Antibiotic macrocyclic peptides

Abstract

The present invention provides compounds of formula (I): (I) wherein X, Y, R1, R2, and R3 are as described herein, as well as pharmaceutically acceptable salts thereof. Further, the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments for the treatment of diseases and infections caused by bacteria.

Description

[0001] Case 39605

[0002] Antibiotic Macrocyclic Peptides

[0003] Field of the Invention

[0004] The present invention provides compounds which exhibit activity against bacteria, in particular against Gram-negative bacteria like Acinetobacter baumannii, their manufacture, pharmaceutical compositions comprising them and their use as medicaments for the treatment of diseases and infections caused by bacteria.

[0005] Background of the Invention

[0006] Acinetobacter baumannii is a Gram-negative, aerobic, nonfermenting bacterium recognized over the last decades as an emerging pathogen with very limited treatment options.

[0007] A. baumannii is considered to be a serious threat by the US Centers for Disease Control and Prevention and belongs to the so called ‘ESKAPE’ pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enter obacter species & E. coll) that currently cause the majority of nosocomial infections and effectively “escape” the activity of antimicrobial agents.

[0008] A. baumannii is most often encountered in intensive care units and surgical wards, where extensive antibiotic use has enabled selection for resistance against all known antimicrobials and where it causes infections that include bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection.

[0009] A. baumannii has an exceptional ability to upregulate and acquire resistance determinats and shows an environmental persistance that allows its survival and spread in the nosocomial setting, making this organism a frequent cause of outbreaks of infection and an endemic, health care-associated pathogen.

[0010] Due to increasing antibiotic resistance to most if not all available therapeutic options, Muti-Drug Resistant (MDR) A. baumanniii infections, especially those caused by Carbapenem resistant A. baumannii, are extremely difficult or even impossible to treat with high mortality rate as well as increased morbidity and length of stay in intensive care unit.

[0011] CNE / 05.12.2025Acinetobacter baumannii has been defined and still remains “a prime example of a mismatch between unmet medical needs and the current antimicrobial research and development pipeline” according to the Antimicrobial Availability Task Force (AATF) of the Infectious Diseases Society of America (IDSA). Thus, there is a high demand and need to identify compounds suitable for the treatment of diseases and infections caused by Acinetobacter baumannii.

[0012] WO2017 / 072062, WO2019185572, and WO2019206853 disclose peptide macrocycles that are active against Acinetobacter baumannii. However, there is still a high unmet medical need for further compounds that are suitable for the treatment of diseases and infections caused by Acinetobacter baumannii, for example in order to overcome potential future resistances to the antibiotic compounds disclosed in the prior art.

[0013] Summary of the Invention

[0014] The present invention provides novel peptide macrocycles that are highly active against Acinetobacter baumannii, including against MDR strains of Acinetobacter baumannii.

[0015] More particularly, in a first aspect, the present invention provides a compound of formula (I)

[0016]

[0017] or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X, Y, R1, R2, and R3are as described herein.

[0018] The present invention further provides processes for manufacturing the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments for the treatment of diseases and infections caused by certain bacteria.Detailed of the invention

[0019] Definitions

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, suitable methods and materials are described below.

[0021] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0022] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0023] The nomenclature used in this Application is based on IUPAC systematic nomenclature, unless indicated otherwise. Biovia Draw 22.1 was employed to generate IUPAC chemical names.

[0024] Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen atom, unless indicated otherwise.

[0025] The term “pharmaceutically acceptable salts” denotes salts which are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. Acid addition salts are those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid,propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Base addition salts are those pharmaceutically acceptable salts formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

[0026] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al. Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511). The prefixes D and L or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or L designating that the compound is levorotatory. A compound prefixed with (+) or D is dextrorotatory.

[0027] The term “halo”, “halogen”, and “halide” are used interchangeably herein and denote fluoro, chloro, bromo, or iodo. Particular examples of halogen are fluoro, chloro, and bromo.

[0028] The term “carboxy” refers to a carboxylic acid moiety, i.e. to a group -C(O)OH.

[0029] The term “alkyl” denotes a monovalent linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“Ci-6-alkyl”). In particular embodiments, alkyl has 1 to 4 carbon atoms, and in more particular embodiments 1 to 3 carbon atoms, for example 1, 2, or 3 carbon atoms.

[0030] Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. A particular, yet non-limiting example of alkyl is methyl.The term “alkoxy” denotes a group of the formula -O-R’, wherein R’ is an alkyl group as defined herein. Non-limiting examples of alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy. A particular, yet non-limiting example of alkoxy is methoxy (-OCH3).

[0031] The term “haloalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro. Preferred, yet non-limiting examples of haloalkyl are trifluoromethyl (CF3), difluoromethyl (CHF2), 1,1 -difluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. Particularly, yet non-limiting examples of haloalkyl are trifluoromethyl (CF3) and difluoromethyl (CHF2).

[0032] The term “haloalkoxy” refers to an alkoxy group as defined herein, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkoxy” refers to an alkoxy group wherein 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of haloalkoxy are trifluoromethoxy, difluoromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy. Further particularly preferred, yet non-limiting examples of haloalkoxy are trifluoromethoxy and difluoromethoxy.

[0033] The term “cycloalkyl” refers to a saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“Cs-io-cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. “Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms. The term also refers to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. Preferably, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[l.l.l]pentanyl, bicyclo[3.1.0]hexanyl, norbornanyl, and l-bicyclo[2.2.2]octanyl.

[0034] Particularly preferred, yet non-limiting examples of cycloalkyl are cyclopropyl and bicyclof 1.1.1 ]pentanyl .

[0035] The term “protecting group” denotes the group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry.Protecting groups can be removed at the appropriate point. Exemplary protecting groups are amino-protecting groups, carboxy -protecting groups or hydroxy-protecting groups, as can be found, for example, in T. W. Greene and P. G. M. Wuts, “Protective groups in Organic Synthesis”, 2nd ed., John Wiley & Sons, Inc., New York, NY, 1991, chapter 7; E. Haslam, “Protecting groups in Organic Chemistry”, J. G. W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T.W. Greene, “Protective groups in Organic Synthesis”, John Wiley and Sons, New York, NY, 1981.

[0036] The terms “pharmaceutical composition” and “pharmaceutical formulation” (or “formulation”) are used interchangeably and denote a mixture or solution comprising a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients to be administered to a mammal, e.g., a human in need thereof.

[0037] The term “pharmaceutically acceptable” denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use.

[0038] The terms “pharmaceutically acceptable excipient”, “pharmaceutically acceptable carrier” and “therapeutically inert excipient” can be used interchangeably and denote any pharmaceutically acceptable ingredient in a pharmaceutical composition having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents or lubricants used in formulating pharmaceutical products.

[0039] The term “therapeutically effective amount” denotes an amount of a compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.The term “treating” or “treatment” of a disease state includes inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.

[0040] Compounds of the Invention

[0041] In a first aspect, the present invention provides a compound of formula (I)

[0042]

[0043] or a pharmaceutically acceptable salt or a stereoisomer thereof,

[0044] wherein:

[0045] X is selected from the group consisting of Se, SO, SO2, CH2, O, and NR4;

[0046] Y is CH or N;

[0047] A is selected from the group consisting of phenyl, pyridyl, and thienyl;

[0048] R1is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, Ci-6-alkoxy, halo-Ci-6-alkyl, halo-Ci-6-alkoxy, Cs-io-cycloalkyl, Ci-6-alkyl-O-CH2-, and C3-10- cycloalkyl-O-CH2-;

[0049] R2is halogen or a group

[0050]

[0051] R3is hydrogen or Ci-6-alkyl;

[0052] R4is hydrogen or Ci-6-alkyl;

[0053] R5is selected from the group consisting of hydrogen, carboxy, SO2OH, and IH-tetrazol- 5-yl; and

[0054] R6is selected from the group consisting of hydrogen, halogen, and Ci-6-alkyl.In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X is SO2or CH2.

[0055] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Xis SO2.

[0056] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, halo-Ci-6-alkyl, halo-Ci-6-alkoxy, and C3-io-cycloalkyl-0-CH2-

[0057] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is selected from the group consisting of hydrogen, fluoro, chloro, methyl, CHF2, CF3, CHF2O-, and cyclopropyl-O-CH2-

[0058] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is selected from the group consisting of halogen, Ci-6-alkyl, and halo-Ci-6-alkyl.

[0059] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is selected from the group consisting of chloro, methyl, and CHF2.

[0060] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0061] R2is halogen or a group

[0062]

[0063] A is phenyl or pyridyl;

[0064] R5is selected from the group consisting of carboxy, SO2OH, and lH-tetrazol-5-yl; and R6is selected from the group consisting of hydrogen, halogen, and Ci-6-alkyl.

[0065] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:R2is bromo or a group

[0066]

[0067] A is phenyl or pyridyl;

[0068] R5is selected from the group consisting of carboxy, SO2OH, and lH-tetrazol-5-yl; and R6is selected from the group consisting of hydrogen, fluoro, and methyl.

[0069] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0070] R2is a group

[0071]

[0072] A is phenyl;

[0073] R5is carboxy; and

[0074] R6is hydrogen.

[0075] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein

[0076]

[0077] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3is hydrogen or methyl.

[0078] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3is hydrogen.

[0079] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3is methyl.In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is hydrogen or methyl.

[0080] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0081] X is selected from the group consisting of Se, SO, SO2, CH2, O, and NR4;

[0082] Y is CH or N;

[0083] A is phenyl or pyridyl;

[0084] R1is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, halo-Ci-6- alkyl, halo-Ci-6-alkoxy, and C3-io-cycloalkyl-0-CH2-;

[0085] R2is halogen or a group

[0086]

[0087] R3is hydrogen or Ci-6-alkyl;

[0088] R4is hydrogen or Ci-6-alkyl;

[0089] R5is selected from the group consisting of carboxy, SO2OH, and lH-tetrazol-5-yl; and R6is selected from the group consisting of hydrogen, halogen, and Ci-6-alkyl.

[0090] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0091] X is selected from the group consisting of Se, SO, SO2, CH2, O, and NR4;

[0092] Y is CH or N;

[0093] A is phenyl or pyridyl;

[0094] R1is selected from the group consisting of hydrogen, fluoro, chloro, methyl, CHF2, CF3, CHF2O-, and cyclopropyl-O-CH2-;

[0095] R2is bromo or a group

[0096]

[0097] R3is hydrogen or methyl;

[0098] R4is hydrogen or methyl;

[0099] R5is selected from the group consisting of carboxy, SO2OH, and lH-tetrazol-5-yl; and R6is selected from the group consisting of hydrogen, fluoro, and methyl.In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0100] X is SO2or CH2;

[0101] Y is CH or N;

[0102] A is phenyl;

[0103] R1is selected from the group consisting of halogen, Ci-6-alkyl, and halo-Ci-6-alkyl;

[0104] R2is a group

[0105]

[0106] R3is hydrogen or Ci-6-alkyl;

[0107] R5is carboxy; and

[0108] R6is hydrogen.

[0109] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0110] X is SO2or CH2;

[0111] Y is CH or N;

[0112] A is phenyl;

[0113] R1is selected from the group consisting of chloro, methyl, and CHF2;

[0114] R2is a group

[0115]

[0116] R3is hydrogen or methyl;

[0117] R5is carboxy; and

[0118] R6is hydrogen.

[0119] In one embodiment, the present invention provides a compound of formula (I) as described herein, selected from:

[0120] 4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-4-chloro-12-(lH-indol-3-ylmethyl)- 13-methyl-l 1, 14,17-trioxo-l 0,13, 16,19-tetrazatri cyclofl 9.4.0.03,8]pentacosa- l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid;

[0121] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-17-(lH-indol-3-ylmethyl)- 16-methyl- 12, 15,18-tri oxo-4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)-16-methyl- 12, 15,18-tri oxo-25-(trifluoromethyl)-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8] pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;

[0122] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-(difluoromethyl)-17-(lH-indol-3- ylmethyl)- 16-methyl- 12, 15,18-tri oxo-4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;

[0123] 4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 1 l-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)- 16,25- dimethyl- 12, 15,18-tri oxo-4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;

[0124] 4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-12-(lH-indol-3-ylmethyl)-13-methyl- 11.14.17-tri oxo-10,13, 16,19-tetrazatri cyclofl 9.4.0.03,8]pentacosa- 1(21), 3, 5, 7,22, 24-hexaen-7- yl]benzoic acid;

[0125] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-fluoro-17-(lH-indol-3-ylmethyl)- 16-methyl- 12, 15,18-tri oxo-4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;

[0126] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)- 16-methyl- 12.15.18-trioxo-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8), 4,6,21,23- hexaen-22-yl]benzoic acid;

[0127] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-17-(lH-indol-3-ylmethyl)- 2,16-dimethyl-12,15,18-trioxo-2,4,10,13,16,19-hexazatricyclo[19.4.0.03’8] pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;

[0128] 4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-12-(lH-indol-3-ylmethyl)-13-methyl- 11.14.17-tri oxo-2, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa-l (21), 3, 5, 7, 22,24- hexaen-7-yl]benzoic acid;

[0129] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-17-(lH-indol-3-ylmethyl)- 16-methyl- 12, 15,18-tri oxo-2, 4, 10, 13, 16,19-hexazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;

[0130] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)- 16-methyl- 12.15.18-trioxo-2,4,10,13,16,19-hexazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6, 21,23- hexaen-22-yl]benzoic acid;

[0131] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)- 16-methyl- 12.15.18-tri oxo-2-selena-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-17-(lH-indol-3-ylmethyl)- 16-methyl-2, 12, 15, 18-tetraoxo-2X4-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;

[0132] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)-16-methyl- 2,2, 12, 15, 18-pentaoxo-25-(trifluoromethyl)-2X6-thia-4, 10,13,16,19-pentazatri cyclo [19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoicacid;

[0133] (1 lS,14S,17S)-14-(4-aminobutyl)-l l-(3-aminopropyl)-22-bromo-25-chloro-17-(lH-indol-3- ylmethyl)- 16-methyl-2,2-dioxo-2X6-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1(25), 3(8), 4, 6, 21, 23 -hexaene- 12, 15, 18-trione;

[0134] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3-ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoicacid;

[0135] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chloro-16-methyl-17-[(2-meth yl- lH-indol-3 -yl)methyl]-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19-pentazatri cyclof 19.4.

[0136] 0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0137] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-(difluoromethyl)-17-(lH-indol-3- ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19-pentazatri cy

[0138] clof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoicacid;

[0139] 4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-m ethyl- 17- [(2 -methyl- lH-indol-3 -yl)methyl]-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0140] 4-[( 12 S, 15 S, 18 S)- 15 -(4- Aminobutyl)- 18-(3 -aminopropyl)-4-(difluorom ethyl)- 12-( 1 H-indol-3 - ylmethyl)- 13 -methyl-2,2, 11,14,17 -pentaoxo-2X6-thia- 10,13,16,19- tetrazatricyclo[19.4.0.03’8]pentacosa-l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid;

[0141] 4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-4-chloro-12-(lH-indol-3-ylmethyl) - 13-methyl-2, 2,11, 14,17-pentaoxo-2X6-thia-l 0,13, 16,19-tetrazatri cyclofl 9.4.0.03,8]penta cosa- l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid;

[0142] 4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-12-(lH-indol-3-ylmethyl)-4,13- dimethyl-2, 2,11, 14,17-pentaoxo-2X6-thia-l 0,13, 16,19-tetr azatri cyclofl 9.4.0.03,8]pentacosa- l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid;

[0143] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chloro-17-(lH-indol-3-ylmeth yl)- 16-methyl-2, 2, 12, 15, 18-pentaoxo-2X6-thia-4,l 0,13, 16,19-pentazatri cyclof 19.4.0.O3,8] pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]-2-fluoro-benzoic acid;4-[(l IS, 14S,17S)- 14-(4- Aminobutyl)- 1 l-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)- 16,25- dimethyl-2, 2, 12, 15, 18-pentaoxo-2X6-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]penta cosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;

[0144] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-(difluoromethoxy)-17-(lH-indol- 3 -ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19-pentazatri cyclo [19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0145] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-fluoro-17-(lH-indol-3-ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19-pentazatri cyclo [19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0146] 4- [( 12S, 15 S, 18 S)- 15 -(4- Aminobutyl)- 18-(3 -aminopropyl)-4-fluoro- 12-( lH-indol-3 -ylmethyl)- 13-methyl-2, 2,11, 14,17-pentaoxo-2X6-thia-l 0,13, 16,19-tetrazatri cyclo [19.4.0.03,8]pentacosa- l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid;

[0147] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-17-[(2-methyl-lH-indol-3- yl)methyl]-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0148] 1-[(1 IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)- 16,25- dimethyl- 12, 15, 18-trioxo-2X6-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- l(25),3(8),4,6,21,23-hexaen-22-yl]piperidine-4-carboxylic acid;

[0149] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-(cyclopropoxymethyl)-17-(lH- indol-3 -ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0150] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chloro-17-(lH-indol-3-ylme thyl)- 16-methyl-2, 2, 12, 15, 18-pentaoxo-2X6-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.O3,8] pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]-2-methyl-benzoic acid;

[0151] 4-[(l lS,14S,17S)-14-(4-aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3-ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzenesulfonic acid;

[0152] 5-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3-ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19-pentazatri cyclo [19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]pyridine-2-carboxylic acid;

[0153] (11S,14S,17S)-14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25 -chloro- 17-( 1 H-indol-3 -ylmethyl)- 16- methyl-2,2-dioxo-22-[4-(lH-tetrazol-5-yl)phenyl]-2X6-thia-4,l 0,13, 16,19-pentazatri cyclo [19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaene- 12, 15, 18-trione;(11S,14S,17S)-14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25 -(difluoromethyl)- 17-( 1 H-indol-3 - ylmethyl)- 16-methyl-2,2-dioxo-22-[4-( lH-tetrazol-5-yl)phenyl]-2X6-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaene-12,15,18-trione; and 4-((7S, 1OS,13S)-13-((1 H-indol-3 -yl)m ethyl)- 10-(4-aminobutyl)-7-(3 -aminopropyl)- 12-methyl- 8,1 l,14-trioxo-5,6,7,8,9,10,l l,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2- p][ 1 ,5,8, 1 l,14]oxatetraazacycloheptadecin-17-yl)benzoic acid;

[0154] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0155] In one embodiment, the present invention provides a compound of formula (I) as described herein, selected from:

[0156] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-17-(lH-indol-3-ylmethyl)- 16-methyl- 12, 15,18-tri oxo-4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;

[0157] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-(difluoromethyl)-17-(lH-indol-3- ylmethyl)-l 6-methyl- 12, 15,18-tri oxo-4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;

[0158] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3-ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoicacid;

[0159] 4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 17- [(2 -methyl- lH-indol-3 -yl)methyl]-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0160] 4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-12-(lH-indol-3-ylmethyl)-4,13- dimethyl-2, 2,11, 14,17-pentaoxo-2X6-thia-l 0,13, 16,19-tetr azatri cyclofl 9.4.0.03,8]pentacosa- l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid; and

[0161] 4-[(l IS, 14S,17S)- 14-(4-Aminobutyl)- 1 l-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)- 16,25- dimethyl-2, 2, 12, 15, 18-pentaoxo-2X6-thia-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]penta cosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;

[0162] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0163] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, which is 4-[( 11 S, 14S, 17S)- 14-(4-Aminobutyl)- 11 -(3 -aminopropyl)-25-chloro- 17-( lH-indol-3 -ylmethyl)-16-methyl- 12, 15,18-tri oxo-4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa-1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid.In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, which is 4-[( 11 S, 14 S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25 -(difluoromethyl)- 17-( 1 H-indol-3 -ylmethyl)- 16-methyl- 12, 15,18-tri oxo-4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa-1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid.

[0164] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, which is 4-[( 11 S, 14S, 17S)- 14-(4-Aminobutyl)- 11 -(3 -aminopropyl)-25-chloro- 17-( lH-indol-3 -ylmethyl)-16-methyl-2,2,12,15,18-pentaoxo-2X6-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoicacid.

[0165] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, which is 4-[( 11 S, 14 S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25 -(difluoromethyl)- 16-m ethyl- 17-[(2-methyl- lH-indol-3 -yl)methyl]-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid.

[0166] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, which is 4-[( 12 S, 15 S, 18 S)- 15 -(4- Aminobutyl)- 18-(3 -aminopropyl)- 12-( 1 H-indol-3 -ylmethyl)-4, 13-dimethyl-2, 2,11, 14,17-pentaoxo-2X6-thia-l 0,13, 16,19-tetr azatri cyclofl 9.4.0.03,8]pentacosa-l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid.

[0167] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, which is 4-[( 11 S, 14S, 17S)- 14-(4-Aminobutyl)- 11 -(3 -aminopropyl)- 17-( lH-indol-3 -ylmethyl)- 16,25-dimethyl-2,2,12,15,18-pentaoxo-2X6-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]penta cosa-1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid.

[0168] In one embodiment, the present invention provides pharmaceutically acceptable salts of the compounds according to formula (I) as described herein. In one embodiment, said pharmaceutically acceptable salts are hydrochloride salts, more particularly dihydrochloride salts. In a further particular embodiment, the present invention provides compounds according to formula (I) as described herein as free bases or acids.In some embodiments, the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to,2H,3H,nC,13C,14C,13N,15N,150,17O,18O,31P,32P,35S,18F,36C1,123I, and125I, respectively. Certain isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0169] Substitution with heavier isotopes, such as deuterium, i.e.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Therefore, deuterated versions of the compounds disclosed herein are to be understood to be within the scope of the present invention. For example, compounds of formula (I) wherein 1-6 hydrogen atoms, for example 1, 2, 3, 4, 5 or 6 hydrogen atoms, are replaced with deuterium atoms are understood to be within the scope of the present invention.

[0170] Substitution with positron emitting isotopes, such asnC,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0171] Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the nonlabeled reagent previously employed.

[0172] Manufacturing Processes

[0173] The compounds of the present invention can be prepared by any conventional means.

[0174] Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents, in particular R1R2, R3, R5, R6, X and Y are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.1. General synthesis of the aldehyde intermediate

[0175] The aldehyde intermediate of formula (II) can be prepared following standard methods known in the art, particularly according to methods as described in the examples.

[0176]

[0177] In compound (II), PG is a suitable amino protecting group, such as 9-fluorenylmethoxycarbonyl, and X, Y, R1and R2are as defined herein.

[0178] 2. General synthesis of the tripeptide

[0179] The tripeptide of formula (III), wherein R3is as defined herein, can be prepared following standard methods known in the art.

[0180]

[0181] The tripeptide (III) can for example be synthesized from dipeptide (IV) and N-methyltryptophan derivative (V) as follows (PG is a suitable protective group, e. g., 9-fluorenylmethoxy carbonyl, and R3is as defined above):

[0182]

[0183] (IV) (v)

[0184] a) In the first step, dipeptide (IV) is reacted with N-methyltryptophan derivative (V) in an amide coupling reaction, using reagents and methods known in the art. For instance, the reaction is performed in the presence of N,N'-diisopropylcarbodiimide and either l-hydroxy-7-azabenzotriazole or 2-hydroxypyridine-N-oxide in asuitable solvent, e. g., di chloromethane, tetrahydrofuran, tert-butyl-m ethyl ether or N,N-dimethylacetamide, at temperatures between -40°C and + 40°C.

[0185] b) In the second step, the protective group (PG) is removed, using methods and reagents known in the art. Suitable reagents for the deprotection reaction are bases such as with a base, preferably a primary or amine such as diethylamine, dicyclohexylamine or tert-amylamine, and the reaction is performed in a suitable solvent, e. g., acetonitrile, at temperatures between -40°C and +50°C. After completion of this step, In a particular embodiment, the N-protected amino acids are protected with 9-fluorenylmethyloxy carbonyl.

[0186] Dipeptide (IV) and N-methyltryptophan derivatives (V) are either commercially available or can be produced using procedures known in the art.

[0187] 3. General procedure for the assembly of macrocyclic intermediate (VIII)

[0188] The intermediates of formula (VIII) can be obtained, for example starting from the compounds of formula (II) and of formula (III) according to Scheme 1. PG is a protective group, e. g., 9-fluorenylmethoxycarbonyl, X, Y, R1, R2and R3are as defined herein.Scheme 1

[0189]

[0190] In scheme 1, step a, aldehyde of formula (II) is coupled with the tripeptide of formula (III) in a reductive amination reaction, producing intermediate (VI). This reaction is performed e. g., in the presence of a suitable reducing agent, e. g., sodium cyanoborohydride or sodium triacetoxyborohydride, in a solvent like toluene or dichloromethane, in the presence of a carboxylic acid selected from acetic acid and propionic acid, at temperatures between 0°C and 50°C.

[0191] In scheme 1, step b, the amine protective group (PG) and the allyl ester are removed, using methods and reagents known in the art, producing intermediate (VII). For instance, the reaction is accomplished in the presence of a palladium catalyst, e. g., tetrakis(triphenylphosphine)palladium(0) and abase, e. g., diethylamine, in a solvent such as acetonitrile, at temperatures between 0°C and 50°C.

[0192] In scheme 1, step c, intermediate of formula (VIII) is finally obtained through cyclisation of intermediate (VII) using methods and reagents known in the art. For instance, the reaction is performed in the presence of coupling reagents such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or carbonyldiimidazole, or N,N’ -diisopropylcarbodiimide andl-hydroxy-7-azabenzotriazole, or 1 -hydroxybenzotriazole and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, in a solvent such as di chloromethane of N,N-dimethylformamide, at temperatures between -20°C and +40°C.

[0193] 4. General procedure for the installation of the carboxylic acid subunit

[0194] Intermediates of formula (VIII) in which R2is as defined before except that R2is not a halogen, are represented by general structure (Vlllb). Alternatively to scheme 1, intermediates (Vlllb) can be also produced from intermediate of formula (Villa) as shown in scheme 2. In scheme 2, R1, R3, R5, R6, X, Y, are as defined before. Hal is a halogen, preferably Br or I.

[0195] Scheme 2

[0196]

[0197] (vnia) (vnib)

[0198] In scheme 2, halo-macrocycle (Villa) is reacted with boronic acid (IXa) or dioxoborolane (IXb) to produce compounds of formula (Vlllb). Particular, yet non-limiting examples of protected carboxylic acids are alkyl esters, such as methyl ester and tert-butyl ester.

[0199]

[0200] The reaction is performed in the presence of a suitable palladium catalyst, e. g., tetrakis(triphenylphosphine)palladium(0), [l,l'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), cataCXiumA-Pd-G3 or bis(tri-tert-butylphosphine)palladium(0), in a solvent such as water, 1,4-di oxane, N,N-dimethylacetamide, tetrahydrofuran, 2-methyltetrahydrofuran or mixtures thereof, in the presence of a base, e. g., sodium carbonate or potassium phosphate, at temperatures between 20°C and 150°C, optionally under microwave irradiation.5. General procedure for the cleavage of the protective groups

[0201] In scheme 3, the protecting groups in intermediate (VIII) are cleaved using methods and reagents known in the art, producing compounds of general formula (I). For instance, a global deprotection can be performed using hydrochloric acid in a suitable solvent or solvent mixture, e. g., 1,4-di oxane, or water / tetrahydrofuran, at temperatures between 0°C and 60°C.

[0202] Scheme 3

[0203]

[0204] Alternatively, the protective groups can be cleaved using trifluoroacetic acid in dichloromethane at temperatures between, followed by evaporation of the solvent and hydrolysis in water or aqueous hydrochloric acid at room temperature. By this sequence, for example the following protecting groups may be removed:

[0205] • a tert-butoxycarbonyl group on the indole nitrogen

[0206] • the two tert-butoxycarbonyl groups at the lysine and ornithine subunits

[0207] • a tert-butyl ester at R2

[0208] In a particular embodiment, where the R2substituent of intermediate (VIII) is contains a methyl ester group, intermediate (VIII) is first hydrolyzed with a base, e. g., sodium hydroxide, in a suitable solvent mixture, e. g., water / tetrahydrofuran or water / ethanol, at temperatures between 20°C and 100°C. This procedure also cleaves the tert-butoxy carbonyl group from the indole nitrogen. In a second step, the remaining protecting groups are cleaved using hydrochloric acid in a suitable solvent mixture, e. g., water / tetrahydrofuran, at temperatures between 0°C and 50°C. By this sequence of deprotection reactions compounds of formula (I) are produced.Pharmaceutical Compositions

[0209] Another aspect of the invention provides pharmaceutical compositions or medicaments comprising the compounds of the invention and a therapeutically inert carrier, diluent or pharmaceutically acceptable excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments.

[0210] Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

[0211] The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0212] In a preferred embodiment, there is provided a pharmaceutical composition comprising one or more compounds of the invention, wherein said pharmaceutical composition is suitable for intravenous administration.

[0213] The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may comprise components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents, antioxidants, and further active agents. They can also comprise still other therapeutically valuable substances.

[0214] A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel H.C. et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro A.R. et al, Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C, Handbook of Pharmaceutical Excipients (2005) PharmaceuticalPress, Chicago. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0215] The dosage at which compounds of the invention can be administered can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of intravenous administration a daily dosage of about 1 to 2000 mg per person of a compound of general formula (I) should be appropriate, although the above upper limit can also be exceeded when necessary.

[0216] An example of a suitable intravenous dosage form is a sterile aqueous solution comprising about 1 mg to about 1000 mg of a compound of the invention. Such a sterile aqueous solution for intravenous administration may be obtained e.g. by dissolving about 1 mg to about 1000 mg of a free base of a compound of the invention in sterile water for injection (SWFI, e.g. about 50 mL) and adjusting the pH to 4-8, preferably around 5 by addition of aqueous hydrochloric acid solution. Alternatively, about 1 mg to about 1000 mg of a pharmaceutically acceptable salt of a compound of the invention, for example of a hydrochloric acid salt, may be dissolved in SWFI, followed by adjusting the pH to 4-8, preferably around 5 by addition of aqueous sodium hydroxide solution. The procedure is completed by terminal sterilisation using methods known in the art. In some instances, it may be necessary to add a stabilizer to the final soluzion in order to prevent API decomposition over time. A suitable stabilizer may be methionine. An exemplary, yet non-limiting intravenous dosage form is as follows:

[0217]

[0218] The sterile aqueous solution may need to be diluted with SWFI prior to intravenous administration. The SWFI may contain 5-10% wt / wt of dextrose and / or 0.9% wt / wt of sodium chloride.In one aspect, the present invention provides an aqueous pharmaceutical composition comprising:

[0219] (i) a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof; and

[0220] (ii) methionine.

[0221] An example of an aerosol formulation can be prepared by dissolving the compound, for example 10 to 100 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such as sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 pm filter, to remove impurities and contaminants.

[0222] Uses

[0223] The compounds of the present invention exhibit potent and selective antibacterial activity against members of the baumannii-calcoaceticus complex of opportunistic bacterial pathogens. Thus, the compounds of the present invention can be used, either alone or in combination with other drugs, for the treatment of diseases caused by infections with members of said ABC complex of pathogens.

[0224] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a therapeutically active substance, in particular for use as an antibiotic.

[0225] In one aspect, the present invention provides a method for the treatment of diseases caused by infections with members of the A. baumannii-calcoaceticus complex of pathogens in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof

[0226] In one embodiment, said diseases caused by infections with members of the A. baumannii-calcoaceticus complex of pathogens are selected from bacteremia, pneumonia, meningitis, urinary tract infection, and wound infection.

[0227] Members of the A. baumannii-calcoaceticus complex of pathogens are notorious for causing invasive infections in hospitalized patients and patients with critical illness, most commonly hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP) and / or bloodstream infections (BSI). Thus, in a preferred embodiment, saiddiseases caused by infections with members of the ABC complex of pathogens are selected from HABP, VABP and / or BSI.

[0228] In one embodiment, said member from the A. baumannii-calcoaceticus complex of pathogens is multi drug resistant (MDR).

[0229] In one embodiment, said member from the A. baumannii-calcoaceticus complex of pathogens is Acinetobacter baumannii.

[0230] In one embodiment, said member from the A. baumannii-calcoaceticus complex of pathogens is colistin-resistant and / or polymyxin B-resistant.

[0231] In one embodiment, said member from the A. baumannii-calcoaceticus complex of pathogens is M Acinetobacter baumannii.

[0232] In one embodiment, said member from the A. baumannii-calcoaceticus complex of pathogens is colistin-resistant and / or polymyxin B-resistant Acinetobacter baumannii.

[0233] In one embodiment, said member from the A. baumannii-calcoaceticus complex of pathogens is carbapenem-resistant A. baumannii (CRAB).

[0234] In one embodiment, said member from the A. baumannii-calcoaceticus complex of pathogens is colistin-resistant and / or polymyxin B-resistant CRAB.

[0235] In one embodiment, said subject is a critically ill hospitalized subject with limited treatment options.

[0236] In one embodiment, the present invention provides a method for the treatment of HABP, VABP and / or BSI caused by infections with colistin-resistant and / or polymyxin B-resistant Acinetobacter baumannii in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof

[0237] In one embodiment, the present invention provides a method for the treatment of HABP, VABP and / or BSI caused by infections with colistin-resistant and / or polymyxin B-resistant Acinetobacter baumannii in a critically ill hospitalized subject with limited treatment options, comprising administering to the critically ill hospitalized subject with limited treatment options a therapeutically effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereofIn one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in a method of treatment described herein.

[0238] In one aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, in a method of treatment described herein.

[0239] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, for the manufacture of a medicament for the treatment of diseases caused by bacterial infections as described herein.

[0240] Numbered Clauses

[0241] The invention is further described by the following numbered clauses:

[0242] 1. A compound of formula (I)

[0243]

[0244] or a pharmaceutically acceptable salt or a stereoisomer thereof,

[0245] wherein:

[0246] X is selected from the group consisting of Se, SO, SO2, CH2, O, and NR4;

[0247] Y is CH or N;

[0248] A is selected from the group consisting of phenyl, pyridyl, and thienyl;

[0249] R1is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, Ci-6-alkoxy, halo-Ci-6-alkyl, halo-Ci-6-alkoxy, Cs-io-cycloalkyl, Ci-6-alkyl-O-CH2-, and C3-10- cycloalkyl-O-CH2-;

[0250] R2is halogen or a group

[0251]

[0252] R3is hydrogen or Ci-6-alkyl;

[0253] R4is hydrogen or Ci-6-alkyl;

[0254] R5is selected from the group consisting of hydrogen, carboxy, SO2OH, and IH-tetrazol- 5-yl; and

[0255] R6is selected from the group consisting of hydrogen, halogen, and Ci-6-alkyl.

[0256] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X is SO2 or CH2.

[0257] The compound of formula (I) according to clause 1 or 2, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, halo-Ci-6-alkyl, halo-Ci-6-alkoxy, and Cs-io-cycloalkyl-O-CH2-.

[0258] The compound of formula (I) according to clause 1 or 2, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is selected from the group consisting of hydrogen, fluoro, chloro, methyl, CHF2, CF3, CHF2O-, and cyclopropyl-O-CFh-

[0259] The compound of formula (I) according to clause 1 or 2, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is selected from the group consisting of halogen, Ci-6-alkyl, and halo-Ci-6-alkyl.

[0260] The compound of formula (I) according to clause 1 or 2, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is selected from the group consisting of chloro, methyl, and CHF2.

[0261] The compound of formula (I) according to any one of clauses 1 to 6, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0262] R2is halogen or a group

[0263]

[0264] A is phenyl or pyridyl;R5is selected from the group consisting of carboxy, SO2OH, and lH-tetrazol-5-yl; and R6is selected from the group consisting of hydrogen, halogen, and Ci-6-alkyl.

[0265] 8. The compound of formula (I) according to any one of clauses 1 to 6, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0266] R2is bromo or a group

[0267]

[0268] A is phenyl or pyridyl;

[0269] R5is selected from the group consisting of carboxy, SO2OH, and lH-tetrazol-5-yl; and R6is selected from the group consisting of hydrogen, fluoro, and methyl.

[0270] 9. The compound of formula (I) according to any one of clauses 1 to 6, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0271] R2is a group

[0272]

[0273] A is phenyl;

[0274] R5is carboxy; and

[0275] R6is hydrogen.

[0276] 10. The compound of formula (I) according to clause 9, or a pharmaceutically acceptable salt

[0277] or a stereoisomer thereof, wherein

[0278]

[0279] 11. The compound of formula (I) according to any one of clauses 1 to 10, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3is hydrogen or methyl.

[0280] 12. The compound of formula (I) according to any one of clauses 1 and 3 to 11, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is hydrogen or methyl.13. The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0281] X is selected from the group consisting of Se, SO, SO2, CH2, O, and NR4;

[0282] Y is CH or N;

[0283] A is phenyl or pyridyl;

[0284] R1is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, halo-Ci-6- alkyl, halo-Ci-6-alkoxy, and C3-io-cycloalkyl-0-CH2-;

[0285] R2is halogen or a group

[0286]

[0287] R3is hydrogen or Ci-6-alkyl;

[0288] R4is hydrogen or Ci-6-alkyl;

[0289] R5is selected from the group consisting of carboxy, SO2OH, and lH-tetrazol-5-yl; and R6is selected from the group consisting of hydrogen, halogen, and Ci-6-alkyl.

[0290] 14. The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0291] X is selected from the group consisting of Se, SO, SO2, CH2, O, and NR4;

[0292] Y is CH or N;

[0293] A is phenyl or pyridyl;

[0294] R1is selected from the group consisting of hydrogen, fluoro, chloro, methyl, CHF2, CF3, CHF2O-, and cyclopropyl-O-CH2-;

[0295] R2is bromo or a group

[0296]

[0297] R3is hydrogen or methyl;

[0298] R4is hydrogen or methyl;

[0299] R5is selected from the group consisting of carboxy, SO2OH, and lH-tetrazol-5-yl; and R6is selected from the group consisting of hydrogen, fluoro, and methyl.

[0300] 15. The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0301] X is SO2or CH2;

[0302] Y is CH or N;is phenyl;

[0303] R1is selected from the group consisting of halogen, Ci-6-alkyl, and halo-Ci-6-alkyl;

[0304] R2is a group

[0305]

[0306] R3is hydrogen or Ci-6-alkyl;

[0307] R5is carboxy; and

[0308] R6is hydrogen.

[0309] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0310] X is SO2or CH2;

[0311] Y is CH or N;

[0312] A is phenyl;

[0313] R1is selected from the group consisting of chloro, methyl, and CHF2;

[0314] R2is a group

[0315]

[0316] R3is hydrogen or methyl;

[0317] R5is carboxy; and

[0318] R6is hydrogen.

[0319] The compound of formula (I) according to clause 1, selected from:

[0320] 4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-4-chloro-12-(lH-indol-3- ylmethyl)-13-methyl-l 1, 14,17-tri oxo- 10, 13, 16,19-tetrazatri cyclofl 9.4.0.03,8]pentacosa- l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid;

[0321] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3- ylmethyl)- 16-methyl- 12,15,18-trioxo-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)-16- methyl-12,15,18-trioxo-25-(trifluoromethyl)-4,10,13,16,19-pentazatricyclo[19.4.0.03’8] pentacosa- 1 (25), 3 (8), 4, 6,21 ,23 -hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-(difluoromethyl)-17-(lH- indol-3 -ylmethyl)- 16-methyl- 12,15,18-trioxo-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)- 16, 25-dimethyl-12, 15,18-tri oxo-4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;

[0322] 4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-12-(lH-indol-3-ylmethyl)-13- methyl-11, 14,17-trioxo-l 0,13, 16,19-tetr azatri cyclofl 9.4.0.03,8]pentacosa- l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid;

[0323] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-fluoro-17-(lH-indol-3- ylmethyl)- 16-methyl- 12,15,18-tri oxo-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)-16- methyl- 12, 15, 18-tri oxo-4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1(25), 3(8), 4,6,21 ,23 -hexaen-22-yl]benzoic acid;

[0324] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-chloro-17-(lH-indol-3- ylmethyl)-2,16-dimethyl-12,15,18-trioxo-2,4,10,13,16,19-hexazatricyclo[19.4.0.03’8] pentacosa- 1 (25), 3 (8), 4, 6,21 ,23 -hexaen-22-yl]benzoic acid;

[0325] 4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-12-(lH-indol-3-ylmethyl)-13- methyl-11, 14,17-tri oxo-2, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1(21), 3, 5, 7, 22,24-hexaen-7-yl]benzoic acid;

[0326] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3- ylmethyl)- 16-methyl- 12,15,18-trioxo-2,4, 10,13,16,19- hexazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)-16- methyl- 12, 15,18-tri oxo-2, 4, 10, 13, 16,19-hexazatri cyclofl 9.4.0.03,8]pentacosa- 1(25), 3(8), 4, 6, 21,23-hexaen-22-yl]benzoic acid;

[0327] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)-16- methyl- 12, 15,18-trioxo-2-selena-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;

[0328] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3- ylmethyl)- 16-methyl-2, 12,15,18-tetraoxo-2X4-thia-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)-16- methyl-2,2, 12,15,18-pentaoxo-25-(trifluoromethyl)-2X6-thia-4, 10,13,16,19- pentazatricyclo [19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoicacid; (1 lS,14S,17S)-14-(4-aminobutyl)-l l-(3-aminopropyl)-22-bromo-25-chl oro-17-(lH-indol- 3 -ylmethyl)- 16-methyl-2,2-dioxo-2X6-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaene-12,15,18-trione; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3- ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoicacid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-16-methyl-17-[(2- meth yl- lH-indol-3 -yl)methyl]-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclo[19.4. 0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-(difluoromethyl)-17-(lH- indol-3 -ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricy clo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoicacid; 4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 17- [(2-methyl- 1 H-indol-3 -yl)methyl] -2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 4-[( 12 S, 15 S, 18 S)- 15 -(4- Aminobutyl)- 18-(3 -aminopropyl)-4-(difluorom ethyl)- 12-( 1 H- indol-3 -ylmethyl)- 13 -methyl-2,2, 11,14,17 -pentaoxo-2X6-thia- 10,13,16,19- tetrazatricyclo[19.4.0.03’8]pentacosa-l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid;

[0329] 4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-4-chloro-12-(lH-indol-3- ylmethyl) - 13 -methyl-2,2, 11,14,17 -pentaoxo-2X6-thia- 10,13,16,19- tetrazatricyclo[19.4.0.03’8]penta cosa-l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid;

[0330] 4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-12-(lH-indol-3-ylmethyl)-4,13- dimethyl-2,2, 11,14, 17-pentaoxo-2X6-thi a- 10,13,16,19- tetrazatricyclo[19.4.0.03’8]pentacosa-l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid;

[0331] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3- ylmeth yl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8] pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]-2-fluoro- benzoic acid;

[0332] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)- 16,25-dimethyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]penta cosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;4-[( 11 S, 14 S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25 -(difluoromethoxy)- 17-( 1 H- indol-3 -ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclo [19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-fluoro-17-(lH-indol-3- ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19-pentazatri cyclo [19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;

[0333] 4- [( 12S, 15 S, 18 S)- 15 -(4- Aminobutyl)- 18-(3 -aminopropyl)-4-fluoro- 12-( lH-indol-3 - ylmethyl)- 13 -methyl-2,2, 11,14,17 -pentaoxo-2X6-thia- 10,13,16,19-tetrazatri cyclo [19.4.0.03’8]pentacosa-l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid;

[0334] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-17-[(2-methyl-lH- indol-3 -yl)methyl]-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 1-[(1 lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)- 16,25-dimethyl- 12,15,18-trioxo-2X6-thia-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]piperidine-4- carboxylic acid;

[0335] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-(cyclopropoxymethyl)-17- ( lH-indol-3 -ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chloro-17-(lH-indol-3-ylme thy 1)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8] pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]-2-methyl- benzoic acid;

[0336] 4-[(l lS,14S,17S)-14-(4-aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3- ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzenesulfonic acid;

[0337] 5-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3- ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19-pentazatri cyclo [19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]pyridine-2-carboxylic acid; (11S,14S,17S)-14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25 -chloro- 17-( 1 H-indol-3 - ylmethyl)- 16-methyl-2,2-dioxo-22-[4-( lH-tetrazol-5-yl)phenyl]-2X6-thia-4, 10,13,16,19- pentazatricyclo [19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaene- 12, 15, 18-trione; (11S,14S,17S)-14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25 -(difluoromethyl)- 17-( 1 H-indol- 3-ylmethyl)-16-methyl-2,2-dioxo-22-[4-(lH-tetrazol-5-yl)phenyl]-2X6-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaene- 12, 15, 18-trione; and

[0338] 4-((7 S, 10 S, 13 S)- 13 -(( 1 H-indol-3 -yl)m ethyl)- 10-(4-aminobutyl)-7-(3 -aminopropyl)- 12- methyl-8,1 l,14-trioxo-5,6,7,8,9,10,l l,12,13,14,15,16-dodecahydrobenzo[b]pyrido[3,2- p] [1 ,5,8, 1 l,14]oxatetraazacycloheptadecin-17-yl)benzoic acid;

[0339] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0340] 18. The compound of formula (I) according to clause 1, selected from:

[0341] 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3- ylmethyl)- 16-methyl- 12,15,18-trioxo-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-(difhroromethyl)-17-(lH- indol-3 -ylmethyl)- 16-methyl- 12,15,18-trioxo-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3- ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoicacid; 4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 17- [(2-methyl- 1 H-indol-3 -yl)methyl] -2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-12-(lH-indol-3-ylmethyl)-4,13- dimethyl-2,2, 11,14, 17-pentaoxo-2X6-thi a- 10,13,16,19- tetrazatricyclo[19.4.0.03’8]pentacosa-l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid; and 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)- 16,25-dimethyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]penta cosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0342] 19. A pharmaceutical composition comprising a compound according to any of clauses 1 to 18, or a pharmaceutically acceptable salt or a stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

[0343] 20. A compound according to any of clauses 1 to 18, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as therapeutically active substance.21. A method for the treatment of diseases caused by infections with members of the A. baumannii-calcoaceticus (ABC) complex of pathogens in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) according to any one of clauses 1 to 18, or of a pharmaceutically acceptable salt or a stereoisomer thereof, or of a pharmaceutical composition according to clause 19.

[0344] 22. A compound of formula (I) according to any of clauses 1 to 18, or a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition according to clause 19 for use in the method according to clause 21.

[0345] 23. Use of a compound of formula (I) according to any of clauses 1 to 18, or of a pharmaceutically acceptable salt or a stereoisomer thereof, or of a pharmaceutical composition according to clause 19 in the method according to clause 21.

[0346] 24. Use of a compound according to any of clauses 1 to 18, or of a pharmaceutically acceptable salt or a stereoisomer thereof, for the manufacture of a medicament for the treatment of diseases caused by infections with members of the A. baumannii- calcoaceticus (ABC) complex of pathogens in a subject.

[0347] Examples

[0348] The invention will be more fully understood by reference to the following examples. They should however not be construed as limiting the scope of the invention.

[0349] All examples and intermediates were prepared under nitrogen atmosphere if not specified otherwise.

[0350] Abbreviations used

[0351] Abbreviations: aq. = aqueous; DMSO = dimethyl sulfoxide; MS = mass spectrometry; HPLC = high-performance liquid chromatography; NMR = nuclear magnetic resonance spectroscopy; CAS-RN = Chemical Abstracts Service Registry Number.

[0352] Example 1

[0353] 4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-4-chloro-12-(lH-indol-3-ylmethyl)-13-methyl-ll,14,17-trioxo-10,13,16,19-tetrazatricyclo[19.4.0.03’8]pentacosa-l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid; dihydrochloride

[0354]

[0355] i-6-(tert-butoxycarbonylamino)-2-

[0356]

[0357] i-5-(tert-butoxycarbonylamino)-2-rr2-rr3-(4-tert-l

[0358]

[0359] i-6-chloro-2-[(9H-fluoren-9-

[0360]

[0361]

[0362] -I -carboxylate

[0363] To a solution of tert-butyl 3-[(2S)-3-allyloxy-2-[[(2S)-2-[[(2S)-2-amino-5-(tert-butoxy carbonylamino)pentanoyl]amino]-6-(tert-butoxycarbonylamino)hexanoyl]-methyl-amino]-3-oxo-propyl]indole-l -carboxylate (CAS-RN [2971012-38-9]; 256 mg, 0.32 mmol) and tert-butyl 4-[4-chloro-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(2-formylphenyl)methyl] phenyl]benzoate (intermediate 2; 210.0 mg, 0.32 mmol) in toluene (3 mL) was added acetic acid (0.05 mL, 0.96 mmol), and the yellow solution was stirred at 40°C for 1 h. Then the solution was cooled to room temperature and sodium triacetoxyborohydride (338 mg, 1.6 mmol) was added slowly, then the yellow suspension was heated at 40°C for another 2 h. After cooling ethyl acetate (20 mL) and water (10 mL) were added and layers were separated. The aqueous phase was extracted with ethyl acetate (2^10 mL). Combined organics was washed with brine (40 mL) and dried over sodium sulfate. The solution was concentrated to give a crude, which was purified by column chromatography (petroleum ether / ethyl acetate 3 : 1) to produce the title compound (360 mg, 55%). Yellow solid, MS: 1443.3 [M+H]+.

[0364]

[0365] i-6- -6-

[0366]

[0367] To a solution of tert-butyl 3-[(2S)-3-allyloxy-2-[[(2S)-6-(tert-butoxycarbonylamino)-2-[[(2S)-5-(tert-butoxycarbonylamino)-2-[[2-[[3-(4-tert-butoxycarbonylphenyl)-6-chloro-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]phenyl]methyl]phenyl]methylamino]pentanoyl]-amino]hexanoyl]-methyl-amino]-3-oxo-propyl]indole-l-carboxylate (360 mg, 0.25 mmol) in acetonitrile (4 mL) was added tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.02 mmol) anddiethylamine (0.25 mL, 2.5 mmol), then the yellow suspension was stirred at 20°C under a nitrogene atmosphere for 5 h, then the mixture was concentrated to give a residue, which was purified by column chromatography (SiCL, dichloromethane / methanol 10: 1) to give the title compound (190 mg, 50%). Yellow solid, MS: 1180.4 [M+H]+.

[0368]

[0369] 1-18-13 -(tert-butoxy tert-l

[0370]

[0371] i-4-chloro- 13 -methyl- 11,1 , 17-trioxo-

[0372]

[0373] .4.0.03,8

[0374]

[0375] i-l(21),3,5,7,22,24-hexaen-12-

[0376]

[0377] 1-carboxylate

[0378] To a solution of 1 -hydroxybenzotriazole hydrate (61.6 mg, 0.4 mmol) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (77 mg, 0.4 mmol) in dichloromethane (10 mL) was added a solution of (2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[2-(aminomethyl)-3-(4-tert-butoxycarbonylphenyl)-6-chloro-phenyl]methyl]phenyl]methylamino]-5-(tert-butoxycarbonylamino)pentanoyl]amino]-6-(tert-butoxycarbonylamino)hexanoyl]-methyl-amino]-3-(l-tert-butoxycarbonylindol-3-yl)propanoic acid (190 mg, 0.16 mmol) in dichloromethane (10 mL) under ice-water bath. The yellow suspension was stirred at 20°C for 2 h, then concentrated to give a residue, which was purified by preparative thin layer chromatography (ethyl acetate) to give the title compound (100 mg, 48%). Yellow solid, MS: 1162.8 [M+H]+.

[0379] ol-3 -

[0380]

[0381] To a yellow solution of tert-butyl 3-[[(12S,15S,18S)-15-[4-(tert-butoxycarbonylamino)butyl]-18-[3-(tert-butoxycarbonylamino)propyl]-7-(4-tert-butoxycarbonylphenyl)-4-chloro-13-methyl-1 l,14,17-trioxo-10,13,16,19-tetrazatricyclo[19.4.0.03’8]pentacosa-l(21),3,5,7,22,24-hexaen-12-yl]methyl]indole- 1-carboxylate (80.0 mg, 0.07 mmol) in 1,4-dioxane (0.1 mL) was added hydrogen chloride solution (4 M in 1,4-dioxane, 8.25 mL, 33 mmol), and the yellow solution was stirred at 40°C for 3 h to give a white suspension. The solid was collected by filtration and washed with acetonitrile (5 mL). The crude produce was dissolved in water (20 mL) and lyophilized to produce the title compound (32 mg, 57%). Light yellow solid, MS: 806.6 [M+H]+.

[0382] The following examples (Ex.) were produced in analogy to example 1, replacing 3-[(2S)-3-allyloxy-2-[[(2S)-2-[[(2S)-2-amino-5-(tert-butoxy carbonylamino)pentanoyl]amino]-6-(tert-butoxycarbonylamino)hexanoyl]-methyl-amino]-3-oxo-propyl]indole-l-carboxylate by the appropriate tripeptide and tert-butyl 4-[4-chloro-2-[(9H-fluoren-9-ylmethoxycarbonylamino)-methyl]-3-[(2-formylphenyl)methyl] phenyl]benzoate by the appropriate aldehyde.

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[0413]

[0414] 31

[0415] 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-(cyclopropoxymethyl)-17-(lH-indol-3-ylmethyl)-16-methyl-2,2,12,15,18-pentaoxo-2k6-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; bis(2,2,2-trifluoroacetate)

[0416]

[0417] Step 1: tert-Butyl 3-((9S,12S,15S)-9-(((2-((2-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-methyl)-4'-(tert-butoxycarbonyl)-4-(cyclopropoxymethyl)-biphenyl]-3-yl)sulfonyl)pyridin-

[0418]

[0419] 3-yl)methyl)amino)-15-((allyloxy)carbonyl)-12-(4-((tert-butoxycarbonyl)amino)butyl)-2,2,14-trimethyl-4.10.13-trioxo-3-oxa-5.l l / 14-triazahexadecan-l 6-yl )-l H-indole-l -carboxylate

[0420] The title compound was produced in analogy to example 1, step 1, from tert-butyl 3-[(2S)-3-allyloxy-2-[[(2S)-2-[[(2S)-2-amino-5-(tert-butoxy carbonylamino)pentanoyl]amino]-6-(tert-butoxycarbonylamino)hexanoyl]-methyl-amino]-3-oxo-propyl]indole-l-carboxylate (CAS-RN [2971012-38-9]) and tert-butyl 4-[4-(cyclopropoxymethyl)-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pyridyl)sulfonyl]phenyl]benzoate (intermediate 25). Light yellow solid, MS: 1529.8 [M+H]+.

[0421] Step 2: (2S)-2-rr(2S)-2-rr(2S)-2-r2-(aminomethyl)-3-(4-tert-butoxycarbonylphenyl)-6-(cyclo

[0422]

[0423] propoxymethyl)phenyl]sulfonyl-3-pyridyl]methylamino]-5-(tert-butoxy carbonylamino)-pentanoyl]amino]-6-(tert-butoxycarbonylamino)hexanoyl]-methyl-amino]-3-(l-tert-but oxycarbonylindol-3-yl)propanoic acid

[0424] The title compound was produced in analogy to example 1, step 2, from tert-butyl 3-((9S,12S,15S)-9-(((2-((2-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)-4'-(tert-butoxycarbonyl)-4-(cyclopropoxymethyl)-[l,l'-biphenyl]-3-yl)sulfo nyl)pyri din-3 -yl)methyl)amino)-15-((allyloxy)carbonyl)-12-(4-((tert-butoxycarbonyl)amino) butyl)-2,2,14-trimethyl-4, 10,13-tri oxo-3-oxa-5,l l,14-triazahexadecan-16-yl)-lH-indole-l -carboxylate. Light yellow solid, MS: 1267.7 [M+H]+.3: tert-Butvl 3-FFC11 S, 14S, 17S)-14-F4-(tert-l 1-1 l-r3-(tert-butoxy -22-(4-tert-1

[0425]

[0426] i-16-methyl-

[0427]

[0428] >-2 6-thia-4, 10, 13,16, 19-i

[0429]

[0430] 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen- 17-

[0431]

[0432] ;-l -carboxylate

[0433] The title compound was produced in analogy to example 1, step3, from (2S)-2-[[(2S)-2-[[(2S)-2-[[2-[2-(aminomethyl)-3-(4-tert-butoxycarbonylphenyl)-6-(cyclopropoxymethyl)phenyl]sulfonyl-3-pyridyl]methylamino]-5-(tert-butoxycarbonylamino)pentanoyl]amino]-6-(tert-butoxycarbonylamino)hexanoyl]-methyl-amino]-3-(l-tert-butoxycarbonylindol-3-yl)propanoic acid. Light yellow solid, MS: 1249.7 [M+H]+.

[0434]

[0435] To a solution of tert-butyl 3-[[(l lS,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-l l-[3-(tert-butoxycarbonylamino)propyl]-22-(4-tert-butoxycarbonylphenyl)-25-(cyclopropoxymethyl)-16-methyl-2,2,12,15,18-pentaoxo-2X6-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-17-yl]methyl]indole-l-carboxylate (35 mg) in di chloromethane (0.2 mL) was added trifluoroacetic acid (0.5 mL) at 25°C, then after 3 h the mixture was concentrated to give a residue, which was purified by preparative HPLC (Phenomenex Luna Cl 8, 150*25mm, 10 pm; gradient 0.05% aq. trifluoroacetic acid to acetonitrile) and lyophilized to produce the title compound (24 mg, 77%). White solid, MS: 893.4 [M+H]+.

[0436] Example 32

[0437] 4-[(l IS, 14S,17S)-14-(4- Aminobutyl)-! l-(3-aminopropyl)-25-chloro-17-(lH-indol-3-ylme thyl)-16-methyl-2,2,12,15,18-pentaoxo-2k6-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8] pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]-2-methyl-benzoic acid; dihydrochloride

[0438]

[0439] 1: tert-Butvl 3-FFC11 S,14S,17S)-14-[4-(tert-l 1-1 l-[3-(tert-butoxy ethyl- >

[0440]

[0441] To a solution of tert-butyl 3-[[(l IS, 14S,17S)-22-bromo-14-[4-(tert-butoxy carbonylamino) butyl]- 11 -[3 -(tert-butoxycarbonylamino)propyl]-25-chloro- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-17-yl]methyl]indole-l -carboxylate (intermediate of Example 16, synthesized in analogy to Example 1, steps 1,3; 110 mg, 0.1 mmol) and tert-butyl 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (37.6 mg, 0.12 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) was added sodium carbonate (26.1 mg, 0.25 mmol) and cataCXiumA-Pd-G3 (CAS-RN [1651823-59-4]; 14.4 mg, 0.02 mmol) in a glove box, and the mixture was stirred at 100°C for 2 h. After cooling the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (Phenomenex Luna Cl 8, 150*25mm, 10 pm; gradient 0.05% aq. trifluoroacetic acid to acetonitrile) and lyophilized to produce the title compound (20 mg, 16%). White solid, MS: 1227.6 [M+H]+.

[0442] >

[0443]

[0444] The title compound was produced in analogy to Example 1, step 4, from tert-butyl 3-[[(llS,14S,17S)-14-[4-(tert-butoxycarbonylamino)butyl]-ll-[3-(tert-butoxycarbonylamino)propyl]-22-(4-tert-butoxycarbonyl-3-methyl-phenyl)-25-chloro-16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19-pentazatricyclo[ 19.4.0.03,8]pentacosa-l(25),3(8),4,6,21,23-hexaen-17-yl]methyl]indole-l-carboxylate. White solid, MS: 871.3 [M+H]+.

[0445] The following Examples (Ex.) were produced in analogy to Example 1, steps 1-3, followed by Example 32, steps 1-2, replacing tert-butyl 4-[4-chloro-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(2-formylphenyl)methyl] phenyl ]benzoate in Example 1, step 1 by the appropriate aldehyde and tert-butyl 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate in Example 32, step 1, by the appropriate boron reagent.

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[0455] Example 38

[0456] Antimicrobial susceptibility testing: 50% Growth Inhibitory Concentration (IC50) determination

[0457] The in vitro antimicrobial activity of the compounds was alternatively determined according to the following procedure:

[0458] The assay used a 10-points Iso-Sensitest broth medium to measure quantitatively the in vitro activity of the compounds against baumannii ATCC 17961, ACC00535, and ACC01073. The MDR strains ACC00535 und ACC01073 are described in Zampaloni, C., Mattei, P., Bleicher, K. et al. A novel antibiotic class targeting the lipopolysaccharide transporter. Nature 625, 566-571 (2024).

[0459] Stock compounds in DMSO were serially twofold diluted (e.g. range from 50 to 0.097 pM or from 10 to 0.020 pM final concentration) in 384 wells microtiter plates and inoculated with 49 pl the bacterial suspension in Iso-Sensitest medium to have a final cell concentration of- 5xl0(5)CFU / ml in a final volume / well of 50 pl / well. Microtiter plates were incubated at 35 ± 2 °C.Bacterial cell growth was determined with the measurement of optical density at X=600 nm each 20 minutes over a time course of 16 h.

[0460] Growth inhibition was calculated during the logarithmic growth of the bacterial cells with determination of the concentration inhibiting 50% (IC50) of the growth.

[0461] Table 1 provides the 50% growth inhibitory concentrations (IC50) in micromoles per liter of the compounds of present invention obtained against the A. baumannii strains ATCC 17961, ACC00535, and ACC01073.

[0462] In one embodiment, compounds of the present invention exhibit an IC50 (ATCC 17961, ACC00535, and ACC01073) < 10 pmol / 1.

[0463] In a preferred embodiment, compounds of the present invention exhibit an IC50 (ATCC17961, ACC00535, and ACC01073) < 1 pmol / 1.

[0464] In a particularly preferred embodiment, compounds of the present invention exhibit an IC50 (ATCC17961, ACC00535, and ACC01073) < 0.5 pmol / 1.

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[0489] Table 1. 50% growth inhibition concentrations (IC50) in micromoles per liter of the compounds of present invention obtained against baumannii strains ATCC 17961, ACC00535, and ACC01073.

[0490] Example 39

[0491] Minimum inhibitory concentration (MIC) experimental procedure

[0492] a) Compounds preparation

[0493] Standard antibiotics are prepared according to the Clinical and Laboratory Standards Institute (CLSI) guidelines while tested compounds are prepared as 5 mg / mL dimethyl sulxoide solutions (active compound concentration). From dimethyl sulfoxide stock solutions 2 fold serial dilutions in dimethyl sulfoxide are prepared at lOOx concentrations. The compounds and dimethyl sulfoxide are added to 50 pL of cation adjusted Mueller-Hinton broth media in 96-well plates using the dispensing platform (Mosquito, TTP Labtech). The same mother plates with compounds serial dilutions are to be used for all experiments. In this manner, compounds and antibiotics are plated in 96-well assay plates in serial two-fold dilutions giving an overall final concentrations range of 32 - 0.06 pg / mL.

[0494] b) Inoculum preparationMicroorganisms are revived from glycerol stock kept at -70°C by plating them on MH agar plates. The following day a single colony of each microorganism is streaked on fresh agar plates. The next day, using the direct colony suspension method, broth solutions that achieve turbidity equivalent to 0.5 McFarland standard for each microorganism are prepared. This results in suspensions containing l-2xl08colony forming units / mL. Out of these suspensions, actual inoculums are prepared by diluting them lOOx with cation adjusted Mueller-Hinton broth media with 40% of human serum added, giving final microorganism count of 2-8xl05CFU / mL. From the second to the twelfth column of 96-well plates, 50 pL of these solutions are transferred per well. To the first column, 50 pL of pure growth media is added. In this manner the first column is used as sterility control of media used, the second column is used as control of microorganism’s growth and the rest of the plate is used for MIC determination. The plates are incubated for 20 h at 37°C.

[0495] c) MIC determination

[0496] MIC value (pg / mL) is determined by visual inspection of bacterial growth within 96-well plates. The first column in which there is no visible growth of bacteria is determined as MIC 100 value for compound or antibiotic tested in that particular row. American Type Culture Collection (ATCC) quality control strains are used as referent strains for which there are designated MIC values for standard antibiotics. In this way, quality control of the assay is determined. The assay is considered valid when MIC values for standard antibiotics are within CLSI designated range for ATCC strain tested.

[0497] Table 2 provides the minimum inhibitory concentrations (MIC) of the compounds of present invention obtained against the baumannii strains ACC00535 and ACC01073.

[0498] In one embodiment, compounds of the present invention exhibit an MIC (ACC00535 and ACC01073) < 16 pg / ml.

[0499] In a preferred embodiment, compounds of the present invention exhibit an MIC (ACC00535 and ACC01073) < 2 pg / ml.

[0500] In a particularly preferred embodiment, compounds of the present invention exhibit an MIC (ACC00535 and ACC01073) < 0.5 pg / ml.

[0501] Table 2

[0502]

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[0504]

[0505] Example 40

[0506] Time kill experimental procedurea) Inoculum preparation

[0507] Microorganisms are revived from glycerol stock kept at -70°C by plating them on Mueller-Hinton agar plates. The following day a single colony of each microorganism is streaked on fresh agar plates. Colonies from agar plates are transferred into 10 mL of cation-adjusted Mueller-Hinton broth with 20% human serum and incubated overnight at 35 ± 2°C in ambient air under shaking (150 rpm). On the next day, the overnight culture is diluted 1 : 10,000 in prewarmed cation-adjusted Mueller-Hinton broth with 20% human serum and flasks are incubated at 35 ± 2°C in ambient air under shaking (200 rpm) to allow the cells to reach the log phase (2 hours). 3 mL of the bacterial log phase suspension are transferred into pre-warmed sterile 6-well plates.

[0508] b) Compounds preparation

[0509] Starting from lOOx concentrated compound dimethyl sulfoxide solutions, 30 pL of each are added according to the experimental design (e.g., IxMIC, 2xMIC, 4xMIC, 8xMIC and 16xMIC values) to the 6-well plates.

[0510] c) Incubation

[0511] 6-well plates are incubated at 35 ± 2 °C in ambient air under shaking (200 rpm). At the selected time points (0, 2, 4, 8, and 24 hours) 100 pL are withdrawn of which 20 pL are directly plated on Mueller-Hinton agar plates and 20 pL are diluted for colony forming units / mL values determination. Bacterial counts at time 0 and 24 hours are also performed on compoundcontaining agar plates (Mueller-Hinton agar with 20% human serum) containing the same amount of the compound of the tested condition in the time kill experiment.

[0512] d) Data analysis

[0513] Time kill results are plotted as colony forming units / mL values versus time using the GraphPad Prism 9 software, representing colony forming unit numbers at different incubation time points. The effect of a tested compound is compared to a control sample (dimethyl sulfoxide), which represents the normal growth kinetic of bacteria in the experiment. The reported read-out is the minimum compound concentration resulting in bacterial eradication to the limit of detection (102colony forming units / mL) without bacterial regrowth up until the 24 h time point.

[0514] Table 3 provides the minimum concentration causing bacterial eradication. In a particularly preferred embodiment, compounds of the present invention cause bacterial eraditacion at concentrations < 16 pmol / 1.Table 3

[0515]

[0516] Reference Example

[0517] <

[0518]

[0519] Intermediate 1

[0520] tert-Butyl 3-[(2S)-3-allyloxy-2-[[(2S)-2-[[(2S)-2-amino-5-(tert-butoxycarbonylamino)-pentanoyl]amino]-6-(tert-butoxycarbonylamino)hexanoyl]-methyl-amino]-3-oxo-propyl]-2-methyl-indole-l-carboxylate

[0521]

[0522] Step 1: (2S)-3-(2-methyl-lH-indol-3-yl)-2-[(2-nitrophenyl)sulfonylamino1propanoic acid

[0523] To a solution of (2S)-2-amino-3-(2-methyl-lH-indol-3-yl)propanoic acid (CAS-RN [33468-32-5]; 3.0 g, 13.8 mmol) in 1,4-dioxane (30 mL) and saturated aq. sodium hydrogen carbonate solution (30 mL, 13.8 mmol) was added 2-nitrobenzenesulfonyl chloride (4.57 g, 20.6 mmol), and the light yellow suspension was stirred at 25°C for 2 h, then the pH of solution was adjusted to around 4~5 by progressive adding 1 M aq. hydrochloric acid solution, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with brine (10 mL) and dried over sodium sulfate. The solution was concentrated to give a residue, which was purified by flash chromatography (petroleum ether / ethyl acetate 1.1) to the title compound (1.60 g, 25%). Dark brown solid, MS: 404.2 [M+H]+.

[0524] Step 2: Allyl (2S)-3-(2-methyl-lH-indol-3-yl)-2-[(2-nitrophenyl)sulfonylamino1propanoate

[0525] To a solution of (2S)-3-(2-methyl-lH-indol-3-yl)-2-[(2-nitrophenyl)sulfonylamino]propanoic acid (1.60 g, 3.97 mmol) in N,N-dimethylformamide (30 mL) was added triethylamine (2.76 mL, 19.8 mmol) and allyl bromide (1.37 mL, 15.9 mmol), and the solution was stirred at 25°C for 16 h, then the mixture was diluted with ethyl acetate (70 mL) and the suspension was washed with water (30 mL). The organic layer was washed with brine (3x10 mL), dried over sodium sulfate and concentrated to give a residue, which was purified by flash chromatography (ethyl acetate / petroleum ether) to give the title compound (1.30 g, 69%). Yellow oil, MS: 444.0 [M+H]+.

[0526]

[0527] To a solution of allyl (2S)-3-(2-methyl-lH-indol-3-yl)-2-[(2-nitrophenyl)sulfonylamino]-propanoate (1.30 g, 2.93 mmol) in ethyl acetate (13 mL) was added potassium carbonate (608 mg, 4.4 mmol) and tetrabutylammonium bromide (94.5 mg, 0.29 mmol), then iodomethane (0.22 mL, 3.52 mmol) was slowly added and the reaction was stirred at 35°C for 4 h, then the suspension was diluted with ethyl acetate (20 mL) and washed with water (10 mL), brine (10 mL) in turn. The organic layer was dried over sodium sulfate and concentrated to give the title compound (1.2 g, 89%), which was used directly in the next step. Light yellow oil, MS: 458.2 [M+H]+.

[0528]

[0529] 1-2-methyl-indole- 1 -carboxylate

[0530] To a solution of allyl (2S)-3-(2-methyl-lH-indol-3-yl)-2-[methyl-(2-nitrophenyl)sulfonyl-amino]propanoate (1.20 g, 2.62 mmol) in dichloromethane (25 mL) were added diisopropylethylamine (0.41 mL, 2.36 mmol), 4-dimethylaminopyridine (32 mg, 0.26 mmol) and di-tert-butyl-dicarbonate (0.45 mL, 1.97 mmol), and the mixture was stirred at 25°C for 16 h, then the mixture was diluted with di chloromethane (20 mL) and washed with water (10 mL), brine (10 mL) in turn. The organic layer was dried over sodium sulfate and concentrated to the title compound (1.40 g, 80%), which was used directly in the next step. Yellow semisolid, MS: 580.2 [M+Na]+.

[0531] Step 5: tert-Butyl 3-[(2S)-3-allyloxy-2-(methylamino)-3-oxo-propyl]-2-methyl-indole-l-carb oxy late

[0532] To a solution of tert-butyl 3-[(2S)-3-allyloxy-2-[methyl-(2-nitrophenyl)sulfonyl-amino]-3-oxo-propyl]-2-methyl-indole-l -carboxylate (1.40 g, 2.51 mmol) in N,N-dimethylformamide (14 mL) was added potassium carbonate (1.04 g, 7.53 mmol) and sodium thiophenolate (885 mg, 8.03 mmol) at -5°C under a nitrogen atmosphere, then after 2 h the mixture was diluted with ethyl acetate (40 mL) and washed with water (2x10 mL), brine (10 mL) in turn. The aqueous layer was extracted with ethyl acetate (20 mL), the organic layer was dried over sodium sulfate and concentrated to give a residue, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether) to give the title compound (600 mg, 60%). Yellow oil, MS: 373.3 [M+H]+.

[0533]

[0534] i-6-(tert-butoxycarbonylamino)-2-rr(2S)-5-(tert-butoxycarbonylamino)-2-(9H-fluoren-9-'

[0535]

[0536] methyl- -3-oxo- -2-methyl-indole-l -carboxylateTo a solution of (2S)-6-(tert-butoxycarbonylamino)-2-[[(2S)-5-(tert-butoxycarbonylamino)-2-(9H-fluoren-9-ylmethoxycarbonylamino)pentanoyl]amino]hexanoic acid (CAS-RN [2971012-33-4]; 1.15 g, 1.69 mmol) in dichloromethane (16 mL) was added N,N'-diisopropylcarbodiimide (0.36 mL, 2.42 mmol) and l-hydroxy-7-azabenzotriazole (526 mg, 3.87 mmol) under ice-water bath, and the mixture was stirred for 5 min at 0°C and some solid was formed. Then a solution of tert-butyl 3-[(2S)-3-allyloxy-2-(methyl amino)-3-oxo-propyl]-2-methyl-indole-l-carboxylate (600 mg, 1.61 mmol) in di chloromethane (8 mL) was added and the mixture was stirred at 0 °C for another 5 h, then the mixture was diluted with ethyl acetate (50 mL) and washed with water (2x10 mL), brine (10 mL) in turn. The organic layer was dried over sodium sulfate and concentrated to give a residue, which was purified by flash chromatography(ethyl acetate / petroleum ether) to give the title compound (1.40 g, 79%). White solid, MS: 1059.5 [M+Na]+.

[0537]

[0538] i-2-[[(2S)-2-amino-5-(tert-butoxycarbonyl-

[0539]

[0540] 2-methyl-indole-l -carboxylate

[0541] To a light yellow solution of tert-butyl 3-[(2S)-3-allyloxy-2-[[(2S)-6-(tert-butoxy carbonyl amino)-2-[[(2S)-5-(tert-butoxycarbonylamino)-2-(9H-fluoren-9-ylmethoxy carbonylamino) pentanoyl]amino]hexanoyl]-methyl-amino]-3-oxo-propyl]-2-methyl-indole-l -carboxylate (400 mg, 0.39 mmol) in acetonitrile (4 mL) was added diethylamine (0.39 mL, 3.83 mmol), and the solution was stirred at 20°C for 4 h, then the solvent was evaporated under reduced pressure to give the residue, which was purified by flash chromatography (ethyl acetate / petroleum ether) and concentrated to give the title compound (270 mg, 83%). White solid, MS: 815.5 [M+H]+.

[0542] Intermediate 2

[0543] tert-Butyl 4-[4-chloro-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(2-formyl phenyl)methyl] phenyl] benzoate

[0544] >

[0545]

[0546] 1 : 6-Bromo-3-chloro-2-methyl-benzonitrileTo a yellow solution of 3-chloro-2-methylbenzonitrile (15.0 g, 99.0 mmol) in 1,2-dichloroethane (200 mL) was added p-toluenesulfonic acid monohydrate (8.52 g, 44.8 mmol), N-bromosuccinimide (19.4 g, 109 mmol) and palladium(II)acetate (1.11 g, 4.95 mmol) under a nitrogen atmosphere, then the yellow mixture was heated at 70°C and stirred for 16 h. After cooling ethyl acetate (200 mL) and water (100 mL) were added and the organic layers were separated. The aqueous phase was extracted with ethyl acetate (2^60 mL). Combined organics were washed with brine (80 mL) and dried over sodium sulfate. The solution was concentrated and the crude was purified by flash chromatography (SiCh petroleum ether / ethyl acetate gradient) to give the title compound (12.5 g, 36%). Yellow solid, MS: 230.9 [M]+.

[0547] Step 2: Tert-Butyl 4-(4-chloro-2-cyano-3-methyl-phenyl) benzoate

[0548] To a solution of 6-bromo-3-chloro-2-methyl-benzonitrile (10.5 g, 45.6 mmol) in toluene (110 mL) and water (11 mL) was added 4-(tert-butoxycarbonyl)phenylboronic acid (11.1 g, 50.1 mmol) , potassium phosphate (14.5 g, 68.3 mmol) and bis(tri-tert-butylphosphine)palladium(0) (466 mg, 0.91 mmol) under a nitrogen atmosphere, then the yellow suspension was stirred at 80°C for 3 h . After cooling ethyl acetate (150 mL) and water (100 mL) were added and layers were separated. The aqueous phase was extracted with ethyl acetate (2x60 mL). Combined organics was washed with brine (80 mL), dried over sodium sulfate and purified by flash chromatography (SiCL; petroleum ether / ethyl acetate gradient) to produce the title compound (11.4 g, 53%). White solid, MS: 270.9 [M-C4H9]+.

[0549] 3: tert-Butyl 4-F3-(bromomethyl)-4-chloro-2-cyano-i

[0550]

[0551] To a solution of tert-butyl 4-(4-chloro-2-cyano-3-methyl-phenyl) benzoate (6.20 g, 18.9 mmol) in 1,2-dichloroethane (70 mL) was added N-bromosuccinimide (5.05 g, 28.4 mmol) and benzoyl peroxide (137 mg, 0.57 mmol) under a nitrogen atmosphere, and the yellow suspension was stirred at 85°C for 16 h. After cooling insoluble material was removed by filtration and the filtrate was concentrated under vacuum to give a crude, which was purified by preparative HPLC (Phenomenex Luna C18 (250*70mm, 10 pm; gradient (water+0.225% formic acid) to acetonitrile / tetrahydrofuran 2:1) to give the title compound (8.70 g, quantitative). Yellow solid, MS: 406.0, [M+H]+.

[0552] Step 4: tert-Butyl 4-r4-chloro-2-cyano-3-(hydroxymethyl) phenyl] methyl]phenyl]benzoate

[0553] To a yellow solution of tert-butyl 4-[3-(bromomethyl)-4-chloro-2-cyano-phenyl]benzoate (1.28 g, 3.15 mmol) and 2-(hydroxymethyl)phenylboronic acid (478 mg, 3.15 mmol) in 1,4-di oxane(13 mL) and water (0.2 mL) were added sodium carbonate (667 mg, 6.29 mmol) and [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) di chloromethane complex (255 mg, 0.31 mmol) in a glove box, and the mixture was stirred at 40°C for 3 h under a nitrogen atmosphere. After cooling ethyl acetate (30 mL) and water (20 mL) were added and layers were separated. The aqueous phase was extracted with ethyl acetate (2^20 mL). Combined organics was washed with brine (40 mL) and dried over sodium sulfate. The solution was concentrated to give a residue, which was purified by flash chromatography (SiCh, petroleum ether / ethyl acetate) to give the title compound (1.0 g, 72%). Yellow solid, MS: 416.2 [M-JLO+H] .

[0554] 5: tert-Butyl 4-[2-(aminomethyl)-4-chloro-3-[[2-(hydroxymethyl)

[0555]

[0556] benzoate

[0557] To a yellow solution of tert-butyl 4-[4-chloro-2-cyano-3-[[2-(hydroxymethyl)phenyl]methyl] phenyl]benzoate (200 mg, 0.46 mmol) in tetrahydrofuran (2 mL) was added borane tetrahydrofuran complex (1 M in tetrahydrofuran, 2.3 mL, 2.3 mmol) under a nitrogen atmosphere, then the dark brown solution was stirred at 60°C for 3 h. After cooling to 0°C methanol was added dropwise, then the solution was heated at 65°C for 1 h, then concentrated to produce the title compound (200 mg, 99%), which was directly used in the next step. Dark brown oil, MS: 438.2 [M+H]+.

[0558]

[0559] -fluoren-9-’

[0560]

[0561] -3-FF2- (hydroxy

[0562]

[0563] To a solution of tert-butyl 4-[2-(aminomethyl)-4-chloro-3-[[2-(hydroxymethyl)phenyl]- methyl]phenyl]benzoate (600 mg, 1.37 mmol) in dichloromethane (10 mL) were added diisopropylethylamine (0.34 mL, 2.05 mmol) and N-(9-fluorenylmethoxycarbonyloxy)- succinimide (555 mg, 1.64 mmol), and the black suspension was stirred at 20°C for 3 h, then dichloromethane (20 mL) and water (10 mL) were added and layers were separated. The aqueous phase was extracted with dichloromethane (2x10 mL). Combined organics was washed with brine (30 mL) and dried over sodium sulfate. The solution was concentrated to give a residue, which was purified by flash chromatography (SiCh; petroleum ether / ethyl acetate gradient) to produce the title compound (490 mg, 36%). Yellow solid, MS: 682.3 [M+Na]+.

[0564] [(9H-fluoren-9-

[0565]

[0566] -3-[(2-formyl

[0567]

[0568] >

[0569] To a yellow solution of tert-butyl 4-[4-chloro-2-[(9H-fluoren-9-ylmethoxy carbonylamino)methyl]-3-[[2-(hydroxymethyl)phenyl]methyl]phenyl]benzoate (450 mg, 0.68 mmol) in 1,2-dichloroethane (20 mL) was added manganese(IV)oxide (1.19 g, 13.6 mmol), then the black suspension was stirred at 60°C for 3 h, then insoluble material was removed by filtration and the filtrate was concentrated to give a residue, which was purified by flash chromatography (4 SiCh; petroleum ether / ethyl acetate gradient) to produce the title compound (230 mg, 47%). White solid, MS: 680.4 [M+Na]+.

[0570] Intermediate 3

[0571] tert-Butyl 4-[4-chloro-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pyridyl)methyl] phenyl] benzoate

[0572]

[0573] Step 1 : tert-Butyl-4-r4-chloro-2-cyano-3-ir3-(k3-dioxolan-2-yl)-2-pyridyl1methyl1phenyl1-benzoate

[0574] To a suspension of activated zinc dust (1.45 g, 22 mmol) in dry tetrahydrofuran (20 mL) was added 1,2-dibromoethane (0.38 mL, 4.43 mmol) under a nitrogen atmosphere, then the reaction suspension was stirred at 70°C for 5 min. After cooling to room temperature trimethylsilylchloride (0.38 mL, 4.43 mmol) was added dropwise and the resulting suspension was stirred at 25°C for 15 min. The suspension was then heated to 65°C and a solution of tertbutyl 4-[3-(bromomethyl)-4-chloro-2-cyano-phenyl]benzoate (intermediate 2, step 3;3.00 g, 7.38 mmol) in tetrahydrofuran (10 mL) was added dropwise over a period of 5 min, and the reaction mixture was stirred at 65°C for 1 h and allowed to cool down to 15°C. The zinc dust was allowed to be settled down and the supernatant was added to a solution of 2-bromo-3-(l,3-dioxolan-2-yl)pyridine (1.70 g, 7.38 mmol) and tetrakis(triphenylphosphine)palladium(0) (852 mg, 0.74 mmol) in dry tetrahydrofuran (20 mL) at 15 °C, then the reaction mixture was heated to 65°C for 16 h. After cooling the reaction mixture was partitioned between saturated aq. ammonium chloride solution (50 mL) and ethyl acetate (40 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flashchromatography (petroleum ether / ethyl acetate 3: 1) to produce the title compound (1.5 g, 38%). Light yellow solid, MS: 477.1 [M+H]+.

[0575] (aminomethyl)-4-chloro-3-[[3-(l,3-dioxolan-2 -yl)-2-

[0576]

[0577] benzoate

[0578] To a colorless solution of tert-butyl 4-[4-chloro-2-cyano-3-[[3-(l,3-dioxolan-2-yl)-2- pyridyl]methyl]phenyl]benzoate (500 mg, 1.05 mmol) in methanol (80 mL) and 25% aq. ammonia solution (8 mL) was added Raney-Ni (500 mg), and the mixture was stirred at 20°C for 4 h under a hydrogen atmosphere (15 Psi), then the reaction mixture was filtered and the filtrate was concentrated to the title compound (500 mg, 49%), which was used directly in the next step. Colorless oil, MS: 481.3[M+H]+.

[0579] -2- i (9H-fluoren-9-

[0580]

[0581] To a colorless suspension of tert-butyl 4-[2-(aminomethyl)-4-chloro-3-[[3-(l,3-dioxolan-2-yl)-2- pyridyl]methyl]phenyl]benzoate (440 mg, 0.91 mmol) in tetrahydrofuran (4 mL) were added saturated aq. sodium hydrogen carbonate solution (4.0 mL, 0.91 mmol) and N-(9- fluorenylmethoxycarbonyloxy)succinimide (339 mg, 1.01 mmol), and the mixture was stirred at 25°C for 16 h, then partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was washed with brine (2^10 mL) dried over sodium sulfate and concentrated to give a residue, which was purified by column chromatograph (petroleum ether / ethyl acetate gradient) to produce the title compound (370. mg, 0.53 mmol, 42%). Yellow oil, MS: 703.2 [M+H]+.

[0582] 9H-fluoren-9-

[0583]

[0584] -3-r(3-formyl-

[0585]

[0586] To a light yellow solution of tert-butyl 4-[4-chloro-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl] methyl]- 2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]phenyl]benzoate (320 mg, 0.46 mmol) in acetone (4 mL) and water (0.4 mL) was added pyridinium toluene-4-sulfonate (114 mg, 0.46 mmol), and the light yellow solution was stirred at 70°C for 3 h. The reaction solution was cooled to room temperature, then another portion of pyridinium toluene-4-sulfonate (114 mg, 0.46 mmol,) was added, then after cooling the reaction mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was washed with brine (10 mL) and dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate 2.1) to produce the title compound(250 mg, 83%). Colourless oil, MS: 659.2 [M+H]+.

[0587] Intermediate 4

[0588] tert-Butyl 4-[2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pyridyl) methyl]-4-(trifluoromethyl)phenyl]benzoate (10)

[0589]

[0590] Step 1: 6-Bromo-2-methyl-3-(trifluoromethyl)benzonitrile

[0591] The title compound was produced in analogy to intermediate 2, step 1, from 2-methyl-3-(trifluoromethyl)benzonitrile and obtained as a light brown solid.

[0592] Step 2: tert-Butyl 4-12-cyano-3-methyl-4-(trifluoromethyl)phenyl1benzoate

[0593] The title compound was produced in analogy to intermediate 2, step 2, from 6-bromo-2-methyl-3-(trifluoromethyl)benzonitrile and obtained as a light yellow solid.

[0594] Step 3: tert-Butyl 4-12- aminomethyl)-3-methyl-4- trifluoromethyl)phenyl1benzoate

[0595] To a mixture of tert-butyl 4-[2-cyano-3-methyl-4-(trifluoromethyl)phenyl]benzoate (8.50 g, 23.5 mmol) in methanol (1000 mL) and 28% aq. ammonia solution (200 mL, 28% purity) was added Raney nickel (10 g), and the mixture was stirred at 50°C for 10 h under a hydrogen atmosphere (50 Psi), then insoluble material was removed by filtration and the filtrate was concentrated to produce the title compound (8.5 g, 88%). Light yellow oil, MS: 366.1[M+H]+.

[0596] Step 4: tert-Butyl 4-r2-r(L3-dioxoisoindolin-2-yl)methyl1-3-methyl-4-(trifluoromethyl)-phenyllbenzoate

[0597] To a mixture of tert-butyl 4-[2-(aminomethyl)-3-methyl-4-(trifluoromethyl)phenyl]benzoate (8.8 g, 24.1 mmol) in tetrahydrofuran (50 mL) and saturated aq. sodium carbonate solution (50 mL) was added N-carbethoxyphthalimide (7.92 g, 36.1 mmol), and the mixture was stirred at 20°Cfor 17 h, then the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (petrol ether / ethyl acetate 10: 1) to produce the title compound (10.0 g, 77%). Light yellow solid, MS: 518.2 [M+Na]+.

[0598] 5: tert-Butvl 4-F3-(bromomethvl)-2-| ,3-dioxoisoindolin-2-

[0599]

[0600] -4-(trifluoromethyl)-

[0601]

[0602] >

[0603] To a solution of tert-butyl 4-[2-[(l,3-dioxoisoindolin-2-yl)methyl]-3-methyl-4-(trifluoromethyl)- phenyl]benzoate (9.00 g, 18.2 mmol) in 1,2-dichloroethane (100 mL) was added N- bromosuccinimide (4.85 g, 27.3 mmol) and benzoyl peroxide (440 mg, 1.82 mmol) under a nitrogen atmosphere, and the brown solution was stirred at 80°C for 16 h. After cooling the reaction mixture was concentrated under vacuum, and the residue was by chromatography (petroleum ether / ethyl acetate 10: 1) to produce the title compound (10.0 g, 96%). White solid, MS: 596.0 [M+Na]+.

[0604]

[0605] -3-|T3-(l,3-dioxolan-2-vl)-2-

[0606]

[0607]

[0608] The title compound was produce in analogy to intermediate 4, step 1 from tert-butyl 4-[3- (bromomethyl)-2-[(l,3-dioxoisoindolin-2-yl) methyl]-4-(trifluoromethyl) phenyl]benzoate and 2- bromo-3-(l,3-dioxolan-2-yl)pyridine. Light yellow oil, MS: 645.1 [M+H]+.

[0609] aminomethvl)-3- -( 1,3 -dioxolan-2-vl)-2-

[0610]

[0611] |-4-(trifluoro-

[0612]

[0613] To a solution of tert-butyl 4-[2-[(l,3-dioxoisoindolin-2-yl)methyl]-3-[[3-(l,3-dioxolan-2-yl)-2- pyridyl]methyl]-4-(trifluoromethyl)phenyl]benzoate (750 mg, 1.16 mmol) in ethanol (1 mL) was added hydrazine hydrate (0.37 mL, 7.23 mmol) at 0 °C under a nitrogen atmosphere, and the mixture was stirred at 20°C for 16 h. The reaction mixture was filtered and the filtrate was partitioned between water (30 mL) and ethyl acetate (30 mL). The organic layer was washed with brine (10 mL) and dried over sodium sulfate, filtered and concentrated under reduced pressure to produce the title compound (270 mg, 40%), which was directly used in the next step. Light yellow oil, MS: 515.3 [M+H]+.

[0614] -2-l(9H-fluoren-9-vlmethoxv-

[0615]

[0616] The title compound was produced in analogy to intermediate 3, step 3. from tert-butyl 4-[2-(aminomethyl)-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]methyl]-4-(trifluoromethyl)phenyl]benzoate. Light yellow solid, MS: 737.3 [M+H]+.

[0617]

[0618] The title compound was produced in analogy to intermediate 3, step 4, from tert-butyl 4-[3-[[3- (l,3-dioxolan-2-yl)-2-pyridyl]methyl]-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-4- (trifluoromethyl)phenyl]benzoate. Light yellow solid, MS: 693.2 [M+H]+.

[0619] Intermediate 5

[0620] tert-Butyl 4-[4-(difluoromethyl)-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3- formyl-2-pyridyl)methyl]phenyl]benzoate

[0621]

[0622] thyl)-2-methyl-benzonitrile

[0623] The title compound was produced in analogy to intermediate 2, step 1 from 3-(difluoromethyl)- 2-methyl-benzonitrile (CAS-RN [1261762-56-4]) Light yellow solid.

[0624] 2: tert-Butyl 4-[2-cyano-4-(difluoromethyl)-3-methyl-

[0625]

[0626] The title compound was produced in analogy to intermediate 2, step 2 from 6-bromo-3- (difluoromethyl)-2-methyl-benzonitrile and 4-(tert-butoxycarbonyl)phenylboronic Yellow solid, MS: 270.1 [M-C4H9+H]+.

[0627] 3: tert-Butyl 4-[3-(bromomethyl)-2-cyano-4-i

[0628]

[0629] The title compound was produced in analogy to intermediate 2, step 4 from tert-butyl 4-[2- cyano-4-(difluoromethyl)-3-methyl-phenyl]benzoate Light yellow oil.

[0630] Step 4: tert-Butyl 4-[2-cvano-4-(difliioromethyl)-3-[[3-(l.3-dioxolan-2-yl)-2--n-

[0631] The title compound was produced in analogy to intermediate 3, step 1 from tert-butyl 4-[3-(bromomethyl)-2-cyano-4-(difluoromethyl)phenyl]benzoate and 2-bromo-3-(l,3-dioxolan-2-yl)pyridine. Light yellow solid, MS: 493.2 ([M+H]+.

[0632] aminomethyl)-4-(difluoromethyl)-3-| -( 1 ,3 -dioxolan-2-yl)-2-

[0633]

[0634]

[0635] The title compound was produced in analogy to intermediate 3, step 2, from tert-butyl 4-[2-cyano-4-(difluoromethyl)-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]methyl]phenyl]benzoate. Light yellow solid, MS: 497.2 [M+H]+.

[0636] 6: tert-Butvl 4-14-(difluoromethyl)-3- -(T,3-dioxolan-2-yl)-2-

[0637]

[0638] fluoren-9-'

[0639]

[0640] The title compound was produced in analogy to intermediate 3, step 3 from tert-butyl 4-[2-(aminomethyl)-4-(difluoromethyl)-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]methyl]phenyl]benzoate. Light yellow solid, MS: 719.4 [M+H]+.

[0641] 7: tert-Butyl 4-14-(difluoromethyl)-2-

[0642]

[0643] -fluoren-9-’

[0644]

[0645] -3-

[0646]

[0647] The title compound was produced in analogy to intermediate 3, step 4, from tert-butyl 4-[4-(difluoromethyl)-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]methyl]-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]phenyl]benzoate. White solid, MS: 675.3 [M+H]+.

[0648] Intermediate 6

[0649] tert-Butyl 4-[2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pyridyl)methyl]-4-methyl-phenyl]benzoate

[0650]

[0651] 1 : 6-Bromo-2 -dimethyl-benzonitrile

[0652] The title compound was produced in analogy to intermediate 4, step 1, from 2,3-dimethyl-benzonitrile. White solid, MS: 209 [M]+.

[0653] Step 2: 6-Bromo-2-(bromomethyl)-3-methyl-benzonitrile

[0654] To a white suspension of 6-bromo-2,3-dimethyl-benzonitrile (14.0 g, 66.7 mmol) in 1,2-dichloroethane (140 mL) was added N-bromosuccinimide (11.9 g, 66.7 mmol) and benzoyl peroxide (484 mg, 2.0 mmol) under a nitrogen atmosphere, and the colorless solution was stirred at 70°C for 16 h. After cooling dichloromethane (200 mL) and water (100 mL) were added and layers were separated. The aqueous phase was extracted with dichloromethane (2^100 mL). The combined extracts were washed with brine (100 mL), dried over sodium sulfate and concentrated under vacuum to give a residue, which was purified by flash chromatography (SiCh, petroleum ether / ethyl acetate gradient) to produce the title compound 15.5 g, 80%), which was obtained as a white solid.

[0655] Step 3: 6-Bromo-2-IT3-(L3-dioxolan-2-yl)-2-pyridyl]methyl]-3-methyl-benzonitrile

[0656] The title compound was produced in analogy to intermediate 2, step 4, from 6-bromo-2-(bromomethyl)-3-methyl-benzonitrile and 2-bromo-3-(l,3-dioxolan-2-yl)pyridine. Light yellow solid, MS: 360.9 [M+H]+.

[0657] Step 4: tert-butyl 4-r2-cvano-3-U3-dioxolan-2-vD-2-pyridyl]methyll-4-methyl-

[0658]

[0659] The title compound was produced in analogy to intermediate 2, step 2, from 6-bromo-2-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]methyl]-3-methyl-benzonitrile and 4-(tert-butoxycarbonyl)phenylboronic acid. Yellow solid, MS: 457.3 [M+H]+.

[0660] Step 5: tert-Butyl 4-r2-(aminomethvl)-3-rr3-(L3-dioxolan-2-vl)-2-pvridyl]rnethvl]-4-methyl- yl] benzoate

[0661] The title compound was produced in analogy to intermediate 2, step 5 from tert-butyl 4-[2-cyano-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]methyl]-4-methyl-phenyl]benzoate. Light yellow oil, MS: 461.4 [M+H]+.

[0662] Step 6: tert-Butyl 4-r3-rr3-dioxolan-2-yl)-2-pyridyl]methyll-2-r(9H-fluoren-9-ylmethoxy-

[0663]

[0664] -4-methyl-iThe title compound was produced in analogy to intermediate 2, step 6, from tert-butyl 4-[2-(aminomethyl)-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]methyl]-4-methyl-phenyl]benzoate. White solid, MS: 683.5, [M+H]+.

[0665]

[0666] -3-l(3-formyl-2-

[0667]

[0668] The title compound was produced in analogy to intermediate 2, step 7, from tert-butyl 4-[3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]methyl]-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-4-methyl-phenyl]benzoate. White solid, MS: 639.4 [M+H]+.

[0669] Intermediate 7

[0670] tert-Butyl 4- [2- [(9H-fluoren-9-ylmethoxycarbonylamino)methyl] -3- [(2-formylphenyl)methyl] phenyl] benzoate

[0671]

[0672] The title compound was produced in analogy to intermediate 2, step 2, from-2-bromo-6-methyl-benzonitrile and 4-(tert-butoxycarbonyl)phenylboronic acid. White solid, MS 238.1 [M-C4H9+H] .

[0673] 2: tert-Butyl 4-13 -(brom omethyl)-2-cyano-

[0674]

[0675] The title compound was produced in analogy to intermediate 2, step 3, from tert-butyl 4-(2-cyano-3-methyl-phenyl)benzoate. White solid, MS: 372.0 [M+H]+.

[0676]

[0677] The title compound was produced in analogy to intermediate 2, step 4, from tert-butyl 4-[3-(bromomethyl)-2-cyano-phenyl]benzoate and 2-(hydroxymethyl)phenylboronic acid. Light yellow solid, MS: 422.1 [M+Na]+.4: tert-Butyl 4-F2-(aminomethyl)-3-

[0678] The title compound was produced in analogy to intermediate 3, step 2, from tert-butyl 4-[2-cyano-3-[[2-(hydroxymethyl)phenyl]methyl]phenyl]benzoate. Light yellow solid, MS: 404.2 [M+H]+.

[0679] - 3 - r F 2-(hy droxymethyl)-

[0680]

[0681] The title compound was produced in analogy to intermediate 2, step 6, from tert-butyl 4-[2-(aminomethyl)-3-[[2-(hydroxymethyl)phenyl] methyl]phenyl]benzoate. White solid, MS:648.4 [M+Na]+.

[0682] -3-FC2-

[0683]

[0684] The title compound was produced in analogy to intermediate 2, step 7, from tert-butyl 4-[2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[[2-(hydroxymethyl)phenyl]methyl]phenyl]benzoate. Light yellow solid, MS: 646.4 [M+Na]+.

[0685] Intermediate 8

[0686] tert-Butyl 4-[2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-4-fluoro-3-[(3-formyl-2-pyridyl)methyl] phenyl] benzoate

[0687]

[0688] The title compound was produced in analogy to intermediate 5, replacing 3-(difluoromethyl)-2-methyl-benzonitrile by 3-fluoro-2-methylbenzonitrile. White solid, MS: 643.2 [M+H]+.

[0689] Intermediate 9

[0690] tert-Butyl 4-[2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pyridyl)methyl] phenyl] benzoate

[0691]

[0692] The title compound was produced in analogy to intermediate 5, steps 2-7, replacing 6-bromo-3-(difluoromethyl)-2-methyl-benzonitrile by 2-bromo-6-methylbenzonitrile. White solid, MS: 625.3 [M+H]+.

[0693] Intermediate 10

[0694] tert-Butyl 4-[4-chloro-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pyridyl)-methyl-amino]phenyl]benzoate

[0695]

[0696] Step 1: 6-Bromo-3-chloro-2-(methylamino)benzonitrile

[0697] To a light yellow solution of 6-bromo-3-chloro-2-fluoro-benzonitrile (CAS-RN [1779124-51-4]; 2.00 g, 8.53 mmol) and methylamine hydrochloride (1.15 g, 17.1 mmol) in acetonitrile (20 mL) was added sodium hydroxide (684 mg, 17.1 mmol) at 25°C, then the light yellow suspension was stirred at 80°C for 5 h in a sealed tube. After cooling insoluble material was removed by filtration, and the filtrate was concentrated and purified by chromatography (SiCh; petroleum ether / ethyl acetate gradient) to produce the title compound (1.60 g, 76%). White solid, MS: 247.2 [M +H]+.

[0698] Step 2: tert-Butyl 4-[4-chloro-2-cyano-3-(methylamino)phenyl1benzoate

[0699] The title compound was produced in analogy to intermediate 2, step 2, from 6-bromo-3-chloro-2-(methylamino)benzonitrile and 4-(tert-butoxycarbonyl)phenylboronic acid. White solid, MS:343.1 [M +H]+.

[0700] 3: tert-Butyl 4-[4-chloro-2-cyano-3-[[3-(L3-dioxolan-2-yl)-2-pyridyl]-methyl-

[0701]

[0702] benzoate

[0703] To a colorless solution of tert-butyl 4-[4-chloro-2-cyano-3-(methylamino)phenyl]benzoate (800 mg, 2.33 mmol) and 2-bromo-3-(l,3-dioxolan-2-yl)pyridine (537 mg, 2.33 mmol) in 1,4-dioxane (10 mL) was added sodium tert-butoxide solution (2 M in tetrahydrofuran, 2.33 mL, 4.67 mmol) and Xphos-Pd-G4 (CAS-RN [1599466-81-5]; 181 mg, 0.23 mmol) under a nitrogen atmosphere, then the red solution was stirred at 90°C for 16 h. After cooling the reaction mixture was diluted with ethyl acetate (60 mL) and then washed with water (2x20 mL) and brine (20 mL) in turn. The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by flash chromatography (petroleum ether / ethyl acetate 5: 1) to produce the title compound (530 mg, 43%). Yellow solid, MS: 492.1 [M+H]+.

[0704] aminomethyl)-4-chloro-3-[[3-(L3-dioxolan-2-yl)-2-pyridyl]-methyl-

[0705]

[0706] The title compound was produced in analogy to intermediate 3, step 2, from tert-butyl 4-[4-chloro-2-cyano-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]-methyl-amino]phenyl]benzoate. Colorless oil, MS: 496.2 [M+H]+.

[0707]

[0708] The title compound was produced in analogy to intermediate 3, step 3, from tert-butyl 4-[2-(aminomethyl)-4-chloro-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]-methyl-amino]phenyl]benzoate. Light yellow solid, MS: 718.2 [M+H]+.

[0709] 6: tert-Butyl 4-[4-chloro-2-[(9H-fluoren-9-

[0710]

[0711] -3-[(3-formyl- 2-1 i-methyl-:

[0712]

[0713] The title compound was produced in analogy to intermediate 3, step 4, from tert-butyl 4-[4-chloro-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]-methyl-amino]-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]phenyl]benzoate. Colorless oil, MS: 674.3 [M+H]+.

[0714] Intermediate 11

[0715] tert-Butyl 4- [2- [(9H-fluoren-9-ylmethoxycarbonylamino)methyl] -3-(2-formylanilino)phenyl] benzoate

[0716]

[0717] Step 1: tert-Butyl 4-(3-amino-2-cyano-phenyl)benzoate

[0718] The title compound was produced in analogy to intermediate 2, step 2, from 2-amino-6-bromo-benzonitrile and 4-(tert-butoxycarbonyl)phenylboronic acid. Light yellow solid, MS: 295.1 [M+H]+.

[0719] Step 2: tert-Butyl 4-[2-cyano-3-r2-(L3-dioxolan-2-yl)anilino1phenyl1benzoate

[0720] To a solution of tert-butyl 4-(3-amino-2-cyano-phenyl)benzoate (2.20 g, 7.47 mmol) and 2-(2-bromophenyl)-l,3-dioxolane (1.71 g, 7.47 mmol) in 1,4-dioxane (44 mL) was added cesium carbonate (6.09 g, 18.7 mmol) and Ruphos-Pd-G2 (CAS-RN [1375325-68-0]; 0.58 g, 0.75 mmol) under a nitrogen atmosphere, then the reaction was stirred at 90°C for 6 h . After cooling the reaction mixture was diluted with ethyl acetate (30 mL), and the solution was washed with water (2x10 mL) and brine (10 mL) in turn. The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by flash chromatography (SiCL petroleum ether / ethyl acetate 85: 15) to produce the title compound (2.70 g, 73%). Light yellow oil, MS: 443.2 [M+H]+.

[0721] Step 3: tert-Butyl 4-r2-(aminomethyl)-3-[2-(L3-dioxolan-2-yl)anilino]phenyl]benzoate

[0722] The title compound was produced in analogy to intermediate 3, step 2, from tert-butyl 4-[2-cyano-3-[2-(l,3-dioxolan-2-yl)anilino]phenyl]benzoate. Light yellow solid, MS: 430.2 [M-NH3+H]+.

[0723] Step 4: tert-Butyl 4-r3-r2-(L3-dioxolan-2-yl)anilino1-2-[(9H-fluoren-9-ylmethoxycarbonyl-amino) methyl]phenyl]benzoate

[0724] The title compound was produced in analogy to intermediate 3, step 3, from tert-butyl 4-[2-(aminomethyl)-3-[2-(l,3-dioxolan-2-yl)anilino]phenyl] benzoate. Light yellow solid, MS: 669.4[M+H]+.

[0725] Step 5: tert-Butyl 4-12-l(9H-fluoren-9-ylmethoxycarbonylamino)methyl1-3-(2-formylanilino)phenyl1 benzoate

[0726] The title compound was produced in analogy to intermediate 3, step 4, from tert-butyl 4-[3-[2-(l,3-dioxolan-2-yl)anilino]-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]phenyl]benzoate. Yellow solid, MS: 625.4 [M+H]+.

[0727] Intermediate 12

[0728] tert-Butyl 4-[4-chloro-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pyridyl)amino] phenyl] benzoate

[0729]

[0730] Step 1: (2-Amino-6-bromo-3-chloro-phenyl)methanol

[0731] To a solution of 2-amino-6-bromo-3 -chi oro-benzoic acid (8.00 g, 31.9 mmol) in tetrahydrofuran (120 mL) was added dropwise borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 120 mL, 120 mmol) over 30 min, then the mixture was stirred at 40°C for 16 h. After cooling methanol (60 mL) was added dropwise, then the mixture was heated at 80°C for 2 h. The reaction mixture was concentrated under vacuum to produce the title compound (7.60 g, quantitative), which was used directly in the next step. Light brown solid, .MS: 218.0 [M-H20+H]+.

[0732] Step 2: 3-Bromo-2-rrtert-butyl(dimethyl)silyl1oxymethyl1-6-chloro-aniline

[0733] To a solution of (2-amino-6-bromo-3-chloro-phenyl)methanol (9.00 g, 38.1 mmol) in dichloromethane (180 mL) was added imidazole (3.89 g, 57.1 mmol) and tert-butyldimethylsilyl chloride (7.46 g, 49.5 mmol) then the mixture was stirred at 25°C. After 16 h insoluble material was removed by filtration, and the filtrate washed with water (40 mL) and brine (40 mL) in turn. The organic layer was dried over sodium sulfate and concentrated to give a residue, which waspurified by flash chromatography (SiCh; petroleum ether) to produce the title compound (11.0 g, 70%). Light yellow oil.

[0734]

[0735] The title compound was produced in analogy to intermediate 2, step 2, from 3-bromo-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-6-chloro-aniline and 4-(tert-butoxycarbonyl)phenylboronic acid. Light yellow oil, MS: 430.9 [M+H]+.

[0736] -4-chl oro-3 -113 -( 1,3 -dioxolan-2-vl)-

[0737]

[0738] To a colorless solution of tert-butyl 4-[3-amino-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4- chloro-phenyl]benzoate (500 mg, 1.12 mmol) and 2-bromo-3-(l,3-dioxolan-2-yl)pyridine (770 mg, 3.35 mmol) in 1,4-di oxane (12 mL) was added sodium tert-butoxide solution (2 M in tetrahydrofuran, 1.39 mL, 2.79 mmol) and Xphos-Pd-G4 (CAS-RN [1599466-81-5]; 174 mg, 0.22 mmol) under a nitrogen atmosphere, then the yellow solution was heated at 110°C and stirred for 2 h. After cooling the reaction mixture was partitioned between ethyl acetate (40 mL) and water (20 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to give a residue, which was purified by flash chromatography (SiCh; petrol ether / ethyl acetate 4: 1) to produce the title compound (100 mg, 9%). Light red oil, MS: 597.2 [M+H]+.

[0739] [3-(L3-dioxolan-2-vl)-2-pvridvl]amino]-2-

[0740]

[0741] >

[0742] To a solution of tert-butyl 4-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-chloro-3-[[3-(l,3- dioxolan-2-yl)-2-pyridyl]amino]phenyl]benzoate (990 mg, 1.66 mmol,) in tetrahydrofuran (20 mL) was added a solution of tetrabutylammonium fluoride (1 M in tetrahydrofuran, 1.99 mL, 1.99 mmol), and the mixture was stirred at 25°C, then after 6 h, then the reaction mixture was evaporated. Chromatography of the residue( SiCh; petroleum ether / ethyl acetate 2:1) produced the title compound (660 mg, 77%). Light yellow solid, MS: 483.1 [M+H]+.

[0743] ethvl)-4-chloro-3-[[3-(L3-dioxolan-2-vl)-2-

[0744]

[0745] To a solution of tert-butyl 4-[4-chloro-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]amino]-2-(hydroxy methyl)phenyl]benzoate (560 mg, 1.16 mmol) in tetrahydrofuran (5 mL) was addeddiphenylphosphoryl azide (0.62 mL, 2.9 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (0.61 mL, 4.06 mmol) under a nitrogen atmosphere, then the mixture was stirred at 25°C for 16 h. The mixture was diluted with ethyl acetate (30 mL) and the solution was washed with water (10 mL), brine (10 mL) in turn. The organic layer was dried over sodium sulfate and concentrated to give a residue, which was purified by flash chromatography (Si O2; petroleum ether / ethyl acetate 7:3) to produce the title compound (550 mg, 87%). Light yellow oil, MS: 508.1 [M+H]+.

[0746] 7: tert-Butyl 4-F2-(aminomethyl)-4-chloro-3- -( 1 ,3 -dioxolan-2-yl)-2-

[0747]

[0748]

[0749] To a solution of tert-butyl 4-[2-(azidomethyl)-4-chloro-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl] amino]phenyl]benzoate (580 mg, 1.14 mmol) in tetrahydrofuran (20 mL) and water (1 mL) was added triphenylphosphine (329 mg, 1.26 mmol), and the mixture was stirred at 25°C for 16 h under a nitrogen atmosphere, then diluted with ethyl acetate (20 mL) and the solution was washed with brine (10 mL). The organic layer was dried over sodium sulfate and concentrated to give a residue, which was purified by chromatography (Si O2; petroleum ether / ethyl acetate 1 : 1 to di chloromethane / methanol 10: 1 gradient) to produce the title compound (700 mg, 80%). Light yellow semisolid, MS: 482.2 [M+H]+.

[0750] 8: tert-Butyl 4-r4-chloro-3-ri3-(L3-dioxolan-2-yl)-2-

[0751]

[0752] -2-1 (9H-fluoren-9-

[0753]

[0754] The title compound was produced in analogy to intermediate 2, step 6, from tert-butyl 4-[2-(aminomethyl)-4-chloro-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl] amino]phenyl]benzoate. White solid, MS: 704.2 [M+H]+.

[0755] 9H-fluoren-9-’

[0756]

[0757] -3-l(3-formyl-

[0758]

[0759] The title compound was produced in analogy to intermediate 3, step 4, from tert-butyl 4-[4-chloro-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]amino]-2-[(9H-fluoren-9-ylmethoxy carbonyl-amino)methyl]phenyl]benzoate. Light yellow solid, MS: 660.2 [M+H]+.

[0760] Intermediate 13

[0761] tert-Butyl 4-[2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pyridyl)-amino]phenyl]benzoate

[0762]

[0763] Step 1: tert-Butyl 4-(3-amino-2-cyano-phenyl)benzoate

[0764] The title compound was produced in analogy to intermediate 2, step 2, from 2-amino-6-bromo-benzonitrile 4-(tert-butoxycarbonyl)phenylboronic acid. Yellow solid, MS: [M+H]+.

[0765] Step 2: tert-Butyl 4-r2-cyano-3-dioxolan-2-yl)-2-pyridyl]amino]phenyl]benzoate

[0766]

[0767] The title compound was produced in analogy to intermediate 3, step 1, from tert-butyl 4-(3-amino-2-cyano-phenyl)benzoate and 2-bromo-3-(l,3-dioxolan-2-yl)pyridine. Yellow solid, MS: 444.2 [M+H]+.

[0768] Step 3: tert-Butyl 4-12-(aminomethyl)-3-(T3-dioxolan-2-yl)-2-

[0769]

[0770] pyridyllaminolphenyllbenzoate

[0771] The title compound was produced in analogy to intermediate 3, step 2, from tert-butyl 4-[2-cyano-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]amino]phenyl]benzoate. Yellow solid, MS: 448.2 [M+H]+.

[0772] Step 4: tert-Butyl 4-13-113-(l -dioxolan-2-yl)-2-pyridyl]amino]-2-l(9H-fluoren-9-ylmethoxycarbonylamino)methyl]phenyl]benzoate

[0773] The title compound was produced in analogy to intermediate 2, step 6, from tert-butyl 4-[2-(aminomethyl)-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]amino] phenyl]benzoate. White solid, MS: 670.4 [M+H]+.

[0774] Step 5: tert-Butyl 4-12-l(9H-fluoren-9-ylmethoxycarbonylamino)methyl1-3-r(3-formyl-2-pyridyl) aminolphenyllbenzoate

[0775] The title compound was produced in analogy to intermediate 3, step 4, from tert-butyl 4-[3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]amino]-2-[(9H-fluoren-9-ylmethoxy carbonylamino)-methyl]phenyl]benzoate. Yellow solid, MS:626.2 [M+H]+.Intermediate 14

[0776] tert-Butyl 4-[2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pyridyl)-selanyl] phenyl] benzoate

[0777]

[0778] nocyanato-benzoate

[0779] To a solution of methyl 2-amino-6-bromo-benzoate (5.00 g, 21.730 mmol) and sodium tetrafluoroborate (4.68 g, 32.6 mmol) in 2 M aq. hydrochloric acid solution (50 mL, 100 mmol) was added a solution of sodium nitrite (1.65 g, 23.9 mmol) in water (35 mL) at 0°C and the mixture was stirred at 0°C for 1 h. Then the pH was adjusted to 6 by adding 0.5 M aq. sodium acetate solution (40.0 mL, 20 mmol) and a solution of potassium selenocyanate (3.76 g, 26.1 mmol) in water (70 mL) was added at 0°C. After that, the mixture was warmed to 20°C and stirred for further 1 h, then diluted with water (50 mL), upon which a precipitate formed. The solid was collected by filtration and dried under reduced pressure to produce the title compound (7.0 g, 86%). Yellow solid, MS: 319.1 [M]+.

[0780] 2: Methyl 2-bromo-6- -bromo-2-methoxycarbonyl-

[0781]

[0782] To a solution of methyl 2-bromo-6-selenocyanato-benzoate (8.3 g, 26.0 mmol) in methanol (100 mL) was added sodium borohydride (1.97 g, 52.0 mmol) slowly and the solution was stirred at 20°C, then after 2 h the pH was adjusted to 6 by dropwise addition of formic acid. After evaporation of volatile material the residue was flash chromatography (SiCL; petroleum ether / ethyl acetate gradient) to produce the title compound (4.6 g, 27%). Light yellow solid, MS: 608.9 [M+Na]+.

[0783]

[0784] A solution of methyl 3-bromo-2-[(3-bromo-2-methoxycarbonyl-phenyl)diselanyl]benzoate (4.55 g, 7.76 mmol), dithiotreitol (1.99 g, 12.9 mmol) and pyridine (2.09 mL, 25.9 mmol) in of N,N-dimethylacetamide (50 mL) was stirred at 40°C under a nitrogen atmosphere for 30 min, then asolution of 2-chl oro-3 -(1,3 -di oxolan-2-yl)pyridine (2.4 g, 12.9 mmol) in 10 mL ofN,N-dimethylacetamide was added and the solution was stirred at 60°C for 16 h. After cooling the solution was poured into 1 M aq. hydrochloric acid solution (100 mL) and extracted with ethyl acetate (2^60 mL), combined organics was dried over sodium sulfate. The solvent was removed to give a crude, which was purified by chromatography (Si O2; petroleum ether / ethyl acetate gradient) to produce the title compound (4.60 g, 72%). Off-white solid, MS: 441.9 [M+H]+.

[0785]

[0786] acid

[0787] To a solution of methyl 2-bromo-6-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]selanyl]benzoate (1.53 g, 3.45 mmol) in tetrahydrofuran (15 mL) and methanol (7 mL) was added 5 M aq. lithium hydroxide solution (7 mL, 35 mmol), then the solution was stirred at 40°C for 16 h. After cooling, the reaction mixture was poured into 20 mL of water and the pH was adjusted to 4-5 by progressively adding 1 M aq. hydrochloric acid solution and the mixture was then extracted with ethyl acetate (3x40 mL). Combined extracts was washed with brine (60 mL), dried over sodium sulfate, and concentrated under reduced pressure to give the residue, which was purified by flash chromatography (SiCL; petroleum ether / ethyl acetate gradient) to produce the title compound (1.2 g, 79%). Yellow solid, MS: 429.9 [M+H]+.

[0788]

[0789] To a solution of 2-bromo-6-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]selanyl]benzoic acid (1.2 g, 2.8 mmol) in tetrahydrofuran (10 mL) was added carbonyldiimidazole (2.72 g, 16.8 mmol), and the mixture was stirred at 20°C for 1 h. Then a solution of sodium borohydride (3.07 g, 81.1 mmol) in tetrahydrofuran (20 mL) and water (10 mL) was added at 0°C under a nitrogen atmosphere, and the suspension was warmed to 20°C. After 16 h the mixture was diluted with water (20 mL) and the pH of the solution was adjusted to 6-7 by progressively adding aq. 1 M aq. hydrochloric acid solution, which caused a solid to precipitate. The precipitate was collected by filtration and dried under reduced pressure to produce the title compound (850 mg, 65%). White solid, MS: 416.0 [M+H]+.

[0790]

[0791] -tert-butyl-dimethyl-silane

[0792] To a solution of [2-bromo-6-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]selanyl]phenyl]methanol (350 mg, 0.84 mmol) in N,N-dimethylformamide (3.5 mL) were added imidazole (402 mg, 5.9 mmol) and tert-butyldimethylsilyl chloride (889 mg, 5.9 mmol) at 25°C. After 16 h the solution was dilutedwith ethyl acetate (5 mL) washed with water (8 mL) and brine (10 mL) in turn. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by flash chromatography (SiCL; petroleum ether / ethyl acetate gradient) to produce the title compound (350 mg, 75%). Colorless oil, MS: 530.0 [M+H]+.

[0793] -3-IT3-(l,3-dioxolan-2-vl)-2-

[0794]

[0795] To a solution of [2-bromo-6-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]selanyl]phenyl]methoxy-tert-butyl-dimethyl-silane (350 mg, 0.66 mmol) and 4-(tert-butoxycarbonyl)phenylboronic acid (264 mg, 1.19 mmol) in toluene (3.5 mL) and water (0.7 mL) was added potassium phosphate (281 mg, 1.32 mmol) and bis(tri-tert-butylphosphine)palladium(0) (16.9 mg, 0.03 mmol) in a glovebox at 25°C, then the mixture was stirred at 80°C. After 2 h the solution was diluted with water (5 mL) and extracted with ethyl acetate (3^10 mL). The organic layer was combined, dried over sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate 3 : 1) to produce the title compound (280 mg, 64%). Yellow solid, MS: 628.2 [M+H]+.

[0796] oxolan-2-yl)-2-pyridyl]selanyl]-2-

[0797]

[0798] The title compound was produced in analogy to intermediate 12, step 5, from tert-butyl 4-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]selanyl]phenyl]benzoate. Yellow solid, MS: 514.1 [M+H]+.

[0799] 9: tert-Butyl 4-r2-(azidomethyl)-3-rr3-(l,3-dioxolan-2-yl)-2-

[0800]

[0801]

[0802] The title compound was produced in analogy to intermediate 12, step 6, from tert-butyl 4-[3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]selanyl]-2-(hydroxymethyl)phenyl]benzoate. Yellow solid, MS: 539.1 [M+H]+.

[0803] 10: tert-Butyl4-r2-(aminomethyl)-3-rr3-(L3-dioxolan-2-yl)-2-

[0804]

[0805]

[0806] The title compound was produced in analogy to intermediate 12, step 7, from tert-butyl 4-[2-(azidomethyl)-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl] selanyl]phenyl]benzoate. Yellow solid, MS: 513.1 [M+H]+.11: tert-Butvl 4-[3-[[3-(l,3-dioxolan-2-vl)-2- |-2-r(9H-fluoren-9-ylmethoxy-

[0807]

[0808] The title compound was produced in analogy to intermediate 2, step 6, from tert-butyl 4-[2-(aminomethyl)-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl] selanyl]phenyl]benzoate. White solid, MS: 735.2 [M+H]+.

[0809] -3-[(3-formyl-2-

[0810]

[0811] The title compound was produced in analogy to intermediate 3, step 4, from tert-butyl 4-[3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]selanyl]-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-phenyl]benzoate. White solid, MS: 691.2 [M+H]+.

[0812] Intermediate 15

[0813] tert-butyl 4-[4-chloro-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pyridyl)sulfinyl] phenyl] benzoate

[0814]

[0815] To a solution of 9H-fluoren-9-ylmethyl N-[[6-bromo-3-chloro-2-[(3-formyl-2-pyridyl)-sulfanyl]phenyl]methyl]carbamate (CAS-RN [2097290-48-5]; 2.00 g, 3.45 mmol) in toluene (20 mL) was added ethylene glycol (1.92 mL, 34.5 mmol) and p-toluenesulfonic acid monohydrate (262 mg, 1.38 mmol) under ice-water bath, and the solution was stirred at 0°C for 5 min, then the mixture was heated at 130°C for 4 h with a Dean- Stark trap. After cooling the solution was diluted with ethyl acetate (60 mL) and washed with water (40 mL) and brine (40 mL) in turn. Then the organics were combined and dried over sodium sulfate, filtered and concentrated under reduced pressure produce the title compound (2.0 g, 72%).. Colorless oil, MS:623.2 [M+H]+.2: 9H-Fluoren-9-ylmethyl N-rr6-bromo-3-chloro-2-rr3-(l,3-dioxolan-2-yl)-2-

[0816]

[0817] To a solution of 9H-fluoren-9-ylmethyl N-[[6-bromo-3-chloro-2-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]sulfanyl]phenyl]methyl]carbamate (1.0 g, 1.6 mmol) in dichloromethane (15 mL) was added 3-chloroperbenzoic acid (325 mg, 1.6 mmol) at 0°C, then after 30 min the suspension was allowed to reach room temperature over 3 h. The suspension was poured into saturated aq. sodium sulfite solution (20 mL), then saturated aq. sodium hydrogen carbonate solution (20 mL) was added, and the solution was extracted with dichloromethane (2^40 mL). The organic layer was washed with brine (20 mL) and dried over sodium sulfate, filtered and evaporated. Flash chromatography of the residue (petroleum ether / ethyl acetate 2:1) produced the title compound (800 mg, 73%). White solid, MS: 639.0 [M+H]+.

[0818] 3: tert-Butyl4-r4-chloro-3-rr3-(L3-dioxolan-2-vl)-2-

[0819]

[0820] -2-F (9H-fluoren-9-

[0821]

[0822] To a solution of 9H-fluoren-9-ylmethyl N-[[6-bromo-3-chloro-2-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]sulfinyl]phenyl]methyl]carbamate(700 mg, 1.09 mmol) and 4-(tert-butoxycarbonyl)phenylboronic acid (243 mg, 1.09 mmol) in toluene (15 mL) and water (1.5 mL) was added potassium phosphate (348 mg, 1.64 mmol) and bis(tri-tert-butylphosphine)-palladium(O) (28 mg, 0.05 mmol) in a glovebox at 25°C, then the mixture was taken out and stirred at 80°C. After 2 the solution was poured into 20 mL of brine and extracted with ethyl acetate (2x20 mL). The combined organics was dried over sodium sulfate and concentrated to give a crude, which was purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate 1 : 1) to produce the title compound (740 mg, 81%). Yellow solid, MS: 737.1 [M+H]+.

[0823] Step 4: tert-Butyl 4-[4-chloro-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pvridvl)sulfmvl]phenvl]benzoate

[0824] The title compound was produced in analogy to intermediate 3, step 4, from tert-butyl 4-[4-chloro-3-[[3-(l,3-dioxolan-2-yl)-2-pyridyl]sulfinyl]-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]phenyl]benzoate. White solid, MS: 693.2 [M+H]+.

[0825] Intermediate 16

[0826] tert-Butyl 4-[2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pyridyl)sulfonyl]-4-(trifluoromethyl)phenyl]benzoate

[0827]

[0828] ifluoromethyl)benzaldehyde

[0829] To a solution of 4-bromo-2-fluorobenzotrifluoride (25.0 g, 103 mmol) in anhydrous tetrahydrofuran (200 mL) was added lithium diisopropylamide solution (2 M in tetrahydrofuran, 67 mL, 134 mmol) at -78 °C under a nitrogen atmosphere, then after 30 min N,N-dimethylformamide (15.9 mL, 206 mmol) was added dropwise while keeping the reaction temperature below -60°C. After 5 min ice water (20 mL) was added and the solution was extracted with ethyl acetate (2^15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give a residue, which was purified by flash chromatography (SiCL; petroleum ether / ethyl acetate 95:5) to produce the title compound (25 g, 90%). Light yellow oil, ‘HNMR (400 MHz, CDC13) 8 ppm 10.36 (s, 1H), 7.73 - 7.58 (m, 2H).

[0830]

[0831] ine-3 -carboxylate

[0832] To a solution of 2-mercaptonicotinic acid (9.45 g, 60.9 mmol) in N,N-dimethylformamide (150 mL) was added sodium hydride (3.99 g, 99.6 mmol) at 0°C under a nitrogen atmosphere, and the mixture was stirred at 25°C for 30 min, then treated with 6-bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde (15.0 g, 55.3 mmol) and the mixture was heated at 80°C for 2 h. After cooling to room temperature potassium carbonate (21.4 g, 155 mmol) was added followed by addition of iodomethane (9.65 mL, 155 mmol). After 30 min the reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL), the organic layer was washed with water (3x50 mL) and saturated brine (2x15 mL) in turn, dried over sodium sulfate and concentrated under reduced pressure to give a crude, which was purified by preparative HPLC (Phenomenex Luna C18 (250*70mm, 10 pm); gradient from 0.05 aq. hydrochloric acid solution to acetonitrile) to produce the title compound (4.8 g, 21%). Light yellow solid, MS: 419.9 [M+H]+.

[0833] Step 3: Methyl 2-r3-bromo-2-r(E)-tert-butylsulfinyliminomethyl1-6-3 -carboxylate

[0834] To a solution of methyl 2-[3-bromo-2-formyl-6-(trifluoromethyl)phenyl]sulfanylpyridine-3-carboxylate (4.8 g, 11.4 mmol) in tetrahydrofuran (50 mL) was added 2-methylpropane-2-sulfinamide (1.38 g, 11.4 mmol) and titanium(IV)ethanolate (11.7 mL, 57.1 mmol), and the solution was heated at 70°C for 3 h to give a colorless solution. After cooling the reaction mixture was poured into water (50 mL), after which a precipitate formed. Insoluble material was removed by filtration, and the filtrate was extracted with ethyl acetate (2^30 mL). The organic layer was washed with brine (20 mL) and dried over sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by flash chromatography (Si O2; petroleum ether / ethyl acetate gradient) to produce the title compound (4.8 g, 80%). Light yellow solid, MS: 523.0 [M+H]+.

[0835]

[0836] -3-

[0837]

[0838] -2-methyl-propane-2-sulfinamide

[0839] To a solution of methyl 2-[3-bromo-2-[(E)-tert-butylsulfinyliminomethyl]-6-(trifluoromethyl)-phenyl]sulfanylpyridine-3-carboxylate (4.8 g, 9.17 mmol) in tetrahydrofuran (60 mL) was added lithium aluminum hydride solution (2.5 M in tetrahydrofuran, 14.7 mL, 36.7 mmol) at -40 °C under a nitrogen atmosphere, then the reaction mixture was treated with water (1.7 mL), 15% aq. sodium hydroxide solution (1.7 mL) and water (5.1 mL) in turn. Insoluble material was removed by filtration, and the filtrate was concentrated to produce the title compound (4.9 g, 87%), which was directly used in the next step. White solid, MS: 497.0 [M+H]+.

[0840] 5: -( Aminomethvl)-3 -bromo-6-1

[0841]

[0842] hydrochloride

[0843] A mixture of N-[[6-bromo-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]-3-(trifluoromethyl)phenyl]methyl]-2-methyl-propane-2-sulfmamide (4.9 g, 9.85 mmol) in hydrogen chloride solution (2 M in 1,4-dioxane, 17.8 mL, 35.6 mmol) was stirred at 25°C for 30 min, then evaporated to produce the title compound (4.2 g, 99%), which was used directly in the next step. White solid, MS: 393.0 [M+H]+.

[0844] o-2-rr3-(hvdroxvmethvl)-2-pvridvl]sulfanvll-3-

[0845]

[0846] The title compound was produced in analogy to intermediate 3, step 2, from [2-[2-(aminomethyl)-3-bromo-6-(trifluoromethyl)phenyl]sulfanyl-3-pyridyl]methanol; hydrochloride.White solid, MS: 615.1 [M+H]+.

[0847] o-2- -(hydroxymethyl)-2-

[0848]

[0849] 1-3-

[0850]

[0851] To a solution of 9H-fluoren-9-ylmethyl N-[[6-bromo-2-[[3-(hydroxymethyl)-2-pyridyl] sulfanyl]-3-(trifluoromethyl)phenyl]methyl]carbamate (1.0 g, 1.62 mmol) in 1,2-di chloroethane (20 mL) was added 3 -chloroperbenzoic acid (1.64 g, 8.12 mmol) at 0°C, and the mixture was stirred for further 30 min. Then the suspension was heated at 60 °C for 5 h. After cooling the reaction mixture was washed with saturated aq. sodium sulfite solution (3^15 mL), saturated aq. sodium hydrogen carbonate solution (20 mL) and brine (20 mL) in turn. The organic layer was dried over sodium sulfate and concentrated to give a residue, which was purified by column chromatography (petroleum ether / ethyl acetate 3 : 1) to produce the title compound (850 mg, 81%). Light yellow solid, MS: 647.2 [M+H]+.

[0852] o-2- -formyl-2-

[0853]

[0854] -3-

[0855]

[0856] The title compound was produced in analogy to intermediate 2, step 7, from 9H-fluoren-9-ylmethyl N-[[6-bromo-2-[[3-(hydroxymethyl)-2-pyridyl]sulfonyl]-3-(trifluoromethyl)-phenyl]methyl]carbamate. Light yellow solid, MS: 645.1 [M+H]+.

[0857] -3-l(3-formyl-2-

[0858]

[0859] The title compound was produced in analogy to intermediate 2, step 2, from 9H-fluoren-9-ylmethyl N-[[6-bromo-2-[(3-formyl-2-pyridyl)sulfonyl]-3-(trifluoromethyl)phenyl]-methyl]carbamate and 4-(tert-butoxycarbonyl)phenylboronic acid. Light yellow solid, MS: 743.4 [M+H]+.

[0860] Intermediate 17

[0861] 9H-Fluoren-9-ylmethyl N-[[6-bromo-3-chloro-2-[(3-formyl-2-pyridyl)sulfonyl]phenyl]methyl]carbamate

[0862]

[0863] Step 1: 9H-Fluoren-9-ylmethyl N-r[6-bromo-3-chloro-2-[[3-(hydroxymethyl)-2-pyridyllsulfonylslphenyllmethyllcarbamate

[0864] The title compound was produced in analogy to intermediate 3, step 2, from [2-[2-(aminomethyl)-3-bromo-6-chloro-phenyl]sulfanyl-3-pyridyl] methanol; hydrochloride (CAS-RN [2134671-73-9]). White solid, MS: 581.0 [M+H]+.

[0865] Step 2: 9H-Fluoren-9-ylmethyl N-r[6-bromo-3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfonyl]phenyl]methyl]carbamate

[0866] The title compound was produced in analogy to intermediate 16, step 7, from 9H-fluoren-9-ylmethyl N-[[6-bromo-3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfanyl]phenyl]-methyl]carbamate. White solid, MS: 635.1 [M+Na]+.

[0867] Step 3: 9H-Fluoren-9-ylmethyl N-bromo-3-chloro-2-[(3-formyl-2-pyridyl)sulfonyl]phenyl]-

[0868]

[0869] methyllcarbamate

[0870] The title compound was produced in analogy to intermediate 2, step 7, from 9H-fluoren-9-ylmethyl N-[[6-bromo-3-chloro-2-[[3-(hydroxymethyl)-2-pyridyl]sulfonyl]phenyl]methyl]carbamate. White solid, MS: 635.1 [M+2+Na]+-

[0871] Intermediate 18

[0872] tert-Butyl 4-[4-chloro-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pyridyl)sulfonyl] phenyl] benzoate

[0873]

[0874] The title compound was produced in analogy to intermediate 2, step 2, from 9H-fluoren-9-ylmethyl N-[[6-bromo-3-chloro-2-[(3-formyl-2-pyridyl)sulfonyl]phenyl]methyl]carbamate (intermediate 17) and 4-(tert-butoxycarbonyl)phenylboronic acid. White solid, MS: 709.3 [M+H]+.

[0875] Intermediate 19

[0876] tert-Butyl 4-[4-(difluoromethyl)-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pyridyl)sulfonyl] phenyl] benzoate

[0877]

[0878] The title compound was produced in analogy to intermediate 16, replacing 4-bromo-2-fluorobenzotrifluoride in step 1 by 4-bromo-l-(difluoromethyl)-2-fluoro-benzene. White solid, MS: 747.5, [M+Na]+.

[0879] Intermediate 20

[0880] tert-Butyl 4- [4-(difluoromethyl)-2- [(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-(2-formylphenyl)sulfonyl-phenyl]benzoate

[0881]

[0882] romethyl)-2-fluoro-benzaldehyde

[0883] The title compound was produced in analogy to intermediate 16, step 1, from 4-bromo-l-difluoromethyl-2-fluorobenzene. Light yellow oil,JH NMR (400 MHz, DMSO-de) 8 ppm 10.24 (s, 1H), 7.93 - 7.78 (m, 2H), 7.49 - 7.13 (m, 1H).

[0884] 2: Methyl 2-13-bromo-6-(difluoromethyl)-2-formyl-i

[0885]

[0886] A mixture of 6-brorno-3-(difluoromethyl)-2-fluoro-benzaldehyde (2.5 g, 9.88 mmol), methyl thiosalicylate (1.99 g, 11.9 mmol) and cesium carbonate (9.66 g, 29.6 mmol) in acetonitrile (40 mL) was stirred at 25°C for 2 h. then insoluble material was removed by filtration. The filtrate was washed with water (20 mL) and brine (20 mL) in turn, then the organic layer was dried over sodium sulfate and concentrated to give the residue, which was purified by flash chromatography (petroleum ether / ethyl acetate 85: 15) and concentrated under reduced pressure produce the title compound (3.5 g, 79%). Light yellow solid, MS: 402.0 [M+H]+.

[0887] Step 3: Methyl 2-r3-bromo-2-r(E)-tert-butylsulfinyliminomethyl1-6-(difluoromethyl)phenyl1-sulfanylbenzoate

[0888] The title compound was produced in analogy to intermediate 16, step 3, from methyl 2-[3-bromo-6-(difluoromethyl)-2-formyl-phenyl]sulfanylbenzoate. Light yellow oil, MS: 504.2 [M+H]+.

[0889] Step 4: N-Bromo-3-(difluoromethyl)-2-12-(hydroxymethyl)phenyl1sulfanyl-phenyl1methyl1-2-methyl-propane-2-sulfinamide

[0890] The title compound was produced in analogy to intermediate 16, step 4, from methyl 2-[3-bromo-2-[(E)-tert-butylsulfinyliminomethyl]-6-(difluoromethyl)phenyl]sulfanylbenzoate. White solid, MS: 478.1 [M+H]+.

[0891] Step 5 : r2-r2-(Aminomethyl)-3-bromo-6-(difluoromethyl)phenyl1sulfanylphenyl1methanol;hydrochloride

[0892] The title compound was produced in analogy to intermediate 16, step 5, from N-[[6-bromo-3-(difluoromethyl)-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]-2-methyl-propane-2-sulfinamide. White solid, MS: 374.1 [M+H]+.

[0893] Step 6: 9H-Fluoren-9-ylmethyl N-bromo-3-(difluoromethyl)-2-r2-

[0894]

[0895] The title compound was produced in analogy to intermediate 16, step 6, from [2-[2-(aminomethyl)-3-bromo-6-(difluoromethyl)phenyl]sulfanylphenyl]methanol; hydrochloride. White solid, MS: 618.1 [M+Na]+.

[0896] Step 7: 9H-Fluoren-9-ylmethyl N-bromo-3-(difluoromethyl)-2-r2-

[0897]

[0898] The title compound was produced in analogy to intermediate 16, step7, from 9H-fluoren-9-ylmethyl N-[[6-bromo-3-(difluoromethyl)-2-[2-(hydroxymethyl)phenyl]sulfanyl-phenyl]methyl]carbamate. White solid, MS: 650.1 [M+Na]+.

[0899] ethylN-rr6-bromo-3-(difluoromethyl)-2-(2-:

[0900]

[0901]

[0902] The title compound was produced in analogy to intermediate 16, step 8, from 9H-fluoren-9-ylmethyl N-[[6-bromo-3-(difluoromethyl)-2-[2-(hydroxymethyl)phenyl]sulfonyl-phenyl]methyl]carbamate. White solid, MS: 648.1 [M+Na]+.

[0903] 9: tert-Butyl 4-r4-(difluoromethyl)-2-r(9H-fluoren-9-'

[0904]

[0905] -3-

[0906]

[0907] The title compound was produced in analogy to intermediate 16, step 9, from 9H-fluoren-9-ylmethyl N-[[6-bromo-3-(difhroromethyl)-2-(2-formylphenyl)sulfonyl-phenyl]methyl]carbamate. Light yellow solid, MS: 746.3 [M+Na]+.

[0908] Intermediate 21

[0909] tert-Butyl 4-[4-chloro-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-(2-formylphenyl)sulfonyl-phenyl]benzoate

[0910]

[0911] The title compound was produced in analogy to intermediate 20, replacing 4-bromo-l-difluoromethyl-2-fluorobenzene in step 1 by 4-bromo-l-chloro-2-fluoro-benzene. Yellow solid, MS: 708.1 [M+H]+.

[0912] Intermediate 22

[0913] tert-Butyl 4- [2- [(9H-fluoren-9-ylmethoxycarbonylamino)methyl] -3-(2-formylphenyl)sulfonyl-4-methyl-phenyl]benzoate

[0914]

[0915] The title compound was produced in analogy to intermediate 20, replacing 4-bromo-l-difluoromethyl-2-fluorobenzene in step 1 by 4-bromo-2-fluoro-l-methyl-benzene. Light yellow solid, MS: 710.1 [M+Na]+.

[0916] Intermediate 23

[0917] tert-Butyl 4-[4-chloro-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pyridyl)sulfonyl]phenyl]-2-fluoro-benzoate

[0918]

[0919] The title compound was produced in analogy to intermediate 18, replacing 4-(tert-butoxycarbonyl)phenylboronic acid by tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate. Light yellow oil, MS: 749.1 [M+Na]+.

[0920] Intermediate 24

[0921] tert-Butyl 4- [2- [(9H-fluoren-9-ylmethoxycarbonylamino)methyl] -3- [(3-formyl-2-pyridyl)sulfonyl]-4-methyl-phenyl]benzoate

[0922]

[0923] The title compound was produced in analogy to intermediate 16, replacing 4-bromo-2-fluorobenzotrifluoride in step 1 by 4-bromo-2-fluoro-l-methyl-benzene. Yellow solid, MS: 689.4 [M+H]+.

[0924] Intermediate 25

[0925] tert-Butyl 4- [4-(cyclopropoxymethyl)-2- [(9H-fluoren-9-ylmethoxycarbonylamino)methyl]- 3-[(3-formyl-2-pyridyl)sulfonyl]phenyl]benzoate

[0926]

[0927] The title compound was produced in analogy to intermediate 16, replacing 4-bromo-2-fluorobenzotrifluoride in step 1 by 4-bromo-l-(cyclopropoxymethyl)-2-fluoro-benzene (intermediate 26). Light yellow solid, MS: 767.2 [M+Na]+.Intermediate 26

[0928] 4-Bromo-l-(cyclopropoxymethyl)-2-fluoro-benzene

[0929]

[0930] To a solution of cyclopropanol (1.19 g, 20.5 mmol) in tetrahydrofuran (100 mL) was added sodium hydride (60% dispersion in oil, 1.12 g, 28.0 mmol) at 0°C under a nitrogen atmosphere, then after 30 min 4-bromo-2-fluorobenzyl bromide (5.0 g, 18.7 mmol) was added dropwise at 0°C. The reaction mixture stirred at 25°C for 16 h, then treated with water (80 mL) at 0°C extracted with ethyl acetate (2^100 mL). The organic layer was washed with saturated brine (40 mL), dried over sodium sulfate and concentrated under reduced pressure to give a residue, which was purified by flash chromatography (petroleum ether) to produce the title compound (3.5 g, 77%). Colourless oil, 'H NMR (400 MHz, DMSO-d6) 8 ppm 7.53 (dd, J= 1.4, 9.7 Hz, 1H), 7.45 - 7.36 (m, 2H), 4.51 (s, 2H), 2.51 (br d, J= 1.6 Hz, 1H), 0.57 - 0.49 (m, 2H), 0.46 (br d, J= 5.3 Hz, 2H).

[0931] Intermediate 27

[0932] tert-Butyl 4-[4-(difluoromethoxy)-2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pyridyl)sulfonyl] phenyl] benzoate

[0933]

[0934] The title compound was produced in analogy to intermediate 16, steps 2-9, replacing 6-bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde in step 2 by 6-bromo-3-(difluoromethoxy)-2-fluoro-benzaldehyde (CAS-RN [853792-32-2]). White solid, MS: 741.4 [M+H]+.

[0935] Intermediate 28

[0936] tert-Butyl 4-[2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-4-fluoro-3-[(3-formyl-2-pyridyl)sulfonyl] phenyl] benzoate

[0937]

[0938] The title compound was produced in analogy to intermediate 16, replacing 4-bromo-2-fluorobenzotrifluoride in step 1 by l-bromo-3,4-difluorobenzene. Yellow solid, MS: 693.2 [M+H]+.

[0939] Intermediate 29

[0940] tert-Butyl 4-[2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-4-fluoro-3-(2-formyl phenyl)sulfonyl-phenyl] benzoate

[0941]

[0942] The title compound was produced in analogy to intermediate 20, replacing 4-bromo-l-difluoromethyl-2-fluorobenzene in step 1 by l-bromo-3,4-difluorobenzene. Yellow MS: 692.3, [M+H]+.

[0943] Intermediate 30

[0944] tert-Butyl 4-[2-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]-3-[(3-formyl-2-pyridyl)sulfonyl] phenyl] benzoate

[0945]

[0946] The title compound was produced in analogy to intermediate 16, replacing 4-bromo-2-fluorobenzotrifluoride in step 1 by l-bromo-3-fluorobenzene. Light yellow solid, MS: 697.2 [M+Na]+.

[0947] Intermediate 31

[0948] 9H-Fluoren-9-ylmethyl N-[[6-bromo-3-(difluoromethyl)-2-(2-formylphenyl)sulfonyl-phenyl] methyl] carbamate

[0949]

[0950] The title compound was produced in analogy to intermediate 17, step 1-8, replacing 4-bromo-2-fluorobenzotrifluoride in step 1 by 4-bromo-l-difluoromethyl-2-fluorobenzene. White solid, MS: 627.2, [M+H]+.

[0951] Intermediate 32

[0952] 9H-Fluoren-9-ylmethyl N- [[2-bromo-6- [(3-formyl-2-pyridyl)oxy] phenyl] methyl] carbamate

[0953]

[0954] The title compound was produced in analogy to intermediate 20, replacing 4-bromo-l-difluoromethyl-2-fluorobenzene in step 1 by l-bromo-3 -fluorobenzene and methyl thiosalicylate in step 2 by methyl 2-hydroxypyridine-3-carboxylate. White solid, MS: 529.2 [M+H]+.

Claims

Claims1. A compound of formula (I)or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:X is selected from the group consisting of Se, SO, SO2, CH2, O, and NR4;Y is CH or N;A is selected from the group consisting of phenyl, pyridyl, and thienyl;R1is selected from the group consisting of hydrogen, halogen, Ci-6-alkyl, Ci-6-alkoxy, halo-Ci-6-alkyl, halo-Ci-6-alkoxy, Cs-io-cycloalkyl, Ci-6-alkyl-O-CH2-, and C3-10- cycloalkyl-O-CH2-;R2is halogen or a groupR3is hydrogen or Ci-6-alkyl;R4is hydrogen or Ci-6-alkyl;R5is selected from the group consisting of hydrogen, carboxy, SO2OH, and IH-tetrazol- 5-yl; andR6is selected from the group consisting of hydrogen, halogen, and Ci-6-alkyl.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X is SO2 or CH2.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is selected from the group consisting ofhydrogen, halogen, Ci-6-alkyl, halo-Ci-6-alkyl, halo-Ci-6-alkoxy, and Cs-io-cycloalkyl-O- CH2-.

4. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is selected from the group consisting of hydrogen, fluoro, chloro, methyl, CHF2, CF3, CHF2O-, and cyclopropyl-O-CFh-5. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is selected from the group consisting of halogen, Ci-6-alkyl, and halo-Ci-6-alkyl.

6. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is selected from the group consisting of chloro, methyl, and CHF2.

7. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:R2is halogen or a groupA is phenyl or pyridyl;R5is selected from the group consisting of carboxy, SO2OH, and lH-tetrazol-5-yl; and R6is selected from the group consisting of hydrogen, halogen, and Ci-6-alkyl.

8. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:R2is bromo or a groupA is phenyl or pyridyl;R5is selected from the group consisting of carboxy, SO2OH, and lH-tetrazol-5-yl; and R6is selected from the group consisting of hydrogen, fluoro, and methyl.

9. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:A is phenyl;R5is carboxy; andR6is hydrogen.

10. The compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt or11. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3is hydrogen or methyl.

12. The compound of formula (I) according to any one of claims 1 and 3 to 11, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R4is hydrogen or methyl.

13. The compound of formula (I) according to claim 1, selected from:4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-4-chloro-12-(lH-indol-3- ylmethyl)-13-methyl-l 1, 14,17-tri oxo- 10, 13, 16,19-tetrazatri cyclofl 9.4.0.03,8]pentacosa- l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid;4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3- ylmethyl)- 16-methyl- 12,15,18-trioxo-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)-16- methyl-12,15,18-trioxo-25-(trifluoromethyl)-4,10,13,16,19-pentazatricyclo[19.4.0.03’8] pentacosa- 1 (25), 3 (8), 4, 6,21 ,23 -hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-(difhroromethyl)-17-(lH- indol-3 -ylmethyl)- 16-methyl- 12,15,18-trioxo-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)- 16, 25-dimethyl-12, 15,18-tri oxo-4, 10, 13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-12-(lH-indol-3-ylmethyl)-13- methyl-11, 14,17-trioxo-l 0,13, 16,19-tetr azatri cyclo[l 9.4.0.03,8]pentacosa- l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid;4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-fluoro-17-(lH-indol-3- ylmethyl)- 16-methyl- 12,15,18-trioxo-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)-16- methyl-12,15,18-trioxo-4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8), 4,6,21 ,23 -hexaen-22-yl]benzoic acid;4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chloro-17-(lH-indol-3- ylmethyl)-2,16-dimethyl-12,15,18-trioxo-2,4,10,13,16,19-hexazatricyclo[19.4.0.03’8] pentacosa- 1 (25), 3 (8), 4, 6,21 ,23 -hexaen-22-yl]benzoic acid;4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-12-(lH-indol-3-ylmethyl)-13- methyl-1 l,14,17-trioxo-2,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(21),3,5,7, 22,24-hexaen-7-yl]benzoic acid;4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3- ylmethyl)- 16-methyl- 12,15,18-trioxo-2,4, 10,13,16,19- hexazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)-16- methyl-12,15,18-trioxo-2,4,10,13,16,19-hexazatricyclo[19.4.0.03’8]pentacosa- 1(25), 3(8), 4, 6, 21,23-hexaen-22-yl]benzoic acid;4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)-16- methyl- 12, 15,18-trioxo-2-selena-4,l 0,13, 16,19-pentazatricy clo[l 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3- ylmethyl)- 16-methyl-2, 12,15,18-tetraoxo-2X4-thia-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)-16- methyl-2,2, 12,15,18-pentaoxo-25-(trifluoromethyl)-2X6-thia-4, 10,13,16,19- pentazatricyclo [19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoicacid; (1 lS,14S,17S)-14-(4-aminobutyl)-l l-(3-aminopropyl)-22-bromo-25-chl oro-17-(lH-indol- 3 -ylmethyl)- 16-methyl -2, 2-di oxo-2X6-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaene-12,15,18-trione;4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3- ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoicacid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-16-methyl-17-[(2- meth yl- lH-indol-3 -yl)methyl]-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclo[19.

4. 0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-(difluoromethyl)-17-(lH- indol-3 -ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19-pentazatricy clo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoicacid;4- [( 11 S, 14S, 17S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25-(difluorom ethyl)- 16-methyl- 17-[(2-methyl-lH-indol-3-yl)methyl]-2,2,12,15,18-pentaoxo-2X6-thia-4,10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 4-[( 12 S, 15 S, 18 S)- 15 -(4- Aminobutyl)- 18-(3 -aminopropyl)-4-(difluorom ethyl)- 12-( 1 H- indol-3 -ylmethyl)- 13 -methyl-2,2, 11,14,17 -pentaoxo-2X6-thia- 10,13,16,19- tetrazatricyclo[19.4.0.03’8]pentacosa-l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid;4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-4-chloro-12-(lH-indol-3- ylmethyl) - 13 -methyl-2,2, 11,14,17 -pentaoxo-2X6-thia- 10,13,16,19- tetrazatricyclo[19.4.0.03’8]penta cosa-l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid;4-[(12S,15S,18S)-15-(4-Aminobutyl)-18-(3-aminopropyl)-12-(lH-indol-3-ylmethyl)-4,13- dimethyl-2,2, 11,14, 17-pentaoxo-2X6-thi a- 10,13,16,19- tetrazatricyclo[19.4.0.03’8]pentacosa-l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid;4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3- ylmeth yl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03’8] pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]-2-fluoro- benzoic acid;4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)- 16,25-dimethyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]penta cosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 4-[( 11 S, 14 S, 17 S)- 14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25 -(difluoromethoxy)- 17-( 1 H- indol-3 -ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclo [19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-fluoro-17-(lH-indol-3- ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19-pentazatri cyclo [19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid;4- [( 12S, 15 S, 18 S)- 15 -(4- Aminobutyl)- 18-(3 -aminopropyl)-4-fluoro- 12-( lH-indol-3 - ylmethyl)- 13 -methyl-2,2, 11,1 , 17-pentaoxo-2X6-thia- 10,13,16,19-tetrazatri cyclo [19.4.0.03’8]pentacosa-l(21),3,5,7,22,24-hexaen-7-yl]benzoic acid;4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-16-methyl-17-[(2-methyl-lH- indol-3 -yl)methyl]-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)-16- methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-25-(cyclopropoxymethyl)-17- ( lH-indol-3 -ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid; 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chloro-17-(lH-indol-3-ylme thy 1)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19- pentazatricyclof 19.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]-2-methyl- benzoic acid;4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3- ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10, 13 , 16, 19- pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22- yl]benzenesulfonic acid;5-[(l lS,14S,17S)-14-(4-Aminobutyl)-l l-(3-aminopropyl)-25-chl oro-17-(lH-indol-3- ylmethyl)- 16-methyl-2,2, 12,15,18-pentaoxo-2X6-thia-4, 10,13,16,19-pentazatri cyclo [19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]pyridine-2-carboxylic acid; (11S,14S,17S)-14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25 -chloro- 17-( 1 H-indol-3 - ylmethyl)- 16-methyl-2,2-di oxo-22-[4-(lH-tetrazol-5-yl)phenyl]-2X6-thia-4, 10, 13, 16,19- pentazatricyclo [19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaene- 12, 15, 18-trione; (11S,14S,17S)-14-(4- Aminobutyl)- 11 -(3 -aminopropyl)-25 -(difluoromethyl)- 17-( 1 H-indol- 3-ylmethyl)-16-methyl-2,2-dioxo-22-[4-(lH-tetrazol-5-yl)phenyl]-2X6-thia- 4,10,13,16,19-pentazatricyclo[19.4.0.03’8]pentacosa-l(25),3(8),4,6,21,23-hexaene- 12, 15, 18-trione; and4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-(lH-indol-3-ylmethyl)-16- methyl- 12, 15, 18-trioxo-2-oxa-4,l 0,13, 16,19-pentazatri cyclofl 9.4.0.03,8]pentacosa- 1 (25), 3 (8), 4, 6, 21 ,23 -hexaen-22-yl]benzoic acid;or a pharmaceutically acceptable salt or a stereoisomer thereof.

14. A pharmaceutical composition comprising a compound according to any of claims 1 to 13, or a pharmaceutically acceptable salt or a stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

15. A compound according to any of claims 1 to 13, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as therapeutically active substance.***

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