] 2-yloxy)benzamido)benzoate

[0583] DIPEA (435 pL, 2.49 mmol, 5.00 equiv.) was added dropwise to a stirred solution of HATU (473 mg, 1.24 mmol, 2.50 equiv.) and the carboxylic acid (331 mg, 1.24 mmol, 2.50 equiv.) in DMF (12 mL). The solution was stirred for 30 min and was then transferred to a stirred solution of the amine (327 mg, 0.50 mmol) in DMF (7 mL). The reaction mixture was stirred at rt for 19 h. The mixture was diluted with EtOAc and washed with a 0.1 M HC1 solution, brine, dried over MgSCL and concentrated under reduced pressure. The crude residue was purified by column chromatography (diy load, MeOH in CH2CI2 - 1%, 5%) to furnish the product (405 mg, 0.45 mmol, 90%) as yellow solid. *H-NMR (400 MHz, DMSO-de) 8 = 10.73 (s, 1H), 10.68 (s, 1H), 10.48 (s, 1H), 9.99 (s, 1H), 8.99 (d, J = 2.3 Hz, 1H), 8.35 (d, J= 8.6 Hz, 1H), 8.30 (dd, J= 2.4, 8.7 Hz, 2H), 8.20-8.18 (m, 2H), 7.90-7.77 (m, 8H), 7.48 (d, J= 8.6 Hz, 1H), 6.07-5.97 (m, 1H), 5.39 (dq, J= 1.7, 17.2 Hz, 1H), 5.22 (dq, J= 1.7, 10.5 Hz, 1H), 4.68-4.61 (m, 3H), 4.59-4.53 (m, 1H), 2.28 (s, 6H), 1.79-1.57 (m, 2H), 1.55 (s, 9H), 1.37 (t, J= 6.2 Hz, 6H), 0.85-0.73 (m, 1H), 0.48-0.34 (m, 2H), 0.22-0.06 (m, 2H) ppm.13C-NMR (101 MHz, DMSO-de) 8 = 171.8, 168.9, 168.6, 164.6, 164.3, 161.1, 149.3, 143.3, 143.0, 142.9, 139.4, 139.3, 138.8, 135.5, 133.5, 133.1, 130.1, 127.1, 126.0, 125.8, 124.6, 122.9, 119.7, 119.0, 118.8, 118.0, 113.8, 105.3, 80.3, 76.3, 74.3, 54.2, 51.7, 38.9, 37.9, 36.2, 27.8, 22.3 (d, J= 6.6 Hz), 7.9, 4.5, 3.9 ppm. HRMS (ESI) calculated for CsoHssNyOgNa [M+Na]+: 918.3802; found: 918.3809. Step b: ferZ-Butyl 4-(4-f5-r -2-({3-r(4-cvanophenyl)carbamoyl1bicvclori.l.l1pentan-l-yn formamido)-3-cyclopropylpropanamido]pyridine-2-amido}-2-hydroxy-3-(propan-2-yloxy) benzamido)benzoate

[0584] The allyl ether (263 mg, 0.29 mmol) was dissolved in THF (13 mL). Aniline (88 pL, 0.97 mmol, 3.30 equiv.) and Pd(PPh3)4 (33.9 mg, 0.03 mmol, O.lO equiv.) were added subsequently and the resulting mixture was stirred at rt for 4 h. The mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (dry load, MeOH in CH2CI2 = 2%, 4%) to furnish the product (220 mg, 0.26 mmol, 88%) as yellow solid. 'H-NMR (600 MHz, DMSO-d6) 8 = 12.45 (s, 1H), 10.74 (s, 1H), 10.73 (s, 1H), 10.61 (bs, 1H), 9.99 (s, 1H), 8.98 (d, J= 2.3 Hz, 1H), 8.30 (dd, J= 2.4, 8.6 Hz, 2H), 8.20-8.18 (m, 2H), 8.11- 8.10 (d, J= 8.8 Hz, 1H), 7.94-7.90 (m, 3H), 7.87-7.85 (m, 4H), 7.78 (d, J= 8.9 Hz, 2H), 4.68 (sept, J= 6.1 Hz, 1H), 4.59-4.54 (m, 1H), 2.28 (s, 6H), 1.78-1.57 (m, 2H), 1.55 (s, 9H), 1.35 (dd, J= 6.1, 9.8 Hz, 6H), 0.81-0.76 (m, 1H), 0.47-0.35 (m, 2H), 0.21-0.07 (m, 2H) ppm.13C-NMR (151 MHZ, DMSO-d6) 8 = 171.8, 168.9, 168.7, 168.6, 164.5, 161.3, 154.1, 143.3, 142.9, 141.9, 139.3, 138.8, 136.8, 134.0, 133.1, 129.9, 127.1, 126.9, 123.5, 123.0, 120.8, 119.7, 119.0, 111.6, 108.3, 105.3, 80.5, 74.3, 54.2, 51.7, 38.9, 37.9, 36.3, 27.8, 22.3 (d, J= 10.3 Hz), 7.9, 4.5, 3.9 ppm. HRMS (ESI) calculated for C47H49N7O9Na [M+Na]+: 878.3489; found: 878.3491.

[0585] Step c:

[0586] The terZ-butyl ester (216 mg, 0.25 mmol) was dissolved in precooled TFA (13 mL) at 0 °C with stirring. The solution was warmed up to rt over 30 min. Et20 was added at 0°C. The precipitate was filtered off, washed with excess of Et2O and dried in vacuo to furnish the product (215 mg, 0.25 mmol, quant.) as yellow solid. *H-NMR (600 MHz, DMSO-d6) 8 = 12.83 (bs, 1H), 12.45 (s, 1H), 10.74 (s, 1H), 10.73 (s, 1H), 10.61 (s, 1H), 10.00 (s, 1H), 8.98 (d, J= 2.4 Hz, 1H), 8.30 (dd, J= 2.3, 8.6 Hz, 2H), 8.20-8.18 (m, 2H), 8.11 8.9 Hz, 1H), 7.97 (d, J= 8.8 Hz, 2H),

[0587] 7.92 (d, J= 9.2 Hz, 1H), 7.87-7.85 (m, 4H), 7.78 (d, J= 8.9 Hz, 2H), 4.68 (sept, J= 6.1 Hz, 1H), 4.57-4.54 (m, 1H), 2.28 (s, 6H), 1.78-1.55 (m, 2H), 1.35 (dd, J= 6.1, 9.8 Hz, 6H), 0.81- 0.75 (m, 1H), 0.47-0.35 (m, 2H), 0.21-0.07 (m, 2H) ppm.13C-NMR (151 MHz, DMSO-d6) 8 = 171.8, 168.9, 168.7, 168.6, 166.9, 161.3, 154.1, 143.3, 142.9, 141.9, 139.3, 138.8, 136.8, 134.0, 133.1, 130.2, 127.1, 126.3, 123.5, 123.0, 120.8, 119.7, 119.0, 111.6, 108.4, 105.3, 74.8, 54.2, 51.7, 38.9, 37.9, 36.3, 27.8, 22.3 (d, J= 10.3 Hz), 7.9, 4.5, 3.9 ppm. HRMS (ESI) calculated for C43H4iN7O9Na [M-H]': 798.2888; found: 798.2902.

[0588] 4-(4- {5- [(25)-2- { [4-(5-Cy ano-l-methy 1-1H -1 ,3-benzodiazol-2-y l)pheny 1] form amido} pent- 4-ynamido]pyridine-2-amido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid

[0589] Step a: / er / -Butyl 4-(4-f5-r(2lSf)-2-H4-(5-cvano-l-methyl-177-l,3-benzodiazol-2-yl)phenyl] formamido} pent-4-ynamido]pyridine-2-amido I -2-(prop-2-en- 1 -yloxy)-3 -(propan-2 -yloxy) benzamido)benzoate

[0590] DIPEA (129 pL, 0.74 mmol, 3.00 equiv.) was added dropwise to a stirred solution of HATU (113 mg, 0.30 mmol, 1.20 equiv.) and fragment A4-1 (82.4 mg, 0.30 mmol, 1.20 equiv.) in DMF (6.0 mL). The solution was stirred for 5 min and was then transferred to a stirred solution of the amine (159 mg, 0.25 mmol) in DMF (3.5 mL). The reaction mixture was stirred at rt for 18 h. The mixture was diluted with EtOAc and washed with a 1 M HC1 solution, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography (MeOH in CH2CI2 = 1%, 2%) to furnish the product (142 mg, 0.16 mmol, 63%) as yellowish solid. 'H-NMR (600 MHz, DMSO-d6) δ = 10.88 (s, 1H), 10.69 (s, 1H), 9.48 (s, 1H), 9.14 (d, J= 7.4 Hz, 1H), 9.03 (d, J= 2.6 Hz, 1H), 8.35-8.32 (m, 3H), 8.28 (dd, J= 0.6, 1.4 Hz, 1H), 8.21 (d, J= 8.6 Hz, 1H), 8.15 (d, J= 8.5 Hz, 2H), 8.04 (d, J= 8.5 Hz, 1H), 7.90-7.88 (m, 3H), 7.83 (d, 8.6 Hz, 2H), 7.74 (dd, J= 1.5, 8.4 Hz, 1H), 7.49 (d,

[0591] J= 8.5 Hz, 1H), 6.05-5.99 (m, 1H), 5.39 (dq, J= 1.7, 17.2 Hz, 1H), 5.21 (dq, J= 1.6, 10.5 Hz, 1H), 4.88-4.84 (m, 1H), 4.65 (sept, J= 5.5 Hz, 1H), 4.62 (d, J= 5.5 Hz, 2H), 3.98 (s, 3H), 2.98 (t, J= 2.6 Hz, 1H), 2.91-2.79 (m, 2H), 1.55 (s, 9H), 1.37 (dd, J= 3.9, 6.1 Hz, 6H) ppm.13C-NMR (151 MHZ, DMSO-d6) 8 = 170.0, 166.0, 164.6, 164.3, 161.1, 154.9, 149.3, 143.5, 143.0, 141.9, 139.5, 139.5, 139.4, 138.6, 135.4, 134.9, 133.5, 132.1, 130.1, 129.4, 128.0, 127.4, 126.0, 125.9, 125.8, 124.6, 124.1, 122.9, 1 19.9, 118.8, 118.2, 113.8, 112.4, 104.3, 80.5, 80.3, 76.3, 74.3, 73.3, 53.6, 32.2, 27.9, 22.3 (d, J= 3.7 Hz), 21.2 ppm. HRMS (ESI) calculated for C51H48N8O8Na [M+Na]+: 923.3493; found: 923.3503.

[0592] Step b: tert-Butyl 4-(4-{5-r(2S)-2-H4-(5-cvano-l-methyl-lH-l,3-benzodiazol-2-yl)phenyl1 formamido}pent-4-ynamido]pyridine-2-amido}-2-hydroxy-3-(propan-2-yloxy)benzamido) benzoate

[0593] The allyl ether (139 mg, 0.15 mmol) was dissolved in THF (7 mL). Aniline (47 pL, 0.51 mmol, 3.30 equiv.) and Pd(PPhs)4(17.8 mg, 0.02 mmol, 0.10 equiv.) were added subsequently and the resulting mixture was stirred at rt for 2 h. The mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (dry load, 3% MeOH in CH2CI2) to furnish the product (98.0 mg, 0.11 mmol, 74%) as colorless solid. ’H-NMR (600 MHz, DMSO- d6) = 12.44 (s, 1H), 10.88 (s, 1H), 10.75 (s, 1H), 10.61 (s, 1H), 9.14 (d, J= 7.4 Hz, 1H), 9.02 (d, J= 2.4 Hz, 1H), 8.34 (dd, J= 2.4, 8.6 Hz, 1H), 8.28 (dd, J= 0.6, 1.4 Hz, 1H), 8.21 (d, J= 8.5 Hz, 1H), 8.15 (d, J= 8.6 Hz, 2H), 8.11 (d, J= 8.7 Hz, 1H), 8.04 (d, J= 8.5 Hz, 2H), 7.93 (d, J= 8.8 Hz, 2H), 7.90 (d, J= 8.5 Hz, 2H), 7.86 (d, J= 8.9 Hz, 2H), 7.74 (dd, J= 1.5, 8.4 Hz, 1H), 4.88-4.84 (m, 1H), 4.68 (sept, J= 6.2 Hz, 1H), 3.98 (s, 3H), 2.98 (t, J= 2.6 Hz, 1H), 2.90-2.79 (m, 2H), 1.55 (s, 9H), 1.35 (dd, J= 4.4, 6.1 Hz, 6H) ppm.13C-NMR (151 MHz, DMSO-d6) 8 = 170.1, 168.6, 166.0, 164.5, 161.2, 154.9, 154.1, 143.5, 141.9, 139.5, 138.7, 136.8, 134.9, 134.0, 132.1, 129.9, 129.4, 128.0, 127.4, 126.0, 125.9, 124.1, 123.5, 122.9, 120.8, 119.9, 112.4, 111.7, 108.4, 104.3, 80.5, 74.8, 73.3, 53.5, 32.2, 27.8, 22.3 (d, J= 3.7 Hz), 21.2 ppm. HRMS (ESI) calculated for C48H44N8O8Na [M+Na]+: 883.3180; found: 883.3184.

[0594] Step c:

[0595] The tert-butyl ester (92.2 mg, 0.11 mmol) was dissolved in precooled TFA (5.4 mL) at 0 °C with stirring. The solution was warmed up to rt over 30 min. EtiO was added at 0 °C. The precipitate was filtered off, washed with excess of EtzO and dried in vacuo to furnish the product (88.6 mg, 0.11 mmol, quant.) as yellowish solid. *H-NMR (600 MHz, DMSO-de) 8 = 12.81 (s, 1H), 12.45 (s, 1H), 10.88 (s, 1H), 10.75 (s, 1H), 10.60 (s, 1H), 9.14 (d, J= 1A Hz, 1H), 9.02 (d, J= 2.6 Hz, 1H), 8.34 (dd, J= 2.4, 8.6 Hz, 1H), 8.29 (d, J= 0.9 Hz, 1H), 8.21 (d, J= 8.6 Hz, 1H), 8.15 (d, J= 8.5 Hz, 2H), 8.11 (d, J= 8.9 Hz, 1H), 8.04 (d, J= 8.5 Hz, 2H), 7.97 (d, J= 8.7 Hz, 2H), 7.92-7.89 (m, 2H), 7.86 (d, J= 8.8 Hz, 2H), 7.74 (dd, J= 1.4, 8.4 Hz, 1H), 4.88-4.84 (m, 1H), 4.68 (sept, J= 6.1 Hz, 1H), 3.98 (s, 3H), 2.98 (t, J= 2.6 Hz, 1H), 2.91- 2.19 (m, 2H), 1.35 (dd, J= 4.4, 6.1 Hz, 6H) ppm.13C-NMR (151 MHz, DMSO-d6) 8 = 170.1, 168.7, 166.9, 166.0, 161.2, 154.9, 154.1, 143.5, 141.9, 141.7, 139.5, 139.5, 138.7, 136.8, 134.9, 134.0, 132.0, 130.2 , 129.4, 128.0, 127.4, 126.3, 126.0, 124.1, 123.5, 122.9, 120.8, 119.9, 112.5, 111.7, 108.4, 104.4, 80.5, 74.8, 73.3, 53.6, 32.2, 22.3 (d, J= 4.1 Hz), 21.2 ppm. HRMS (ESI) calculated for C44H35N8O8 [M-H]’: 803.2578; found: 803.2588.

[0596] 4-(4-{5-[(15',2R )-l-[4-(5-Cyano-l-methyl-1H-1,3 -benzodiazol-2-yl)benzamido]-2- ethenyicyclopropaneamido]pyridine-2-amido}-2-hydroxy-3-(propan-2-yloxy) benzamido)benzoic acid (TSG28)

[0597] Step a: ter / -Butyl 4-(4-f5-r(l»S',27?)-l-r4-(5-cvano-l-methyl-l / / -l,3-benzodiazol-2-yl) benzamido]-2-ethenylcyclopropaneamido1pyridine-2-amido)-2-(prop-2-en-l-yloxy)-3- (propan-2-yloxy)benzamido)benzoate

[0598] DIPEA (123 pL, 0.70 mmol, 3.00 equiv.) was added dropwise to a stirred solution of HATU (107 mg, 0.28 mmol, 1.20 equiv.) and fragment A4-1 (78.1 mg, 0.28 mmol, 1.20 equiv.) in DMF (6.0 mL). The solution was stirred for 5 min and then transferred to a stirred solution of the amine (154 mg, 0.23 mmol) in DMF (3.4 mL) at 0 °C. The reaction mixture was stirred for 18 h while warming to rt. The mixture was diluted with EtOAc and washed with a 1 M HC1 solution, brine, dried over MgSCU and concentrated under reduced pressure. The crude residue was purified by column chromatography (MeOH in CH2CI2 = 1%, 2%) to furnish the product (142 mg, 0.16 mmol, 66%) as yellowish solid. 'H-NMR (600 MHz, DMSO-d6) 8 = 10.62 (s, 1H), 10.48 (s, 1H), 10.29 (s, 1H), 9.33 (s, 1H), 9.00 (d, J= 2.5 Hz, 1H), 8.37-8.34 (m, 2H), 8.29-8.28 (m, 1H), 8.20-8.17 (m, 3H), 8.04 (d, J = 8.6 Hz, 2H), 7.91-7.88 (m, 3H), 7.82 (d, J= 8.7 Hz, 2H), 7.75-7.73 (dd, J= 1.5, 8.4 Hz, 2H), 7.48 (d, J= 8.6 Hz, 2H), 6.05-5.97 (m, 1H), 5.79-5.72 (m, 1H), 5.40-5.32 (m, 2H), 5.21 (dq, J= 1.6, 10.5 Hz, 1H), 5.14-5.12 (m, 1H), 4.65 (sept, J= 6.0 Hz, 1H), 4.61 (d, J= 5.5 Hz, 1H), 3.97 (s, 3H), 1.99-1.96 (m, 1H), 1.54 (s, 9H), 1.43-1.40 (m, 1H), 1.35 (dd, J= 6.3, 7.4 Hz, 6H), 1.23 (m, 1H) ppm.13C-NMR (151 MHz, DMSO-d6) 8 = 169.1, 166.9, 164.6, 164.3, 161.1, 154.9, 149.3, 143.4, 143.0, 141.9, 140.2, 139.5, 139.4, 138.7, 135.5, 135.1, 134.4, 133.5, 132.1, 130.1, 129.3, 128.2, 128.1, 126.0, 126.0, 125.8, 124.6, 124.1, 122.7, 119.9, 118.8, , 117.4, 113.7, 112.4, 104.3, 80.3, 76.3, 74.3, 42.2, 32.2, 27.9, 22.3 (d, J= 7.4 Hz), 22.3 ppm. HRMS (ESI) calculated for C^^HsoNsOsNa [M+Na]+: 937.3649; found: 937.3690.

[0599] Step b: tert-Butyl 4-(4-f5-f(l£27f)-l-f4-(5-cvano-l-methyl-177-L3-benzodiazol-2-yl) benzamido]-2-ethenylcyclopropaneamido1pyridine-2-amido)-2-hydroxy-3-(propan-2-yloxy) benzamido benzoate

[0600] The allyl ether (137 mg, 0.15 mmol) was dissolved in THF (7.5 mL). Aniline (45 pL, 0.49 mmol, 3.30 equiv.) and Pd(PPh3)4 (17.3 mg, 0.02 mmol, O.lO equiv.) were added subsequently and the resulting mixture was stirred at rt for 90 min. The mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (dry load, MeOH in CH2C12 = 2%, 3%) to furnish the product (107 mg, 0.12 mmol, 82%) as yellowish solid. 'H-NMR (500 MHz, DMSO-d6) 8 = 12.44 (s, 1H), 10.75 (bs, 1H), 10.62 (bs, 1H), 10.28 (s, 1H), 9.33 (s, 1H), 8.99 (d, J= 2.6 Hz, 1H), 8.37 (dd, J= 2.4, 8.6 Hz, 1H), 8.29 (dd, J= 0.6, 1.5 Hz, 1H), 8.19 (d, J= 8.6 Hz, 2H), 8.17 (d, J= 8.8 Hz, 1H), 8.07 (bs, 1H), 8.04 (d, J= 8.5 Hz, 2H), 7.93-7.88 (m, 4H), 7.85 (d, J= 8.9 Hz, 2H), 7.74 (dd, J= 1.5, 8.4 Hz, 2H), 5.75-5.69 (m, 1H), 5.34 (dd, J= 1.4, 17.1 Hz, 1H), 5.13 (dd, J= 1.7, 10.4 Hz, 1H), 4.68 (sept, J= 6.0 Hz, 1H), 3.97 (s, 3H), 1.99-1.96 (m, 1H), 1.55 (s, 9H), 1.43- 1.40 (m, 1H), 1.33 (t, J= 6.6 Hz, 6H), 1.23 (m, lH) ppm.!3C-NMR (126 MHz, DMSO-d6) 8 = 169.1, 168.6, 166.9, 164.6, 161.2, 154.9, 143.4, 141.9, 140.2, 139.5, 138.7, 136.7, 135.1, 134.4, 134.0, 132.1, 131.5, 131.4, 129.9, 129.3, 128.8, 128.7, 128.2, 128.0, 126.0, 124.1, 123.6, 122.7, 120.7, 119.9, 117.4, 112.4, 104.4, 80.5, 74.6, 42.2, 32.2, 27.8, 22.3 (d, J= 6.5 Hz), 22.3 ppm. HRMS (ESI) calculated for C49H45N8O8 [M-H]': 873.3360; found: 873.3354.

[0601] Step c:

[0602] The tert-butyl ester (103 mg, 0.12 mmol) was dissolved in precooled TFA (6 mL) at 0 °C with stirring. The solution was warmed up to rt over 30 min. Et20 was added at 0 °C. The precipitate was filtered off, washed with excess of Et20 and dried in vacuo to furnish the product (84.1 mg, 0.10 mmol, 87%) as colorless solid. ’H-NMR (500 MHz, DMSO-d6) 8 = 12.82 (bs, 1H), 12.44 (s, 1H), 10.76 (s, 1H), 10.60 (s, 1H), 10.28 (s, 1H), 9.33 (s, 1H), 8.99 (d, J= 2.4 Hz, 1H), 8.37 (dd, J= 2.5, 8.6 Hz, 1H), 8.29 (d, J= 0.9 Hz, 1H), 8.20-8.17 (m, 3H), 8.11 (d, J= 9.0 Hz, 1H), 8.04 (d, J= 8.4 Hz, 2H), 7.97 (d, J= 8.7 Hz, 2H), 7.92 (dd, .7= 2.4, 8.8 Hz, 2H), 7.85 (d, J= 8.8 Hz, 2H), 7.74 (dd, J= 1.4, 8.4 Hz, 1H), 5.79-5.72 (m, 1H), 5.35 (d, J= 17.0 Hz, 1H), 5.13 (d, J= 10.5 Hz, 1H), 4.68 (sept, J= 6.1 Hz, 1H), 3.97 (s, 3H), 1.99-1.96 (m, 1H), 1.43- 1.40 (m, 1H), 1.33 (t, J= 6.5 Hz, 6H), 1.34-1.15 (m, 1H) ppm.13C-NMR (126 MHz, DMSO- d6) § = 169.1, 168.7, 166.9, 166.9, 161.3, 154.9, 154.1, 143.4, 141.9, 141.8, 140.3, 139.5, 138.7, 136.8, 135.1, 134.4, 133.9, 132.1, 130.2, 129.3, 128.2, 128.0, 126.3, 126.0, 124.1, 123.5, 122.7, 120.8, 119.9, 117.4, 112.4, 111.6, 108.3, 104.4, 74.7, 42.3, 32.2, 22.3 (d, J= 6.4 Hz), 22.3 ppm. HRMS (ESI) calculated for C45H37N8O8 [M-H]’: 817.2734; found: 817.2750.

[0603] 4-(4-{5-[(15,2R )-1-[3-(5-Cyano-l-methyl-1Z7-1,3-benzodiazol-2-yl)bicyclo[1.1.1|pentane- 1-amido]-2-ethenylcycIopropaneamido]pyridine-2-amido}-2-hydroxy-3-(propan-2-yloxy) benzamido)benzoic acid (MST284)

[0604] Step a: Prop-2-en-l-yl 4-(4- -l-[3-(5-cyano-l-methyl-17f-l,3-benzodiazol-2-yl) bicyclol 1.1.1 ]pentane- 1 -amido]-2-ethenylcyclopropaneamido1pyridine-2-amido) -2-(prop-2- en- 1 -yloxy)-3 -(propan-2-yloxy)benzamido)benzoate

[0605] The carboxylate (10.5 mg, 1.0 eq.) and HATU (14.4 mg, 1.1 eq.) were added to the amine hydrochloride (1.0 eq.) and dissolved in dry DMF (0.80 mL) under argon atmosphere. DIPEA (17.6 pL, 3.0 eq.) was added and the reaction mixture was stirred at rt while being screened with TLC. After 1 h, the mixture was partitioned between EtOAc / HCl (0.1 M) (15 mL each) and the aqueous phase was extracted with EtOAc(2 x 15 mL). The organic phases were combined and dried over Na2SO4 before solvents were removed under reduced pressure. The crude product was used without further purification.

[0606] Step b: The crude starting material and Pd(PPh3)4 (3.2 mg, 0.08 eq.) were added to a flask under argon atmosphere and dissolved in dry THF (0.70 mL). Aniline (18.9 pL, 6.0 eq.) was added and the reaction was stirred at rt for 3 h while being screened with TLC. Solvents were removed under reduced pressure and the crude product was purified by RP-HPLC (H2O with lO mM NITiHCCh / Acetonitrile). A pure and a mixed product fraction was obtained, latter containing aniline. The pure product was freeze-dried over 5 days. Colorless solid, 10 mg. A impure fraction (~30 mL aqueous solution) was carefully acidified with HC1 solution (1 M, 1.0 mL) to adjust the pH to ~3-4. A precipitate was formed that was extractable with EtOAc(10 mL). The aqueous phase was extracted again with EtOAc(2 x 10 mL) and the combined organic phases were washed with brine before removing solvents under reduced pressure. The material was purified again by RP-HPLC and freeze-dried to give 7 mg additional compound. Final yield: 17 mg (61%). ’H NMR (700 MHz, DMSO): 3(ppm) = 12.82 (br s, 1H), 12.50 (br s, 1H), 10.74 (s, 2H), 10.71 (s, 1H), 9.05 (d, J= 2.4 Hz, 1H), 8.96 (s, 1H), 8.38 (dd, J= 8.6, 2.4 Hz, 1H), 8.17 (d, <7= 8.6 Hz, 1H), 8.12 (d, J= 1.4 Hz, 1H), 8.11 (d, J= 8.9 Hz, 1H), 8.01 (d, J= 9.1 Hz, 1H), 7.96 (d, J= 8.7 Hz, 2H), 7.89 (d, J= 8.8 Hz, 2H), 7.75 (d, J= 8.4 Hz, 1H), 7.64 (dd, J= 8.4, 1.5 Hz, 1H), 5.55 (ddd, J= 17.1, 10.4, 8.9 Hz, 1H), 5.28 (dd, J= 17.0, 1.8 Hz, 1H), 5.09 - 5.04 (m, 1H), 4.67 (hept, J= 6.2 Hz, 1H), 3.89 (s, 3H), 2.61 - 2.57 (m, 6H), 2.34 (q, J= 8.7 Hz, 1H), 1.88 (dd, J= 7.7, 5.4 Hz, 1H), 1.34 (d, J= 6.1 Hz, 6H), 1.29 - 1.20 (m, 2H).13C NMR (126 MHz, DMSO): 8(ppm) = 170.0, 168.8, 166.9, 161.4, 154.3, 154.2, 143.3, 142.0, 141.2, 139.8, 139.0, 139.0, 136.8, 134.2, 134.0, 130.2, 129.4, 127.5, 126.3, 125.6, 123.8, 123.6, 122.8, 120.9, 120.0, 117.5, 111.7, 111.6, 108.3, 103.8, 74.8, 53.2, 41.9, 40.9, 35.0, 31.7, 30.9, 22.4.

[0607] 4-(4-{5-[(25)-2-{[3-Chloro-4-(5-cyano-l-methyl-ljH-l,3-benzodiazoI-2-yl)phenyl] formamido}pent-4-ynamido]pyridme-2-amido}-2-hydroxy-3-(propan-2-yIoxy) benzamido)benzoic acid (DK942) The amino acid derivative (116.9 pmol) was coupled with the carboxylic acid using General Procedure 8. The product was obtained by deprotection with General Procedures 10 and 11. Colorless solid, 55 mg (53% over 3 steps). ’H-NMR (500 MHz, DMSO-d6, 300 K): 5 (ppm) = 12.82 (br s, 1H), 12.47 (br s, 1H), 10.91 (s, 1H), 10.75 (s, 1H), 9.31 (d, 1H, J = 7.4 Hz), 9.02 (d, 1H, J = 2.6 Hz), 8.34 (dd, 1H, J = 2.4 Hz, 8.7 Hz), 8.31 (dd, 1H, J = 0.5 Hz, 1.4 Hz), 8.26 (d, 1H, J = 1.6 Hz), 8.21 (d, 1H, J = 8.6 Hz), 8.12 - 8.07 (m, 2H), 7.97 (d, 2H, J = 8.7 Hz), 7.92 - 7.88 (m, 2H), 7.87 - 7.83 (m, 3H), 7.77 (dd, 1H, J = 1.5 Hz, 8.4 Hz), 4.85 (q, 1H, J = 7.4 Hz), 4.68 (hept., 1H, J = 6.1 Hz), 3.72 (s, 3H), 3.01 (t, 1H, J = 2.6 Hz), 2.84 (dddd, 2H, J - 2.6 Hz, 7.4 Hz, 11.4 Hz, 16.8 Hz), 1.34 (dd, 6H, J = 3.6 Hz, 6.1 Hz).13C-NMR (126 MHz, DMSO-d6, 300 K): δ (ppm) = 169.9, 168.7, 166.9, 164.8, 161.2, 154.3, 152.8, 143.6, 142.0, 141.8, 139.6, 138.6, 138.4, 137.0, 136.7, 134.1, 133.2, 132.7, 131.6, 130.2, 128.7, 127.4, 126.8, 126.2, 124.5, 123.6, 123.0, 120.8, 119.9, 112.5, 111.8, 108.2, 104.5, 80.4, 74.8, 73.5, 53.7, 31.1, 22.3, 21.2. HRMS (ESI) calculated 839.2339 [M+H+], 839.2347 found.

[0608] 4-(4-{4-[(2S',31?)-2-{[4-(4-Cyanobenzamido)phenyl]formamido}-3-hydroxybutanamido] benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid (DK799)

[0609] The crude amine (167.8 pmol) was coupled with the carboxylic acid using General Procedure 8. The product was obtained by deprotection with General Procedures 10 and 11. Colorless to off-white solid, 49 mg (37% over 3 steps). ’H-NMR (700 MHz, DMSO-de, 300 K): δ (ppm) = 12.78 (br s, 1H, 12.31 (br s, 1H), 10.72 (s, 1H), 10.40 (s, 1H), 9.36 (br s, 1H), 8.16 - 8.13 (m, 3H), 8.05 (d, 2H, J = 8.4 Hz), 7.99 - 7.94 (m, 6H), 7.92 (d, 2H, J = 8.8 Hz), 7.85 (d, 2H, J = 8.7 Hz), 7.83 - 7.80 (m, 3H), 7.66 (d, 1H, J = 8.0 Hz), 5.08 (d, 1H, J = 6.5 Hz), 4.61 - 4.56 (m, 2H), 4.23 - 4.18 (m, 1H) 1.26 (dd, 6H, J = 1.8 Hz, 6.1 Hz), 1.20 (d, 3H, J = 6.3 Hz).I3C-NMR (176 MHz, DMSO-d6, 300 K): δ (ppm) = 169.9, 168.4, 166.9, 166.2, 164.1, 142.3, 141.7, 138.7, 136.8, 136.4, 132.5, 130.2, 129.2, 128.6, 128.5, 128.3, 126.1, 122.9, 120.5, 119.6, 118.9, 118.3, 114.1, 1 12.7, 74.5, 66.8, 60.6, 22.3, 20.4. HRMS (ESI) calculated 799.2722 [M+H+], 799.2736 found.

[0610] 4-(4-{4-[(25,3R )-2-{[3-Cyano-4-(4-cyanobenzamido)phenyl]formamido}-3- hydroxybutanamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid

[0611] The crude amine (99.6 pmol) was coupled with the carboxylic acid using General Procedure 8. The product was obtained by deprotection with General Procedures 10 and 11. Colorless solid, 31 mg (38% over 3 steps). 'H-NMR (500 MHz, DMSO-d6, 300 K): δ (ppm) = 12.60 (br s, 1H), 11.09 (br s, 1H), 10.42 (s, 1H), 9.26 (br s, 1H), 8.63 (d, 1H, J = 8.0 Hz), 8.51 (d, 1H, J = 2.1 Hz), 8.26 (dd, 1H, J = 2.1 Hz, 8.5 Hz), 8.17 (d, 2H, J = 8.6 Hz), 8.10 (d, 2H, J = 8.6 Hz), 7.95 - 7.91 (m, 4H), 7.84 - 7.80 (m, 4H), 7.76 (d, 1H, J = 8.5 Hz), 7.72 (d, 1H, J = 8.2 Hz), 7.51 (br s, 1H), 5.11 (d, 1H, J = 5.8 Hz), 4.69 (br s, 1H), 4.59 (dd, 1H, J = 5.3 Hz, 8.0 Hz), 4.24 - 4.16 (m, 1H), 1.24 (dd, 6H, J = 1.3 Hz, 6.1 Hz), 1.21 (d, 3H, J = 6.3 Hz).13C-NMR (126 MHz, DMSO-de, 300 K): δ (ppm) = 169.6, 168.1, 167.0, 164.7, 164.4, 163.9, 142.4, 142.1, 137.3, 136.8, 136.2, 133.2, 132.8, 132.6, 131.8, 130.3, 128.8, 128.2, 126.3, 123.2, 120.0, 119.0, 118.3, 116.5, 114.6, 108.5, 73.5, 66.7, 61.0, 22.5, 20.4. HRMS (ESI) calculated 824.2675 [M+H+],

[0612] 824.2689 found.

[0613] 4-(4-{4-[(25,3R)-2-{[4-(6-Cyano-l-inethyl-1H- 1,3-benzodiazoI-2-yl)phenyI]formamido}-

[0614] 3-hydroxybutanamido]benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid (DK1029)

[0615]

[0616] The crude amine (99.6 pmol) was coupled with the carboxylic acid and the allyl ether deprotected using General Procedure 13. The product was obtained by deprotection with General Procedure 11. Colorless solid, 50 mg (61% over 3 steps). 'H-NMR (500 MHz, DMSO- d6, 300 K): δ (ppm) = 12.82 (br s, 1H), 12.30 (br s, 1H), 10.71 (br s, 1H), 10.46 (s, 1H), 9.42 (s, 1H), 8.49 (d, 1H, J = 8.0 Hz), 8.37 (d, 1H, J = 0.8 Hz), 8.15 (d, 2H, J = 8.5 Hz), 8.06 (d, 2H, J = 8.5 Hz), 7.99 - 7.95 (m, 4H), 7.89 (d, 1H, J = 8.4 Hz), 7.87 - 7.81 (m, 5H), 7.69 - 7.65 (m, 2H), 5.13 (d, 1H, J = 6.6 Hz), 4.63 (dd, 1H, J = 5.0 Hz, 8.0 Hz), 4.55 (quint., 1H, J = 5.7 Hz), 4.26 - 4.19 (m, 1H), 3.99 (s, 3H), 1.26 (d, 6H, J = 5.6 Hz), 1.22 (d, 3H, J = 6.3 Hz).13C-NMR (126 MHz, DMSO-d6, 300 K): 5 (ppm) = 169.7, 168.5, 167.0, 166.2, 164.2, 155.6, 145.3, 142.3, 142.2, 137.0, 136.5, 135.4, 132.0, 130.3, 129.6, 128.5, 128.0, 126.2, 125.6, 122.9, 120.7, 120.3, 120.0, 118.9, 116.4, 112.6, 104.3, 74.7, 66.8, 60.8, 32.3, 22.4, 20.5. HRMS (ESI) calculated 810.2882 [M+H+], 810.2893 found.

[0617] 4-(4-{4-[(25,35)-2-{[4-(4-Cyanobenzamido)phenyl]formamido}-3-hydroxybutanamido] benzamido}-2-hydroxy-3-(propan-2-yloxy)benzamido)benzoic acid (DK786)

[0618] The crude amine (129.3 umol) was coupled with the carboxylic acid using General Procedure 8. The product was obtained by deprotection with General Procedures 10 and 11. White solid, 39 mg (38% over 3 steps). ‘H-NMR (700 MHz, DMSO-d6, 300 K): 5 (ppm) = 12.82 (br s, 1H), 12.30 (s, 1H), 10.69 (s, 1H), 10.61 (br s, 1H), 10.40 (br s, 1H), 9.38 (s, 1H), 8.45 (d, 1H, J = 8.2 Hz), 8.13 (d, 2H, J = 8.5 Hz), 8.05 (d, 2H, J = 8.5 Hz), 7.98 - 7.94 (m, 6H), 7.89 (d, 2H, J = 8.8 Hz), 7.87 - 7.84 (m, 5H), 7.71 (d, 1H, J = 8.8 Hz), 5.16 (d, 1H, J = 5.2 Hz), 4.57 - 4.50 (m, 2H), 4.14 - 4.09 (m, 1H), 1.27 (dd, 6H, J = 0.9 Hz, 6.1 Hz), 1.23 (d, 3H, J = 6.2 Hz).13C- NMR (176 MHz, DMSO-de, 300 K): δ (ppm) = 170.5, 168.5, 166.9, 165.9, 164.4, 164.2, 154.1, 142.5, 142.0, 141.6, 138.7, 137.1, 136.3, 132.5, 130.2, 129.2, 128.6, 128.4, 128.3, 128.2, 126.3, 122.8, 120.7, 119.5, 118.8, 118.3, 114.0, 112.4, 112.1, 74.9, 66.5, 60.7, 22.3, 21.0. HRMS (ESI) calculated 799.2722 [M+H+], 799.2718 found.

[0619] 4-[4-({4-[(25,3^!)-2-{[4-(6-Cyano-l-niethyl-lZr-l,3-benzodiazol-2-yl)phenyl]formamido}-

[0620] 3-hydroxybutanamido]-2-fluorophenyl}carbamoyl)-2-hydroxy-3-(propan-2-yloxy) benzamido] benzoic acid (DK1048)

[0621] The crude amine (116.6 pmol) was coupled with the carboxylic acid and the allyl ether deprotected using General Procedure 13. The product was obtained by deprotection with General Procedure 11. White to off-white solid, 54 mg (56% over 3 steps). ’H-NMR (500 MHz, DMSO-de, 300 K): δ (ppm) = 12.84 (br s, 1H), 12.09 (br s, 1H), 11.01 (br s, 1H), 10.34 (s, 1H), 10.27 (s, 1H), 8.43 (d, 1H, J = 8.1 Hz), 8.36 (d, 1H, J = 0.9 Hz), 8.15 (d, 2H, J = 8.5 Hz), 8.09 - 8.04 (m, 3H), 7.97 (d, 2H, J = 8.8 Hz), 7.90 - 7.84 (m, 4H), 7.79 (dd, 1H, J = 2.2 Hz, 13.4 Hz), 7.67 (dd, 1H, J = 1.5 Hz, 8.4 Hz), 7.38 - 7.32 (m, 2H), 5.10 (d, 1H, J = 6.6 Hz), 4.72 (dt, 1H, J = 5.9 Hz, 12.0 Hz), 4.59 (dd, 1H, J = 5.0 Hz, 8.1 Hz), 4.24 - 4.18 (m, 1H), 3.99 (s, 3H), 1.28 (d, 6H, J = 6.2 Hz), 1.21 (d, 3H, J = 6.3 Hz).13C-NMR (500 MHz, DMSO-d6, 300 K): 8 (ppm) = 169.4, 167.7, 166.9, 166.1, 163.3, 155.6, 153.1 (d, J = 242.8 Hz), 145.3, 144.1, 142.0, 136.5, 136.3 (d, J = 10.7 Hz), 135.4, 132.2, 131.9, 130.3, 129.5, 128.0, 126.3, 125.5, 123.7, 122.9, 121.0 (d, J = 11.5 Hz), 120.6, 120.3, 120.0, 119.7, 118.1, 116.4, 115.1, 106.6 (d, J = 24.7 Hz), 104.3, 75.9, 66.8, 60.7, 32.3, 21.8, 20.4.19F-NMR (470 MHz, DMSO-d6, 300 K): δ (ppm) = - 124.22. HRMS (ESI) calculated 828.2788 [M+H+], 828.2783 found. 4-[4-({4-[(25)-3-Carbamoyl-2-{[4-(6-cyano-l-methyl-l T-l,3-benzodiazol-2-yl)phenyl] formamido}propanamido]-2-fluorophenyl}carbamoyl)~2-hydroxy-3-(propan-2-yIoxy) benzamido] benzoic acid (DK1060)

[0622] The crude amine (79.5 pmol) was coupled with the carboxylic acid using General Procedure 8. The product was obtained by deprotection with General Procedures 10 and 12. Off-white solid, 30 mg (45% over 3 steps). ’H-NMR (500 MHz, DMSO-d6, 300 K): δ (ppm) = 12.64 (br s, 1H), 10.61 (br s, 1H), 10.36 (br s, 1H), 8.94 (d, 1H, J = 7.4 Hz), 8.35 (d, 1H, J = 1.1 Hz), 8.24 (t, 1H, J = 8.9 Hz), 8.11 (d, 2H, J = 8.4 Hz), 8.03 (d, 2H, J = 8.4 Hz), 7.91 (d, 2H, J = 8.7 Hz), 7.88 (d, 1H, J = 8.4 Hz), 7.83 (d, 2H, J = 8.7 Hz), 7.78 (dd, 1H, J = 2.1 Hz, 13.6 Hz), 7.71 - 7.64 (m, 2H), 7.41 (s, 1H), 7.39 - 7.35 (m, 1H), 7.03 - 6.98 (m, 2H), 5.16 - 5.02 (m, 1H), 4.94 (dd, 1H, J = 7.3 Hz, 14.1 Hz), 3.98 (s, 3H), 2.72 - 2.69 (m, 2H), 1.26 (d, 6H, J = 6.2 Hz).13C-NMR (500 MHz, DMSO-de, 300 K): δ (ppm) = 171.3, 170.2, 167.3, 167.1, 165.7, 164.0, 155.6, 152.3 (d, J = 242.1 Hz), 145.3, 143.7, 136.5, 135.7 (d, J = 10.5 Hz), 135.3, 131.9, 130.4, 129.5, 128.7, 128.2, 128.1, 127.9, 125.5, 124.7, 123.3, 122.4, 121.6 (d, J = 11.1 Hz), 120.5, 120.3, 120.0, 119.5, 116.4, 115.2, 106.5 (d, J = 24.3 Hz), 104.2, 73.4, 51.6, 36.9, 32.3, 21.9. HRMS (ESI) calculated 841.2740 [M+H+], 841.2722 found.

[0623] 4-[4-({4-[(lS',2J?)-l-[3-(5-Cyano-l-methyl-1H-l,3-benzodiazol-2-yl)bicyclo[l.l.l]pentane- l-amido]-2-ethenylcyclopropaneamido]phenyl}carbamoyl)-2-hydroxy-3-(propan-2- yloxy)benzamido] benzoic acid (MST401)

[0624] The crude amine (1 eq.) was dissolved in dry DMF (0.70 mL) under argon atmosphere together with the carboxylate (23.3 mg, 1.1 eq.) and HATU (29.1 mg, 1.1 eq). DIPEA (35 pL, 3.0 eq.) was added and the mixture was stirred at rt. After 2h, the solution was partitioned between

[0625] EtOAc / HCl (0.1 M) (20 mL each) and brine (10 mL) and the aqueous phase was extracted with EtOAc(2 x 15 mL). The combined organic phases were dried over Na2SO4 and all volatiles were removed under reduced pressure. The crude product was directly used in next step.

[0626] The crude allyl ether (63 mg), aniline (19 pL, 3.0 eq.) and Pd(PPhs)4 (spatula tip) were suspended in dry THF (1.0 mL) under argon atmosphere. Then the reaction was stirred overnight at rt. The crude material was absorbed on silica and purified by flash column chromatography (solid loading, Cy / acetone, 40% acetone) to give a colorless solid that was used without further purification in the final deprotection.

[0627] The crude tert-butyl ester was dissolved in dry CH2CI2 (1.0 mL) and TFA (0.27 mL, 15 eq.). The reaction was stirred at rt. After 1 h 50 min the mixture was diluted with ACN. All volatiles were removed under reduced pressure and by coevaporation with ACN (3x) before purifying the sample using RP-HPLC (H2O with lO mM NFLHCCh / Acetonitrile and freeze-dried. Colorless fluffy solid, 39 mg (69% over 3 steps). *H NMR (700 MHz, DMSO-de): 8(ppm) = 12.54 (s, 1H), 10.45 (s, 1H), 9.50 (s, 1H), 8.61 (s, 1H), 8.18 - 8.08 (m, 1H), 7.88 (d, J = 8.9 Hz, 2H), 7.83 - 7.79 (m, 2H), 7.75 (dd, J = 8.5 Hz, 0.8 Hz, 1H), 7.70 - 7.66 (m, 2H), 7.64 (dd, J = 8.4 Hz, 1.5 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 9.2 Hz, 2H), 6.66 (d, J = 7.8 Hz, 1H), 5.59 (ddd, J = 17.1 Hz, 10.5 Hz, 9.2 Hz, 1H), 5.27 (dd, J = 17.1 Hz, 1.8 Hz, 1H), 5.06 (dd, J = 10.3 Hz, 2.2 Hz, 2H), 3.89 (s, 3H), 2.55 (s, 6H), 2.25 - 2.19 (m, 1H), 1.85 - 1.80 (m, 1H), 1.25 - 1.18 (m, 7H).13C NMR (126 MHz, DMSO-d6) 8(ppm) = 169.9, 167.2, 164.9, 154.2, 141.4, 139.0, 134.9, 134.8, 134.1, 130.5, 125.6, 123.7, 123.6, 120.7, 120.1, 119.5, 118.9, 116.9, 111.6, 103.7, 53.1, 41.6, 40.9, 34.9, 31.5, 30.9, 22.3, 22.3, 20.5. 4-[4-({4-{(LS',2R )-1-[3-(6-Cyano-1-methyl-1H -1,3-benzodiazol-2-yl)bicyclo[1.1.1]pentane-

[0628] 1-amido]-2-ethenyIcyclopropaneamido]phenyl}carbamoyI)-2-hydroxy-3-(propan-2- yloxy)benzamido] benzoic acid (MST404)

[0629] The crude amine (1 eq.), the carboxylate (26.4 mg, 1.1 eq.) and HATU (32.9 mg, 1.1 eq.) were dissolved in dry DMF (0.80 mL) under argon atmosphere. DIPEA (40 pL, 3.0 eq.) was added and the mixture was stirred at rt. After 2h the solution was partitioned between EtOAc / HCl (0.1 M) (20 mL each) and brine (10 mL) and the aqueous phase was extracted with EtOAc(2 x 15 mL). The combined organic phases were dried over Na2SO4 and all volatiles removed under reduced pressure. The crude product was directly used in next step.

[0630] The crude allyl ether, aniline (22 pl, 3.0 eq) and Pd(PPh3)4 (spatula tip) were dissolved in dry THF (0.8 mL). The reaction was stirred at rt for 2 h 45 min. The solvents were removed under reduced pressure and the crude material was purified by flash column chromatography (solid loading, Cy / acetone, 30% acetone->40%->50%). After solvent removal under reduced pressure and coevaporation with cyclohexane (2x) a brownish sticky solid was obtained that was used without further purification in the next step.

[0631] The crude tert-butyl ester (68 mg, 1 eq.) was suspended in dry CH2CI2 (1.2 mL) under argon atmosphere and TFA (0.30 mL, 50 eq.) was added dropwise. The reaction was stirred at rt and after 1.5 h the reaction mixture was diluted with CH2CI2. Solvents were removed under reduced pressure and by coevaporation with CH2CI2 (2x). The sample was purified using RP-HPLC (H2O with 10 mM NH4HCO3 / Acetonitrile) and freeze-dried. Colorless fluffy solid, 47 mg (74% over 3 steps). ’H NMR (500 MHz, DMSO-d6): 8(ppm) = 15.42 (s, 1H), 10.51 (s, 1H), 9.92 - 9.84 (m, 1H), 9.23 - 9.13 (m, 1H), 8.22 - 8.17 (m, 1H), 7.83 (d, J = 7.5 Hz, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 9.0 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.59 - 7.50 (m, 4H), 6.57 (d, J = 8.4 Hz, 1H), 5.63 - 5.51 (m, 1H), 5.25 (dd, J = 17.1 Hz, 2.0 Hz, 1H), 5.22 - 5.14 (m, 1H), 5.04 (dd, J = 10.1 Hz, 2.2 Hz, 1H), 3.87 (s, 3H), 2.55 (s, 6H), 2.21 (q, J = 8.9 Hz, 1H), 1.85 - 1.78 (m, 1H), 1.26 - 1.18 (m, 7H).13C NMR (126 MHz, DMSO-d6): 8(ppm) = 170.5, 169.9, \61A, 166.6, 166.0, 165.0, 155.0, 147.5, 144.8, 141.5, 135.8, 134.9, 134.8, 134.3, 133.6, 129.8, 128.8, 125.0, 123.7, 121.0, 120.6, 120.1, 119.8, 119.4, 117.8, 116.8, 115.5, 107.0, 103.7, 71.2, 53.1, 41.7, 41.0, 34.9, 31.4, 30.9, 22.3, 20.3.

[0632] 4-{4-[(2S',3R )-2-{[4-(6-Cyano-1-methyl-1H-1,3-benzodiazoI-2-yI)phenyl]formamido}-3- hydroxybutanamido]benzamido}-2-hydroxy-3-(propan-2-yIoxy)-7V-(4-sulfamoylphenyl)

[0633] The amine (84.9 pmol) was coupled with the carboxylic acid using General Procedure 5 and deprotected using General Procedure 6. The product was obtained by General Procedure 13 and deprotection with General Procedure 11. Off-white solid, 18 mg (26% over 5 steps). ‘H-NMR (700 MHz, DMSO-d6, 300 K): δ (ppm) = 12.30 (br s, 1H), 10.70 (br s, 1H), 10.43 (s, 1H), 9.39 (br s, 1H), 8.45 (d, 1H, J = 8.1 Hz), 8.36 (d, 1H, J = 0.9 Hz), 8.15 (d, 2H, J = 8.5 Hz), 8.06 (d, 2H, J = 8.5 Hz), 7.97 (d, 2H, J = 8.8 Hz), 7.90 - 7.87 (m, 3H), 7.85 - 7.81 (m, 5H), 7.67 (dd, 1H, J = 1.5 Hz, 8.3 Hz), 7.31 (s, 2H), 5.11 (d, 1H, J = 6.6 Hz), 4.63 (dd, 1H, J = 5.0 Hz, 8.1 Hz), 4.60 - 4.55 (m, 1H), 4.26 - 4.21 (m, 1H), 3.99 (s, 3H), 1.26 (dd, 6H, J = 1.7 Hz, 6.1 Hz), 1.23 (d, 3H, J = 6.3 Hz).13C-NMR (700 MHz, DMSO-d6, 300 K): δ (ppm) = 169.7, 168.5, 166.2, 164.2, 155.6, 145.3, 142.3, 141.0, 139.4, 136.9, 136.4, 136.4, 135.4, 131.9, 129.5, 128.5, 128.4, 127.9, 126.5, 125.5, 122.8, 121.0, 120.2, 119.9, 118.9, 116.4, 112.5, 104.3, 74.7, 66.8, 60.8, 32.2, 22.3, 20.4. HRMS (ESI) calculated 845.2712 [M+H+], 845.2703 found.

[0634] BIOLOGICAL ACTIVITIES The synthesized cystobactamid derivatives were tested against various Gram-negative and Gram-positive bacteria. Experimental procedures used for the biological characterization of the compounds are the same described in Wiegand et al., Nature Protocols 3, 163-175 (2008).

[0635] Bioactivity testing

[0636] Bacterial strains used in susceptibility assays (minimum inhibitory concentration, MIC) were either part of our internal strain collection or purchased from the German Collection of Microorganisms and Cell Cultures Deutsche Sammlung von Mikroorganismen und Zellkulturen, DSMZ) and the American Type Culture Collection (ATCC). The susceptible E. coli strain (WT) and fluoroquinolone-resistant mutants E. coli WT-3 and WT-III were kindly provided by Prof. Dr. P. Heisig, Pharmaceutical Biology and Microbiology, University of Hamburg, Germany. The efflux-deficient strain P. aeruginosa EmexAB was kindly provided by Prof. Dr. S. HauBler, Institute for Molecular Bacteriology, TWINCORE, Hannover, Germany. A. baumannii ATCC BAA-1710, CIP-105742, CIP-107292, ACC00535, and R835, E. coli LM705 and CH448, E. aerogenes CIP 106754, E. cloacae ATCC BAA-2468, P. aeruginosa PAO1, P. mirabilis ATCC BAA-2081, and K. pneumoniae CIP 104298, KPI 0581, and R-1525 were kindy provided by Evotec. A. baumannii 038 OXA-23, and 070 NDM-1 were kindly provided by Prof. Dr. H. Seifert, University of Cologne, Koln, Germany. P. aeruginosa CRPA / 4MRGN, S. aureus MRSA, and S. pneumoniae PRSP were kindly provided by Prof. Dr.

[0637] D. Schlueter and Dr. C. Baier, Hannover Medical School, Hannover, Germany. All compounds were prepared as DMSO stocks and MIC values were determined in standard microbroth dilution assays in 96-well MTPs using colony suspention method as described inWiegand et al., Nat Protoc 2008; 3, 163-175. In brief, bacteria were plated on Columbia blood agar (BBL1M, BD; 5. pneumoniae, P. aeruginosa, and S', aureus), TSB agar (TSB agar: 1.7% peptone casein, 0.3% peptone soymeal, 0.25% glucose, 0.5% NaCI, 0.25% K2HPO4, 1.5% agar; pH 7.3; E. aerogenes, E. cloacae, and E. faecalis), or CASO agar (Carl Roth; all other bacteria). Agar plates were incubated 18-24 h at 30-37 °C in presence of 5% CO2 (S. pneumoniae, E. aerogenes,

[0638] E. cloacae, and E. faecalis) or in normal atmosphere (all other strains). The following day four to five normal looking colonies were suspended in saline solution (0.9% NaCI) to obtain turbidity of 0.5 McFarland. Next, bacterial suspentions were diluted in either tryptic soy broth (TSB: 1.7% peptone casein, 0.3% peptone soymeal, 0.25% glucose, 0.5% NaCI, 0.25% K2HPO4; pH 7.3; S. pneumoniae, E. aerogenes, E. cloacae, and E. faecalis) or cation-adjusted Muller-Hinton Broth (BBL™, BD; all other bacteria) to obtain the final inoculum size of 5 x 105cfii / mL. Bacteria were grown in the presence of the derivatives in serial dilution for approx. 16-20 h at 30-37 °C in presence of 5% CO2 (S'. pneumoniae, E. aerogenes, E. cloacae, and E. faecalis) or in normal atmosphere (all other strains). MIC values were determined and were defined as the antibiotic concentration at which no visual growth of bacteria was observed.

[0639] The target activity on E. coli gyrase was assessed as described in Baumann et al., Angew Chem Int Ed Engl. 2014; 53(52): 14605-9 using a commercial supercoiling (sc) assay kit from Inspiralis according to the manufacturer’s instructions. The samples were separated on 1 % (w / v) agarose gels and relaxed and supercoiled plasmid was visualized by ethidium bromide staining. Half-inhibitory concentrations (IC50) were calculated after image analysis and quantification (Image J) based on sigmoidal curve fitting (GraphPad Prism).

[0640] The following tables show the antibacterial activities (MIC pg / mL) of cystobactamid derivatives of the present invention:

[0641] Table 1

[0642]

[0643] Table 2

[0644] Table 3

[0645] Table 4

[0646]

[0647] Table 5

[0648]

[0649] Table 6

[0650] Table 7

[0651] SOLUBILITY

[0652] Thermodynamic (Equilibrium) solubility in selected buffer: The selected compound is suspended in phosphate buffer (50 mM, pH 7.4) at a target concentration of 1 mg / mL. After overnight stirring at room temperature, protected from light, suspensions are filtered through a 0.45pm PTFE membrane. An aliquot of the resulting supernatant is quantified using UPLC UV method against a reference solution obtained by preparation of a DMSO stock solution. The solubility value is expressed as pg per mL.

[0653] Table 8

Claims

Claims1. A compound of formula (I):whereinAr is selected from the following groups:R2is a Ci-6 alkyl group or a Ci-6 haloalkyl group;L1is is a group of formula -CO-NH-; -CS-NH-; -C(=NH)-NH-; or -NH-CO-;A is is selected from the following groups:R3is hydrogen, -CN, fluorine or chlorine;L2is selected from the following groups:R4is selected from the following groups:R5is a group of formula -CH=CH2 or -C=CH;W is CH, N, CF or COCF3;X is CH, N, CF or COCF3;Y is CH, N, CF or COCF3;Z is CH, N, CF or COCF3;L3is a group of formula -CO-NH-; -CS-NH-; -C(=NH)-NH-; or -NH-CO-;L4is a group of formula -CO-NH-; -CS-NH-; -C(=NH)-NH-; or -NH-CO-; andR1is a group of formula -COOH or -SO2NH2; or a salt thereof; wherein the following compounds are excluded:

2. A compound according to claim 1, wherein L1is a group of formula -CO-NH-.

3. A compound according to claim 1 or 2, wherein R2is a group of formula -CH3 or - CH2CH3.

4. A compound according to any one of the preceding claims, wherein L2is a group of the following formula:

5. A compound according to any one of the preceding claims, wherein R4is selected from the following groups:

6. A compound according to any one of the preceding claims 1 to 4, wherein R4is a group of the following formula:

7. A compound according to any one of the preceding claims 1 to 3, wherein L2is a group of the following formula:

8. A compound according to any one of the preceding claims 1 to 3, wherein L2is a group of the following formula:

9. A compound according to any one of the preceding claims, wherein X is CH, CF or N.

10. A compound according to any one of the preceding claims, wherein Y is CH; Z is CH; and / or W is CH.

11. A compound according to any one of the preceding claims, wherein L3is a group of formula -CO-NH- or -NH-CO-.

12. A compound according to any one of the preceding claims, wherein L4is a group of formula -CO-NH-.

13. A compound according to any one of the preceding claims, wherein R1is a group of formula -COOH.

14. A compound according to any one of the preceding claims 1 to 12, wherein R1is a group of formula -SO2NH2.

15. A compound according to any one of the preceding claims, wherein Ar is selected from the following groups:especially wherein R2is a group of formula -CH3 or -CH2CH3.; especially preferably wherein R2is a methyl group.

16. A compound according to any one of the preceding claims, wherein L3is a group of formula -NH-CO-; and X is CH or CF.

17. A compound according to any one of the preceding claims 1 to 3, 7 and 9 to 16, wherein L2is a group of the following formula:and A is the following group:

18. Pharmaceutical composition comprising a compound according to anyone of the preceding claims and optionally one or more carrier substances and / or one or more adjuvants.

19. Compound according to anyone of claims 1 to 17 or pharmaceutical composition according to claim 18 for use in the treatment or prophylaxis of bacterial infections.

20. Use of a compound according to any one of claims 1 to 17 or of a pharmaceutical composition according to claim 18 for the manufacture of a medicament for the treatment or prophylaxis of bacterial infections.

21. A method for the treatment or prophylaxis of a bacterial infection comprisingadministering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutical composition according to claim 18.

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